VirchowsArchiv B Cell Pathol (1992) 62:207 220

9 Springer-Verlag1992

The role of insulin-like growth factors and IGF-binding proteins in the physiological and pathological processes of the kidney Walter Zumkeller 1,2 and Paul N. Schofield 2

Institute of Child Health1, Universityof London, London, UK Department of Anatomy2, Universityof Cambridge, Cambridge, UK ReceivedOctober 24, 1991 / AcceptedFebruary 18, 1992 Summary. Insulin-like growth factors (IGFs) and their binding proteins are implicated in the growth regulation of the kidney during embryogenesis and differentiation. Recent evidence also suggests that IGFs play a role in kidney physiology (glomerular filtration rate, renal plasma flow) and pathology (diabetic renal hypertrophy, nephritis, glomerulosclerosis, kidney tumours, chronic renal failure). This review focuses on the biology of IGFs at the molecular, protein and receptor levels and considers their importance in renal physiology and pathology. The current data demonstrate a central role for the IGFs in the mediation of a wide variety of effects on renal growth, function and malignancy. Key words: Insulin-like growth factors - IGF-binding proteins - IGF-receptors - Renal physiology - Renal pathology

Introduction

Polypeptide growth factors are implicated in various physiological and pathological processes of the kidney such as embryogenesis, growth and development, regeneration, hypertrophy and tumourigenesis (Avner 1990). Released from their cell of origin, growth factors act locally through specific high-affinity receptors on the cell surfaces of their target tissues in an autocrine or paracrine fashion. Both IGF-I and IGF-II are single-chain polypeptides consisting of 70 (Mr 7646) and 67 (Mr 7471) amino acids respectively and are structurally similar to insulin (Van den Brande 1992). The insulin-like growth factors (or somatomedins) are growth promoting agents and stimulate sulphate incorporation into cartilage, differentiation Correspondence to: W. Zumkeller,Universit/its-KrankenhausEppendorf, Kinderklinik, MartinistraBe 52, W-2000 Hamburg 20, Federal Republicof Germany

of mesodermal cells, regulate metabolic processes and exert insulin-like effects on glucose metabolism (Daughaday and Rotwein 1989; Humbel 1990). Their biological effects are mediated through specific receptors. The type I IGF (IGF-I) receptor is a glycoprotein with two disulfide-linked ~-subunits (135 kD) which binds IGF-I, and two fl-subunits (95 kD) which possess intrinsic kinase activity. It binds IGF-I with greater affinity than IGF-II and insulin. The type II IGF (IGF-II) receptor, which is a monomer of approximately 250 kD, is identical to the cation-independent mannose-6-phosphate receptor and binds preferentially to IGF-II as well as IGF-I to a lesser extent but not insulin (Clemmons 1989; Moxham and Jacobs 1992). IGFs are bound to a variety of specific binding proteins. To date, six different IGF-binding proteins (IGFBP-1 to -6) have been purified and sequenced (McCusker and Clemmons 1992). These binding proteins may either enhance or inhibit the effects of IGFs thus regulating their biological effects at a cellular level. IGFBP-I has been isolated from amniotic fluid (Prvoa etal. 1984) and appears to be regulated by insulin. IGFBP-3, the predominant IGF-binding protein in serum, is regulated by growth hormone (Baxter and Martin 1989). However, the mechanism of regulation for the other BPs has yet to be established in detail. Expression of IGF and IGFBP mRNA transcripts

The human IGF-I gene is located on chromosome 12, and consists of 5 exons and 4 introns. The IGF-II gene which consists of 8 exons and four promoters is located at the tip of the short arm of chromosome 11 (Schofield 1991; Ward and Elliss 1992). Both genes are subject to complex patterns of regulation and show alternative splicing which in the case of IGF-I leads to large differences in the carboxyl terminus of the protein (Rotwein 1986). In IGF-II, alternative splicing inserts a 4-amino acid stretch (Arg-Leu-Pro-Gly) into the peptide itself, but the functional significance of this is not yet clear.

208 Expression of the IGF-II gene is developmentally regulated by differential promoter usage in fetal and postnatal life. Three of the four alternative promoters are utilised in the kidney, amongst other tissues, and are maximally active during the fetal period. Messenger RNA levels in the kidney are reduced 50-100-fold as the organ differentiates (Schofield and Tate 1987).

Embryonic andfetal patterns of IGF mRNA expression IGF-II mRNA levels are very high during development and the different results which have been obtained for IGF-II mRNA expression in the fetal kidney almost certainly reflect dynamic changes in the pattern of gene expression which are dependant on the state of differentiation of the tissue (see Han and Hill 1992 for review). While Scott et al. (1985) found IGF-II mRNA expression in the human using Northern blots, Beck et al. (1987) obtained negative results in rats. The same technique using fetal kidney revealed 6.0-, 4.8- and 1.9-kb IGF-II transcripts (Paik et al. 1989) showing a 70% decrease in IGF-II mRNA expression postnatally (Brown et al. 1986). The spatial distribution of this mRNA was shown to coincide with the rapidly dividing metanephric blastemal component in the first trimester (Brice et al. 1989) with peak expression when the first nephrogenic vescicles are formed at week 6 to 7. This was confirmed by Paik et al. (1989) and Hirvonen et al. (1989) who showed predominantly IGF-II mRNA expression in stromal and blastemal cells of the human fetal kidney with an apparent lack of hybridization over the epithelial components, suggesting that IGF-II acts as a paracrine stimulus for the growth and differentiation of the kidney epithelium. Dot blot hybridization showed that IGF-II mRNA expression in the fetal kidney is 200-fold higher than IGF-I mRNA (Han et al. 1988a), but that the IGF-I mRNA is much more efficiently translated than that for IGF-II (Hill 1990). In the late second and third trimesters, in situ hybridization in the human fetal kidney detected both IGF-I and reduced levels of IGF-II mRNA in the capsule, calyces, and interstitium of the inner cortex and medulla but not in the glomerulus and tubules (Han et al. 1987). Only low to moderate IGF-II mRNA expression in kidney sections of day 10-16 fetal rat embryos were detected (Stylianopoulou et al. 1988). This hypothesis gains direct experimental support from the observation that IGF-II stimulates the production of inositol triphosphates in the proximal kidney tubule cell membranes and supports the differentiation and proliferation of the metanephros in vitro (Rogers et al. 1991 b).

Postnatal patterns of IGF mRNA expression In postnatal life, both IGF-I and IGF-II are expressed in the kidney (Adamo et al. 1989; Bondy et al. 1990). Normal postnatal kidney expresses very small quantities of the 6.0-kb IGF-II mRNA transcript with a pro-hormone coding sequence identical to that found in the

liver but with a distinct 5'-untranslated region (Irminger et al. 1987). Using Northern blot techniques, human glomerular mesangial cells have been found to express a 2.0-kilobase IGF-I mRNA transcript while the 1.0-kb abundantly present in human liver was undetectable in mesangial cells (Aron et al. 1989). However, Fagin and Melmed (1987) detected a 1.3-kb IGF-I mRNA transcript in the kidney poly(A) § RNA during compensatory renal hypertrophy, similar in size to that in the rat liver. The differences in the abundance of these transcripts may reflect tissue-specific differences in mRNA processing. In collecting ducts, IGF-I mRNA is expressed 12-fold higher than in isolated glomeruli and 7-fold higher than in isolated proximal tubules estimating the level of IGF-I mRNA to about 25% of that in the liver (Bortz et al. 1988). A rat cDNA encoding an IGF-I precursor protein has also been isolated from adult rat kidney (Murphy et al. 1987a).

Expression of lGF-binding proteins Six IGFBPs have been cloned so far. The gene for IGFBP-1 is located on the human chromosome 7p12p13 (Brinkman et al. 1988) containing four exons (Cubbage et al. 1989) and is highly expressed in human fetal but low in adult liver (Brinkman et al. 1988). The human IGFBP-2 gene consists also of four exons (Binkert et al. 1989) and is located on chromosome 2. It is highly expressed in kidney, liver and brain and is higher in fetal than adult tissues (Orlowski et al. 1990). The human IGFBP-3 gene consists of five exons (Cubbage et al. 1990) and is located on chromosome 7; it is expressed by a variety of tissues. IGFBP-4 to -6 have been cloned very recently (Shimasaki et al. 1990, 1991; Kiefer et al. 1991 a, b) but to date little data is available. The expression of IGFBPs has been shown in fetal and adult kidneys. Northern blots using the rlGFBP-1 cDNA demonstrated hybridization with a 1.6-kb transcript in poly(A) § RNA derived from adult kidney (Murphy et al. 1990) and a 1.65-kb IGFBP-1 mRNA transcript was also detected in Wilms' tumours (Lee et al. 1988). A 2.0-kb IGFBP-2 mRNA transcript has been found in fetal rat kidney (Brown et al. 1989; Orlowski et al. 1990) and the human embryonic kidney cell line 293 expressed the 1.6-1.8-kb transcript (Zapf et al. 1990) while a single 1.4-kb transcript was observed in the kidney of adult sheep (Delhanty et al. 1991). The NRK-52E cells, an epithelial-like clone of normal rat kidney cells, express IGFBP-2 mRNA as well (Yang et al. 1990). In the MDBK cell line, forskolin treatment resulted in a 30-fold increase in IGFBP-3 mRNA expression, further enhanced by the addition of insulin, and a decrease in IGFBP-2 mRNA, whereas IGF-I and IGFII marginally increased it (Cohick and Clemmons 1991). Expression of IGFBP-3 mRNA in 6-week-old rat kidneys has also been demonstrated by Northern blotting (Shimasaki et al. 1989) and in contrast to earlier indications, Schwander et al. (1991) demonstrated high expression in adult rat kidneys. While IGFBP-4 and IGFBP-6 mRNA were undetectable in the human embryonic kid-

209 ney cell line 293 (Kiefer et al. 1991 a), IGFBP-5 mRNA transcripts were produced by the kidney (Kiefer et al. 1991 b). In 3-month-old male rats, IGFBP-5 mRNA migrating at 6.0-kb was seen in the kidney while in contrast to other IGFBP mRNAs, the signal was very weak in the liver (Shimasaki et al. 1991). Considering the abundance of IGFBP-5 mRNA, it may play an important part in the autocrine and paracrine regulation of the IGF mediated effect in the kidney. However, the complex interaction of these binding proteins has still to be elucidated.

cortical collecting ducts and medullary thick ascending limbs of Henle's loop (Kobayashi et al. 1991). Furthermore, a binding protein isolated from conditioned medium of MDBK-cells is quite similar in amino acid sequence to the human IGFBP-2 (Szabo et al. 1988; Ballard et al. 1989). Treatment with forskolin decreased IGFBP-2 secretion by 75% and induced the appearance of IGFBP-3 and a 24 kD IGFBP (Cohick and Clemmons 1991). Specific IGF-II binding proteins (Causin et al. 1988) and IGFBP-1 immunoreactivity have been found in human urine (Zumkeller and Hall 1990).

Localization of IGF and IGFBP proteins

Receptors and intracellular signal transmission

Insul&-like growthfactors

The kidney membrane possesses both type I and type II IGF receptors as well as specific degrading enzymes distinct from insulin neutral protease (D'Ercole et al. 1977; Bhaumick and Bala 1987). Type I IGF receptor gene expression in the rat mesonephros has been shown in early embryogenesis (Bondy et al. 1990). IGF-I receptors have been localized in the basolateral surface of proximal tubular cells (Hammerman and Rogers 1987; Lajara etal. 1989) and glomerular mesangial cells (Arnqvist et al. 1988; Doi et al. 1989). Distinct type I IGF receptors for IGF-I have been described in glomerular and tubular membranes. Glomerular [lzsI]IGF-I binding species were seen at >230, 140-150 and 40 kD whereas tubular membranes showed receptor proteins at >230, 225, 120-140 and 50 kD (Pillon et al. 1988). Cross-linking of [lzsI]IGF-I to membranes from proliferating rat glomerular mesangial cells showed specific binding to a 145 kD protein and a 95 kD membrane protein (which is consistent with the fl-subunit of the type I IGF receptor) from a partially purified receptor preparation that was autophosphorylated after incubation with IGF-I. Confluent mesangial cells do not express type I IGF receptors whereas proliferating cells express large numbers of receptors (Abrass et al. 1988). Conti et al. (1989) described a single electrophoretic species at an apparent Mr of 145,000 under reducing conditions in mouse glomerular endothelial and epithelial cells. In cultured bovine glomerular endothelial cells, immunoprecipitation with specific antibodies against type I IGF receptor revealed a band with an apparent molecular mass of 140 kD (Ohashi et al. 1991). MDCK cells display both type I and type II IGF but few if any insulin receptors (Krett et al. 1986). IGF-I stimulated the tyrosine kinase activity of the 97 kD-subunit of the IGF-I receptor resulting in receptor autophosphorylation and an increase in kinase activity toward a peptide substrate. Furthermore, IGF-I induced a six-fold increase in c-fos expression whereas IGF-II produced a minor, and insulin no effect (Hauguel-de Mouzon and Kahn 1991). IGF-I stimulated tyrosine phosphorylation of a 185 kD substrate in normal rat kidney (Izumi et al. 1987) and mesangial cells as determined by immunoblots with antiphosphotyrosine antibodies (Oemar et al. 1990). Electron microscope autoradiography showed that after luminal endocytic uptake IGF-I was to a large extent present in the lysosomes

In human fetal kidneys, immunostainable IGF is limited to the epithelial cells of the tubules (Han et al. 1987 and 1988b; Hill et al. 1989) suggesting secondary accumulation of the peptide. In the adult rat kidney, IGF-I immunoreactivity was mostly limited to the cells in the medullary collecting ducts and in parts of the thin limb of Henle's loop located in the outer medulla; no IGF-I immunoreactivity was seen in the proximal and distal tubules (Bortz et al. 1988; Andersson et al. 1988a; Hansson etal. 1988; Rosendahl etal. 1991). Hammerman (1989) also suggested that IGF-I is produced by the collecting tubule while Aron et al. (1988, 1991) showed synthesis of IGF-I by the rat collecting duct. Immunocytochemical staining with anti-IGF-I using the peroxideantiperoxidase method showed appreciable amounts of IGF-I in tubular cells (Bennington et al. 1983). Human and mouse mesangial cells (Conti et al. 1988a; Aron et al. 1989; Doi et al. 1989; Perfetti et al. 1989) as well as glomerular endothelial and epithelial cells (Conti et al. 1989) produce IGF-I. D'Ercole et al. (1984, 1986) found 2.59 + 0.80 units IGF-I/g of kidney in normal male rats whereas the IGF-I content in human fetuses during the first half of gestation (9-19 week) was about 130 mU/g tissue. Goldstein and Phillips (1991) extracted the kidney IGF-I of male Sprague-Dawley rats using a combined neutral/acid technique and found about 20 ng IGF-I/g wet weight which amounts to nearly 1/3 of the respective hepatic IGF-I content. Growth hormone injections in rats leads to an increase in renal IGF-I levels (Orlowski and Chernausek 1988). Immunoreactive IGF-II in the urine of human adults was detected at much higher levels than IGF-I indicating that the kidney is a source of urinary IGF-II; evidence for the secretion of a high molecular form of IGF-II was also found (Zumkeller and Hall 1990). IGF-II was found in the adult rat kidney at high concentrations, exceeded only by those in the pituitary, and was predominantly located in the connecting segment and cortical collecting duct (Lee et al. 1991).

IGF-binding proteins Immunohistochemistry revealed IGFBP-1 mostly in the papillary collecting ducts, with moderate staining in the

210 (Flyvbjerg et al. 1991) which is in marked contrast to the processing of other hormones, e.g. insulin. Fasting induced a 2.5-fold increase in IGF-I receptor mRNA levels in the kidney of male Sprague-Dawley rats (Lowe et al. 1989). Levels of the IGF-II/mannose-6-phosphate receptor in the rat kidney are developmentally regulated suggesting an important role in fetal and neonatal development (Sklar et al. 1989; Ballesteros et al. 1990). Using antibodies specific for IGF-II receptors, staining was observed in glomeruli, tubules and Bowman's capsules (Valentino et al. 1988). De novo synthesis of soluble IGF-II receptors from rat kidney explants was demonstrated and could be inhibited by the protein synthesis inhibitor cycloheximide (Bobek et al. 1991). An increased number of type II IGF receptors has been observed in the rat kidney during compensatory growth and confirmed by polyacrylamide electrophoresis estimating the size to 270 kD (Polychronakos et al. 1985) but other Mr sizes have also been described (Taylor et al. 1987). A specific high affinity type II IGF receptor with an apparent molecular mass of 255 kD has been demonstrated in the rat kidney glomerulus and binding of [125I]IGF-II was inhibited by a polyclonal antibody directed against this receptor type (Haskell et al. 1988). These receptors are also distributed in the basolateral and brush border membranes of the proximal tubules (Hammerman and Rogers 1987). Specific binding of [125I]IGF-II was also measured in basolateral membranes isolated from proximal tubular cells in the dog kidney which resulted in stimulated phosphorylation of a Mr 135,000 band suggesting that IGF-II stimulates the activity of a protein kinase which then results in the phosphorylation of a 135 kD protein. Furthermore, IGF-I had no effect on phosphorylation implying therefore that the IGF-II stimulation of phosphorylation was not mediated through the type I IGF receptor (Hammerman and Gavin 1984, 1986). IGF-II activates phospholipase C in the basolateral membrane of the renal proximal tubular cell leading to an increase in inositol 1,4,5-triphosphate and diacylglycerol (Rogers and Hammerman 1988). Mannose-6-phosphate (Man-6-P) potentiates this effect which suggests that mannose-6-phosphate or mannosylated proteins may act as a modulator of IGF-II signal transmission through the type II IGF receptor (Rogers and Hammerman 1989 a).

epithelial cells, however, the IGF-I concentration required for optimal cell growth (EDso 17 ng/ml) was considerably less than the insulin requirement (EDso 252 ng/ ml) (Zhang et al. 1991). Nevertheless it has also been shown that GH has a direct, IGF-I independent mitogenic effect. In contrast to IGF-I, GH increases the expression of the c-myc proto-oncogene in the kidney of hypophysectomized rats (Murphy etal. 1987b). The diuretic furosemide which increases Na+-transport in the distal convoluted tubules and collecting ducts as welt as hypertrophy of these segments, also caused a marked increase in staining for IGF-I in the superficial distal nephron which was not associated with an increase of IGF-I mRNA (Kobayashi et al. 1991). IGF-I stimulates anabolic processes such as gluconeogenesis in the canine renal proximal tubules (Rogers and Hammerman 1989b), and has been shown to increase the content of diacylglycerol and other cell lipids in these cells (Troyer and Gonzalez 1989). Stimulation of sodium/hydrogen antiport across the brush border of proximal tubular cells by IGF-II suggests a potential role in growth control of the proximal tubule (Mellas et al. 1986). It was suggested that enhanced Na+/H + exchange in isolated segments indicates that one physiological action of IGF-II may be to alkalinize proximal tubular cells in vivo (Rogers and Hammerman 1988). In growth or GH-related (patho)physiological conditions, changes in the tubular inorganic phosphate (Pi) reabsorption are often associated with alterations in the plasma levels of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], a hormone implicated in the homeostasis of Pi (Bonjour et al. 1982). Like GH, IGF-I increases the tubular reabsorption of Pi by a PTH- and cAMP-independent mechanism (Caverzasio etal. 1990). IGF-I when added in vitro, selectively stimulated the Na+-de pendent Pi transport in cultured kidney epithelia (Caverzasio and Bonjour 1988, 1989) which suggests that the action is mediated by the renal receptor for IGF-I in a specific way. In the proximal convoluted tubule, IGF-I stimulates phosphate but not bicarbonate transport and acts through basolateral and apical membranes (Quigley and Baum 1991). Recent evidence indicates that IGF-I mediates the GH-dependent homeostasis of plasma P~ (Gray and Garthwaite 1985; Gray 1987; Halloran and Spencer 1988; Caverzasio etal. 1990; Thomas and Spencer 1990).

Normal and altered physiological states

Renal function

Renal physiology

Renal function is modulated by a wide range of endocrine systemic, local as well as nutritional factors. Since the effect of GH on kidney function appears to be delayed by several days (Hirschberg et al. 1989), it has been suggested that IGF-I is involved in its regulation (Hirschberg and Kopple 1988, 1989a, b; Hirschberg et al. 1989, 1990, 1991; Guler 1989a, b; Haylor et al. 1991). Administration of GH in man causes an increase in IGF-I serum levels and in creatinine clearance at the same time (Hirschberg et al. 1989). An increased creatinine clearance is also achieved by the administration

Several studies have shown that IGF-I in hypophysectomized (Guler et al. 1988), partially nephrectomized (Kovacs et al. 1991), dwarf (Skottner et al. 1989) and transgenic mice or rats expressing IGF-I (Mathews et al. 1988) induces renal growth. The fact that IGF-I is a potent mitogen for mesangial cells (Conti et al. 1988b) suggests that it may regulate glomerular cell function under different physiological conditions. Both insulin and IGF-I stimulate the growth of rat proximal tubule

211 of IGF-I which resulted in a suppression of endogenous GH (Guler et al. 1989a) indicating that the renal effects previously ascribed to GH are in fact caused by endogenous IGF-I. A fall in creatinine, urea and uric acid plasma levels was achieved by IGF-I infusion as well as a depression of IGF-II levels (Guler et al. 1989b). Treatment with either GH or IGF-I enhanced inulin and paminohippurate clearance in rats with normal kidneys, but had no effect on the reduced clearance in rats with reduced renal mass (Miller et al. 1990 a). A rise in renal plasma flow (RPF) and glomerular filtration rate (GFR) concomitantly with a several-fold increased IGF-I level was observed in a GH-deficient patient 24 h after administration of a single dose of human growth hormone (Hirschberg and Kopple 1988). Increased filtration rates as well as a significant reduction in renal vascular resistance was observed in seven normal subjects (Hirschberg et al. 1989) as well as in fasted rats (Hirschberg and Kopple t989a) after a single injection of GH. Indomethacin abolished the IGF-I-induced rise in GFR and RPF (Hirschberg and Kopple 1989a) as well as the effect on renal vascular resistance (RVR) in fasting rats (Kopple and Hirschberg 1990).

Compensatory growth The removal of one kidney from an adult animal results in a rapid increase in size of the contralateral organ (Fine 1986) associated with increased IGF-I mRNA (Stiles etal. 1985; Fagin and Melmed 1987), IGF-I (Flyvbjerg et al. 1988; Le Carpentier et al. 1989) and IGF-II tissue levels (Lee et al. 1991). Compensatory growth after unilateral nephrectomy was followed within 5 days by the appearance of IGF-I immunoreactivity in all contralateral kidney sections of the collecting ducts as well as in the entire thin limb of Henle's loop. Furthermore, the IGF-I content (expressed in ng/g wet weight) in the cortex increased significantly in the same period while the control level in the inner medulla remained virtually unchanged (Andersson et al. 1988a). In contrast to kidneys from adult rats, kidneys from immature rats had a four-fold increase in exon 1 IGF-I mRNA levels and a three-fold increase in exon 2 IGF-I mRNA level 1 to 2 days after unilateral nephrectomy (Mulroney et al. 1991). Fetal and maternal plasma IGF-I levels are elevated following fetal bilateral nephrectomy suggesting that the growth retardation often observed in renal agenesis and fetal nephrectomy is not only due to oligohydramnios but implies that the fetal kidney plays a pivotal role in the regulation of fetal growth and metabolism (Beanland et al. 1991). Unilateral ureteric obstruction in male Wistar rats led to a rapid increase in kidney weight associated with a fall of IGF-I content probably due to oedematous and reactive changes. At the same time, the contralateral kidney increased in weight as well as in IGF-I content by 48% at day 10 (Marshall et al. 1991). Renal IGF-I is likely to play a causative role in renal hypertrophy observed in hypersomatotropism (Miller et al. 1990b). Injection of 7.4 gg of recombinant IGF-I, three times

daily over a period of 4 weeks, to snell dwarf mice resulted in a 50% increase in kidney weight (van BuulOffers et al. 1986). Guler et al. (1988) achieved a doubling in kidney size in hypophysectomized rats after treatment with recombinant human IGF-I for a period of 18 days but observed a much less clear effect with GH. Enhanced potency of truncated IGF-I (des(13)IGF-I) was achieved relative to IGF-I in lit~lit mice (Gillespie et al. 1991). Interestingly, IGF action in baby hamster kidney fibroblasts is enhanced in the presence of IGFBP-3 (Blum et al. 1989a). Increased immunoreactivity for IGF-I was observed in rat renal tubules regenerating from ischemic injury (Andersson et al. 1988b). It has been suggested that increased expression of IGF-I receptors on basolateral membranes following nephron loss are pivotal for the growth and maintenance of renal cell mass (Corbin et al. 1990). Both growth hormone and epidermal growth factor (prepro-EGF mRNA have been found at high levels in the distal tubules of the mouse (Crawford et al. 1985)) and may be implicated in these processes since they stimulated IGF-I mRNA expression in the collecting ducts (Rogers et al. 1990, 1991 a). Furthermore, EGF is a potent mitogen for epithelia of polycystic kidneys whereas IGF-I has no effect (Das et al. 1989). However, it has been shown that after uni-nephrectomy or limited renal ablation, compensatory renal growth occurs in growth hormone-deficient rats and in a mutant strain of rats with a selective defect in pituitary transcription of GH (Charlton et al. 1988) which might underline the autocrine or paracrine role of IGF-I in this process (Le Carpentier et al. 1989; El Nahas et al. 1990a). Kidney IGF-I levels after unilateral nephrectomy increased only in rats on medium or high protein intake (El Nahas et at. 1989). However, hypophysectomy prevented the high protein intake-induced increase in renal size and urinary IGF-I excretion which supports an important role for the growth hormoneIGF-I-axis in the initial phase of renal hypertrophy induced by a high protein diet (Murray et al. 1991).

Involvement in pathological processes

Diabetes Streptozotocin (STZ)-induced diabetes leads to rapid kidney enlargement associated with an increase in kidney mRNA and protein levels. Diabetic renal hypertrophy is preceded by a rise in kidney tissue IGF-I levels reaching its peak value 24-48 h after the onset of diabetes (Flyvbjerg et al. 1988, 1989). STZ-induced diabetes in postpubertal rats resulted in an early increase of IGF-I tissue levels followed by a significant higher kidney weight gain on day 7 compared with prepubertal diabetic rats (Bach and Jerums 1990). Furthermore, the IGF-I mRNA expression (at sizes of 7.4-, 4.8-, 1.8- and 1.0-kb), 12 h after STZ-treatment, was more pronounced in postpubertal than in prepubertal rats (Bach et al. 1991). A decline of about 40% in IGF-I mRNA expression 4 days (Bornfeldt et al. 1989) and to an even greater extent 7 days after the onset of diabetes (Fagin et al. 1989) have

212 previously been described. However, no change in kidney IGF-I mRNA has been observed during the first 4 days of diabetes (Flyvbjerg et al. 1990a). In addition, kidney growth and IGF-I tissue levels are correlated with the severity of diabetes, in particular with blood glucose levels and 24-hour urinary glucose output (Flyvbjerg and Orskov 1990). IGF-I infusion in diabetic rats enhanced renal hypertrophy while insulin normalized the size of the kidney (Arnqvist et al. 1991). The combined induction of diabetes and unilateral nephrectomy in the same animal induces an additive increase in both kidney IGF-I content and renal hypertrophy (Flyvbjerg et al. 1990b). STZ-treated rats showed an upregulation of the type I IGF receptor in the basolateral membranes which may have a key role in renal growth and subsequent haemodynamic changes (Still et al. 1990). An increase in kidney IGF-I and IGF-II receptor concentration and mRNA expression was found 1-2 weeks after induction of experimental diabetes (Werner et al. 1990) whereas there was no change in IGF-I receptor number and affinity (Marshall et al. 1990). Immunoblot analysis of MC membranes with a site-specific antibody to the ~-subunit of the type I IGF receptor indicated that the diabetic cells express more receptor protein than their controls (Oemar et al. 1990). These studies in experimental diabetes indicate that IGF-I is involved in renal hypertrophy at an early stage although the pathological mechanism has yet to be established. Chronically elevated kidney IGF-I levels may finally lead to diabetic nephropathy. In this concept, it is rather striking that octreotide, a somatostatin analogue, has improving effects on long-term kidney changes in diabetic rats by reducing long-term renal hypertrophy and urinary albumin excretion (Flyvbjerg et al. 1992). Therefore, the understanding of the role of IGFs in these processes are vital for achieving any future progress in the prevention and treatment of diabetic nephropathy.

Nephritis The pathogenesis of the different forms of tubulo-interstitial nephritis is mainly unknown. The release of IGF-I by rabbit papillary collecting duct (PCD) cells and the potent PCD-stimulated [3H]thymidine incorporation in quiescent 3T3 fibroblasts has been demonstrated. IGF-I has thereby been implicated as a mediator of fibroblast response in interstitial cells and in consequence, as the causative factor in the pathogenesis of interstitial nephritis (Norman et al. 1989). Furthermore, inner medullary collecting duct (IMCD) cells stimulated DNA synthesis in medullary fibroblasts, an effect mimicked by exogenous IGF-I but not FGF or TGFfl (Knecht et al. 1990). Watanabe et al. (1991) studied the effects of insulin and IGFs on the growth of a murine renal proximal tubular epithelial cell line and found a potent 3H-thymidine incorporation with IGF-I but not insulin which might suggest a pathogenetic role for IGF-I in the development of interstitial renal disease.

Glomerulosclerosis Several factors, such as systemic hypertension, increased glomerular capillary pressure and proteinuria have been implicated in the development of glomerulosclerosis (El Nahas et al. 1990b). Furthermore, E1 Nahas et al. (1991) suggested that elevated GH levels during chronic renal failure (CRF) may be responsible for the progression of the renal scarring process. A rise in renal IGF-I may contribute to the development of glomerular sclerosis through its stimulation of microvascular collagen and proteoglycan synthesis (Bar et al. 1987). Transgenic mice expressing GH, GH-releasing hormone (GHRH) and IGF-I but not those only expressing IGF-I developed progressive glomerulosclerosis (Doi et al. 1988; Quaife et al. 1989). Rats bearing GH-secreting tumours developed glomerulosclerosis with glomerular enlargement but the lesions were somewhat different from those the reported in transgenic mice (Kawaguchi etal. 1991). Body and organ weight paralleled IGF-I levels in both groups. In the mesangial areas of GH mice, type IV collagen and heparin sulphate proteoglycan (HSPG) levels as well as mesangial type I collagen were increased. In mice transgenic for IGF-I, these matrix alterations were not observed (Doi et al. 1990a, b). This suggests that chronic elevated GH and GHRH levels may constitute a predisposition for the development of progressive glomerulosclerosis and renal failure. Whether the development of glomerulosclerosis is induced by a stimulus to mesangial cell proliferation and/or collagen gene expression or by chronic glomerular hyperfiltration and/or increased transcapillary pressure is still a matter of speculation and needs further investigation.

Wilms' tumour (nephroblastoma ) In nephroblastoma (Wilms' tumour; WT) which arises as a consequence of abnormal proliferation of blastemal cells, IGF-II mRNA expression is increased dramatically over normal postnatal kidney tissue (Reeve et al. 1985; Scott et al. 1985; Schofield and Tate 1987; Haselbacher et al. 1987; Irminger et al. 1989; Paik et al. 1989; Wilkins et al. 1989). This has lead to the suggestion that inappropriate expression of IGF-II is able to drive, firstly hyperplastic, and finally overtly malignant proliferation in these tumours. This gains some support from in vitro observations. Type I IGF (Gansler et al. 1988) receptors have been shown in WT and high concentrations of antibodies against type I IGF receptors inhibited WT growth in culture and in athymic mice (Gansler et al. 1989). We have also found evidence for autocrine growth loops operative in the in vitro culture of a series of established WT cell lines. In WT there exist several predisposing genetic conditions (WAGR, Wilms'/aniridia, genitourinary abnormality/mental retardation; Beckwith-Wiedemann syndrome, BWS) which involve the short arm of chromosome 11; llpl3, llpl5 respectively, and another unlinked site (see Engstr6m etal. 1988; Brown 1990; Mitchgll

213 1991 for review). Lesions in lip are also seen in sporadic tumours of these classes and nearly all involve allele losses, with or without reduplication, resulting in either hemi- or homozygosity (Reeve et al. 1989; Koufos et al. 1985). In nearly all cases, investigators have shown either the insulin gene or the IGF-II gene to be lost. A reduction in IGF-II gene dosage or rearrangement is also found in such tumours (Irminger et al. 1989) which for similar intuitive reasons would not be expected if selection were occurring for IGF-II overexpression. Moreover, enhanced IGF-II mRNA expression does not necessarily correlate with the growth of primary WT (Little et al. 1987) and protein levels may not be increased either (Haselbacher et al. 1987), implying posttranscriptional regulation of expression. More recently it has been shown that forced expression of IGF-II from a retroviral construct suppressed tumour formation in nude mouse grafts or tumourigenic fibroblasts (Schofield et al. 1991). It is now clear that the chromosomal locus involved in allele loss on chromosome 11 in WT is distinct from that affected in tumour predisposing syndromes. In the Beckwith-Wiedemann syndrome, it is localized on the short arm of chromosome 11 at 11p15.5 (Koufos et al. 1989). Where chromosome lesions have been detected, these involve duplications of the end of lip suggesting that an increased dosage of genes in this region is involved in the aetiology of the syndrome, contributing to the congenital hyperplastic phenotype and to tumourigenesis. As IGF-II is found at 11p15.5, it has been suggested that fetal overexpression of IGF-II is responsible for the syndrome (Engstr6m etal. 1988; Little etal. 1991). The situation is complicated by the recently recognised effects of parental imprinting. In WT derived from patients suffering from WAGR or BWS there is frequently loss of heterozygosity at a tumour-suppressing locus on the short arm of chromosome 11. This is also seen in sporadic WT. Interestingly it is always the maternal allele which is lost, implying that there are gamete of origin specific imprints on the two alleles (Brown et al. 1990). This has been interpreted as loss of the active member of a pair of alleles in which the other is normally constitutively suppressed by parental imprinting, leading to an effective complete loss of functional alleles, whilst retaining the actual DNA for one of them. It is clear as there is still extensive expression of IGF-II that in cases where a paternal allele remains this is still expressed at high levels, and in this case there is no evidence for IGF-II acting as a tumour suppressor. Moreover, it indicates that if the IGF-II locus is parentally imprinted, the paternal copy remains active. In the context of BWS the situation is more complex but more intriguing. The pattern of inheritance in the few families studied by linkage analysis suggests a parental sex-dependant pattern of inheritance, with the active lesion only manifest when inherited through the female line (Koufos et al. 1989; Nystr6m et al. 1992b). Most BWS patients show no overt changes in the dosage of the IGF-II gene, which has been confirmed at the molecular level in sporadic tumours by ourselves (Schofield

etal. 1989; Nystr6m etal. 1992a) and others (Spritz et al. 1986). However, the dosage of genes may not be as important as parental origin. Following some rare reports of cytogenetically detectable duplications of the paternal copy of the short arm of chromosome 11, there have now been several reports of exclusively paternal parental isodisomies of the short arm of chromosome 11 in sporadic BWS patients (Henry etal. 1991; Nystr6m et al. 1992 b). The rarity of this condition lends force to the argument that only constitutive duplication of the paternal gene complement, rather than the maternal, is able to give rise to BWS, again implying that the paternal gene copy is active and the maternal suppressed. Recent work on the mouse has been interpreted as indicating that the maternal allele of murine IGF-II (chromosome 7) might be imprinted, thus rendering the paternal allele as the most important source of IGF-II (DeChiara et al. 1990, 1991). If BWS were to have at its root a duplication of the IGF-II gene, one could argue that the ensuing level of overexpression would produce the overgrowth of organs seen in the syndrome and produce a pre-neoplastic hyperproliferative state in several susceptible tissues (Koufos et al. 1989; Brown et al. 1990). The possible biological rationale for this arrangement is discussed more fully by Moore and Haig (1991). Regarding the proposed constitutive overexpression of IGF-II in BWS patients, data is not extensive. Although elevated IGF-II levels have been reported in one patient (Spencer et al. 1980) two patients examined by us (Nystr6m et al. unpublished) showed no perinatal serum IGF-II elevation. Several groups have reported elevated IGF-I levels (Spencer 1980, 1981; Gruner et al. 1981) but even this data is not entirely consistent (Weninger et al. 1984). However, as the gene is downregulated in most tissues except the liver late in gestation it would be possible to argue that levels could stabilize by birth. Perinatal hypoglycemia may be due to nesidioblastosis and islet cell hyperplasia frequently found in these patients (Dammacco et al. 1973), and elevated IGF-I associated with an endocrine defect in the growth hormone axis (Barlow 1980). Insufficient evidence is therefore available to come to any meaningful conclusions.

Renal cell carcinoma

Interestingly, unspecified types of renal cell carcinoma (RCC) cells express 300-800-fold higher levels of IGF-I mRNA than IGF-II mRNA (Bennington et al. 1990), secrete IGFs (Strewler et al. 1985) and express type I IGF receptors (Pekonen et al. 1989). Hintz et al. (1991) found that IGFBP-3 mRNA transcripts are overexpressed in human renal cell carcinomas. Blocking the type I IGF receptor on IGF-secreting RCC cells in vitro led to a significant inhibition of cell proliferation. Furthermore, one RCC cell line expressed IGFBP-3 mRNA 30 to 50 times higher than the other two cell lines and an excess of IGFBP-3 added to this cell line enhanced the IGF-I mediated increase in the rate of cell proliferation whereas in the other two cell lines, IGFBP-3 had

214

an inhibitory effect (Bennington et al. 1991). As this lesion is of adult rather than fetal origin and of a completely different histopathological type, we might expect a situation more akin to the hyperplasia seen in adult renal hypertrophy rather than a recapitulation or continuation of fetal organogenesis as has been suggested for WT. This is consistent with the reported rise in IGF-I levels, both protein and mRNA, in non malignant hyperplastic processes in the kidney (see above).

Chronic renal failure Conflicting results concerning the serum concentrations of IGFs in uraemic patients have been reported (Saenger et al. 1974; Schwalbe et al. 1977; Phillips et al. 1978; Phillips and Kopple 1981; Baxter et al. 1982; Goldberg et al. 1982; Arnold et al. 1983; Powell et al. 1986, 1987; Hokken-Koelega et al. 1990). Levels of IGF-I in acid ethanol-extracted serum from uraemic adults were decreased by 50% whereas the IGF-II concentrations were increased by 350% compared with normal values but no significant differences were seen in the two groups when the sera were acid chromatographed (Powell et al. 1986). The immunoreactive serum IGF-I from nine uraemic children rose by 65% in each child combined with an increased growth velocity in most of them after they had undergone kidney transplantation (Saenger et al. 1974). Basal IGF-I serum levels were stimulated significantly by the administration of supraphysiologic doses of hGH in children with end-stage renal disease while there was also a slight but significant increase of serum IGF-II during hGH treatment (T6nshoff et al. 1989, 1990). The effect of GH and IGF-I on G F R is obliterated in uraemic compared with healthy rats and no differences in mitosis and weight gain was observed in the two groups (Mehls et al. 1991). Another study showed significant higher kidney/body weight ratios in rats with renal failure compared with controls (Martin et al. 1991). Bone formation in uraemia correlated with serum IGF-I but not IGF-II indicating that IGF-I is promoting bone formation in uraemic patients with hyperparathyroidism (Andress et al. 1989). Serum levels of IGF-binding proteins and binding activity are increased in children with chronic renal failure (CRF; Powell et al. 1989; Blum et al. 1991) which might explain the relative hGH/IGF-I resistance (Mehls et al. 1988). In addition, the presence of IGF-inhibitors in uraemic serum has earlier been described (Phillips et al. 1984). Liu et al. (1990) showed that the 33 and 28 kD IGFBPs, which were hardly detectable in normal serum, are elevated in CRF. Both of them were immunoprecipitated by antibodies directed against IGFBP-1 indicating an apparent antigenic similarity. The free IGFI-binding capacity of uraemic serum was severalfold increased in CRF compared with normal controls (Blum et al. 1989b). Increased IGFBP-1 and IGFBP-3 levels, determined by specific radioimmunoassays, were reported in children with CRF which suggests that they play a role in the growth retardation of these patients (Lee et al. 1989). Sex-hormone binding-globulin (SHBG)

was found elevated in CRF while IGF-I serum levels were normal underlying a peripheral resistance to IGF-I (Belgorosky et al. 1991).

Conclusions

Insulin-like growth factors have a variety of effects on renal physiology and their implication in the pathology of the kidney has become increasingly evident over the past few years. Integration, both of physiological and developmental processes is of paramount importance, especially in the kidney where the organ rudiments are derived from different embryological sources, and interact to form a quantitatively and qualitatively accurate balance of differentiated tissues. One might intuitively expect that in such a situation cells would need to communicate extensively with each other, and it is now becoming clear that along with signals from the extracellular matrix the growth factors, and particularly IGF-II, must have a vital function in these processes. It is a unique property of the insulin-like growth factors that they are able to exert profound anabolic and other physiological effects directly through their high affinity receptors and not through an intermediary process. This opens the route to using recombinant peptides in a therapeutic context in situations of metabolic disturbance where pharmaceutical agents are either inadequate or produce unwanted side effects. It would have been impossible to write this overview five years ago; dramatic progress in the field of molecular biology has been made very recently and increased our understanding of the regulation and integration of kidney function and ontogeny has accrued beyond all expectation, allowing us to dissect molecular details of normal and pathological processes with increasing precision. It is clear that this will occur at even greater pace in the future.

Acknowledgements. Dr Walter Zumkeller is the recipient of a postdoctoral stipendium from the Deutsche Forschungsgemeinschaft (DFG) and wishes to express his gratitude to Professor M.A. Preece for his continued support. Dr Paul N. Schofield would like to acknowledge the Cancer Research Campaign of Great Britain for their long term support, Ciba Geigy for supporting international collaborations in which much of the unpublished work cited here was carried out, and the Nuffield Foundation. References Abrass CK, Raugi GJ, Gabourel LS, Lovett DH (1988) Insulin and insulin-like growth factor I binding to cultured rat glomerular mesangial cells. Endocrinology 123:2432-2439 Adamo M, Lowe WL Jr, LeRoith D, Roberts CT (1989) Insulinlike growth factor I messenger ribonucleic acids with alternative 5'-untranslated regions are differentially expressed during development of the rat. Endocrinology 124: 2737-2744 Andersson GL, Skottner A, Jennische E (1988a) Immunocytochemical and biochemical localization of insulin-like growth factor I in the kidney of rats before and after uninephrectomy. Acta Endocrinol (Copenh) 119:555-560 Andersson GL, Jennische E (1988b) IGF-I immunoreactivity is expressed by regenerating renal tubular cells after ischemic injury in the rat. Acta Physiol Scand 132:453-457

215 Andress DL, Pandian MR, Endres DB (1989) Elevated plasma insulin-like growth factor I (IGF-I) correlates with bone formation in uremic hyperparathyroidism [Abstract]. Kidney Int 35 : 376 Arnold WC, Uthne K, Spencer EM, Piel C, Holliday MA (1983) Somatomedin in children with chronic renal insufficiency - relationship to growth rate and energy intake. Int J Pediatr Nephrol 4: 29-34 Arnqvist HJ, Ballermann BJ, King GL (1988) Receptors for and effects of insulin and IGF-I in rat glomerular mesangial cells. Am J Physiol 254: C411-C416 Arnqvist HJ, Bornfeldt KE, Flyvbjerg A, Orskov H (1991) Effect of IGF-I infusion on kidney hypertrophy in diabetic rats [Abstract]. Acta Endocrinol (Copenh) 124 [Suppl 3]:4 Aron DC, Rosenzweig JL, Abboud HE (1988) Synthesis and binding of insulin-like growth factor I in rat kidney collecting duct. J Cell Biol 107:811-819 Aron DC, Rosenzweig JL, Abboud HE (1989) Synthesis and binding of insulin-like growth factor I by human glomerular mesangial cells 68 : 585-591 Aron DC, Saadi HF, Nye CN, Douglas JG (1991) Secretion of insulin-like growth factor I and its binding proteins by collecting duct cells. Kidney Int 39 : 27-32 Avner ED (1990) Polypeptide growth factors and the kidney: a developmental perspective. Pediatr Nephrol 4:345-353 Bach LA, Jerums G (1990) Effect of puberty on initial kidney growth and rise of kidney IGF-I in diabetic rats. Diabetes 39: 557-562 Bach LA, Stevenson JL, Allen TJ, Jerums G, Herington AC (1991) Kidney insulin-like growth factor-I mRNA levels are increased in postpubertal diabetic rats. J Endocrinol 129:5-10 BaUard JF, Upton FM, Szabo L, Ross M, Wallace JC (1989) Sequence characterization of the MDBK binding protein and its effects on biological activities in cultured cells. In: Drop SLS, Hintz RL (eds) Insulin-like growth factor binding proteins. Proceedings of a workshop on insulin-like growth factor binding proteins, Vancouver BC, Canada, June 1989. Excerpta Medica, Amsterdam New York Oxford, pp 117-122 Ballesteros M, Scott CD, Baxter RC (1990) Developmental regulation of insulin-like growth factor-II/mannose-6-phosphate receptor mRNA in the rat. Biochem Biophys Res Commun 172:775-779 Bar RS, Dake BL, Stueck S (1987) Stimulation of proteoglycans by IGF I and IGF II in microvessel and large vessel endothelial cells. Am J Physiol 253 :E21-E27 Barlow GB (1980) Excretion of polyamines by children with Beckwith's syndrome. Arch Dis Child 55:153-155 Baxter RC, Brown AS, Turtle JR (1982) Radioimmunoassay for somatomedin-C: Comparison with radioreceptor assay in patients with growth hormone disorder, hypothyroidism and renal failure. Clin Chem 28:488-495 Baxter RC, Martin JL (1989) Binding proteins for the insulin-like growth factors: structure, regulation and function. Progr Growth Factor Res 65:423-431 Beanland CJ, Wlodek ME, Browne CA, Young IR, Thorburn GD (1991) Fetal and maternal plasma IGF-I concentrations are elevated following fetal nephrectomy [Abstract]. Program of the 2nd International Symposium on Insulin-like Growth Factors/Somatomedins, January 12-16th 1991, San Francisco (USA), p 146 Beck F, Samani NJ, Penschow JD, Thorley B, Tregear GW, Coghlan JP (1987) Histochemical localization of IGF-I and -II mRNA in the developing rat embryo. Development 101 : 175184 Belgorosky A, Ferraris JR, Ramirez JA, Jasper H, Rivarola MA (1991) Serum sex hormone-binding globulin and serum nonsex hormone-binding globulin-bound testosterone fractions in prepubertal boys with chronic renal failure. J Clin Endocrinol Metab 73:107-110 Bennington JL, Spencer EM, Raber K (1983) Immunoperoxidase localization of insulin-like growth factor-I containing tissues.

In: Spencer EM (ed) Insulin-like growth factors/ Somatomedins. De Gruyter, Berlin, pp 563-571 Bennington JL, Strathearn M, Spencer EM, Williams RD (1990) Implications of insulin-like growth factors in renal cell carcinoma. Eur Urol 18 [Suppl 2] : 13-14 Bennington JL, Strathearn M, Williams RD, Spencer EM (1991) Autocrine stimulation by IGF-I of renal cell carcinoma growth in vitro. Spencer EM (ed). Modern concepts of insulin-like growth factors. Proceedings of the Second International Symposium on Insulin-like Growth Factors/Somatomedins held in San Francisco (USA), January, 12-16th, 1991. Elsevier, New York, pp 567-571 Bhaumick B, Bala RM (1987) Binding and degradation of insulinlike growth factors I and II by rat kidney membranes. Endocrinology 120:1439-1448 Binkert C, Landwehr J, Mary JL, Schwander J, Heinrich G (1989) Cloning sequence analysis and expression of a cDNA encoding a novel insulin-like growth factor binding protein (IGF-BP-2). EMBO J 8:2497-2502 Blum WF, Jenne EW, Reppin F, Kietzmann K, Ranke MB, Bierich JR (1989 a) Insulin-like growth factor I (IGF-I)-binding protein complex is a better mitogen than free IGF-I. Endocrinology 125 : 766-772 Blum WF, Ranke MB, Kietzmann K, T6nshoff B, Mehls O (1989b) Excess of IGF-binding proteins in chronic renal failure: evidence for relative GH resistance and inhibition of somatomedin activity. In: Drop SLS, Hintz RL (eds) Insulin-like growth factor binding proteins. Excerpta Medica, Amsterdam, pp 93-101 Blum WF, Ranke MB, Kietzmann K, T6nshoff B, Mehls O (1991) Growth hormone resistance and inhibition of somatomedin activity by excess of insulin-like growth factor binding protein in uraemia. Pediatr Nephrol 5 : 539-544 Bobek G, Scott CD, Baxter RC (1991) Secretion of soluble insulinlike growth factor-II/mannose-6-phosphate receptor by rat tissue in culture. Endocrinology 128:2204-2206 Bondy CA, Werner H, Roberts CT Jr, LeRoith D (1990) Cellular pattern of insulin-like growth factor-I (IGF-I) and type I IGF receptor gene expression in early organogenesis: comparison with IGF-II gene expression. Mol Endocrinol 4:1386-1398 Bonjour JP, Caverzasio J, Miihlbauer R, Trechsel U, Troehler U (1982) Are 1,25(OH)2D3 production and tubular phosphate transport regulated by one common mechanism which would be defective in X-linked hypophosphatemia rickets? In: Vitamin D - Chemical, Biochemical and Clinical Endocrinology of Calcium Metabolism. Walter de Gruyter & Co., Berlin New York, pp 427-433 Bornfeldt KE, Arnqvist H J, Enberg B, Mathews LS, Norstedt G (1989) Regulation of insulin-like growth factor I and growth hormone receptor gene expression by diabetes and nutritional state in rat tissues. J Endocrinol 122:651-656 Bortz JD, Rotwein P, De Vol D, Bechtel P J, Hansen VA, Hammerman MR (1988) Focal expression of insulin-like growth factor I in rat renal collecting duct. J Cell Biol 107:811-819 Brice AL, Cheetham JE, Bolton VN, Hill NCW, Schofield PN (1989) Temporal changes in the expression of the insulin-like growth factor II gene associated with tissue maturation in the human fetus. Development 106:543-554 Brinkman A, Groffen CAH, Kortleve D J, Geurts van Kessel A, Drop SLS (1988) Isolation and characterization of a cDNA encoding the low molecular weight insulin-like growth factor binding protein (IBP-1). EMBO J 7: 2417-2423 Brown AL, Graham DE, Nissley SP, Hill D J, Strain A J, Rechler MM (1986) Developmental regulation of insulin-like growth factor II mRNA in different rat tissues. J Biol Chem 261:13144-13150 Brown AL, Chiariotti L, Orlowski CC, Mehlman T, Burgess WH, Ackermann EJ, Bruni CB, Rechler MM (1989) Nucleotide sequence and expression of a cDNA clone encoding a fetal rat binding protein for insulin-like growth factors. J Biol Chem 264:5148-5154 Brown KW, Williams JC, Maitland NJ, Mott MG (1990) Genomic

216 imprinting and the Beckwith-Wiedemann syndrome. Am J Hum Genet 46:1000-1001 Causin C, Waheed A, Braulke T, Junghans U, Maly P, Humbel RE, von Figura K (1988) Mannose-6-phosphate/insulin-like growth factor-II binding proteins in human serum and urine. Biochem J 252: 795-799 Caverzasio J, Bonjour JP (1988) Influence of recombinant IGF-I (somatomedin C) on sodium-dependent phosphate transport in cultured renal epithelium. Prog Clin Biol Res 252:385-386 Caverzasio J, Bonjour JP (1989) Insulin-like growth factor stimulates Na-dependent Pi transport in cultured kidney cells. Am J Physiol 257:F712-F717 Caverzasio J, Montessuit C, Bonjour JP (1990) Stimulatory effect of insulin-like growth factor-1 on renal Pi transport and plasma 1,25-dihydroxyvitamin D 3. Endocrinology 127 : 453-459 Charlton HM, Clark RG, Robinson IC, Porter-Goff AE, Cox BS, Bugnon C, Bloch BA (1988) Growth hormone-deficient dwarfism in the rat: an new mutation. J Endocrinol 119:51-58 Clemmons DR (1989) Structural and functional analysis of insulinlike growth factors. Br Med Bull 5:465-480 Cohick VS, Clemmons DR (1991) Regulation of insulin-like growth factor binding protein synthesis and secretion in a bovine epithelial cell line. Endocrinology 129:1347-1354 Conti FG, Striker LJ, Elliot SJ, Andreani D, Striker GE (1988a) Synthesis and release of insulin-like growth factor I by mesangial cells in culture. Am J Physiol 255:F1214-F1219 Conti FG, Striker LJ, Lesniak MA, MacKay K, Roth J, Striker GE (1988b) Studies on binding and mitogenic effect of insulin and insulin-like growth factor I in glomerular mesangial cells. Endocrinology 122:2788-2795 Conti FG, Elliot SJ, Striker LJ, Striker GE (1989) Binding of insulin-like growth factor-I by glomerular endothelial and epithelial cells: further evidence for IGF-1 action in the renal glomerulus. Biochem Biophys Res Commun 163:952-958 Corbin AL, Still WPT, Hise MK (1990) Expression of the insulinlike growth factor-I (ILGF-I) receptor in rat kidney following nephron loss [Abstract]. Kidney Int 37: 526 Crawford R J, Penschow JD, Niall HD, Coghlan JP (1985) Mouse pre-pro-epidermal growth factor synthesis by the kidney and other tissues. Nature 313:228-231 Cubbage ML, Suwanichkul A, Powell DR (1989) Structure of the human chromosomal gene for the 25 kilodalton insulin-like growth factor binding protein. Mol Endocrinol 3:846-851 Cubbage ML, Suwanichkul A, Powell DR (1990) Structure of the human binding protein-3 : organization of the human chromosomal gene and demonstration of promoter activity. J Biol Chem 265 : 12642-12649 Dammacco F, Carnevale F, Albrizio M (1973) Nesidioblastosis in Beckwith syndrome, J Pediatr 86:647-648 Das K, Gabow PA, Wilson PD (1989) Abnormal growth factor response by human adult polycystic kidney disease (APKD) epithelia in vitro [Abstract]. Kidney Int 35:151 Daughaday WH, Rotwein P (1989) Insulin-like growth factors I and II peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev 10:68-91 De Chiara TM, Efstratiadis A, Robertson EJ (1990) A growth deficiency phenotype in heterozygous mice carrying an insulinlike growth factor II gene disrupted by targeting. Nature 345 : 78-80 De Chiara TM, Robertson EJ, Efstratiadis A (1991) Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64: 849-859 Delhanty PJD, Nygard K, Han VKM (1991) The ovine insulin-like growth factor binding protein-2 (IGFBP-2): characterization of its cDNA structure and mRNA expression in adult sheep tissues [Abstract]. Program of the 2nd International Symposium on Insulin-like Growth Factors/Somatomedins, January 12-16th 1991, San Francisco (USA), p 307 D'Ercole JA, Decedue CJ, Furlanetto RW, Underwood LE, Van Wyk JJ (1977) Evidence that somatomedin-C is degraded by the kidney and inhibits insulin degradation. Endocrinology 101:577-586

D'Ercole JA, Stiles AD, Underwood LE (1984) Tissue concentrations of somatomedin C: further evidence for multiple sites of synthesis and paracrine or autocrine mechanisms of action. Proc Natl Acad Sci USA 81:935-939 D'Ercole AJ, Hill DJ, Strain AJ, Underwood LE (1986) Tissue and plasma IGF I concentrations in the human fetus in the first half of gestation. Pediatr Res 20:1069-1077 Doi T, Striker LJ, Quaife C, Conti FG, Palrniter R, Behringer R, Brinster R, Striker GE (1988) Progressive glomerulosclerosis develops in transgenic mice chronically expressing growth hormone and growth hormone releasing factor but not in those expressing insulin-like growth factor-I. Am J Physiol 131:398403 Doi T, Conti F, Striker L, Elliot S, Striker G (1989) Insulin-like growth factor-I (IGF-I) is a progression factor for human mesangial cells in vit~'o [Abstract]. Kidney Int 35:171 Doi T, Striker L, Striker G (1990a) Glomerular hypertrophy, mesangial sclerosis, and matrix composition: role in IGF-I and growth hormone (GH) [Abstract]. Kidney Int 37 : 504 Doi T, Striker L J, Gibson CC, Agodoa LYC, Brinster RL, Striker GE (1990b) Glomerular lesions in mice transgenic for growth hormone and insulinlike growth factor-I. I. Relationship between increased glomerular size and mesangial sclerosis. Am J Pathol 137:541-552 E1 Nahas AM, Le Carpenter JE, Bassett AH, Hill DJ (1989) Dietary protein and insulin-like growth factor I content following unilateral nephrectomy. Kidney Int 36 [Suppl] : 515-519 E1 Nahas AM, Le Carpentier JE, Bassett AH (1990a) Compensatory renal growth: Role of growth hormone and insulin-like growth factor-I. Nephrol Dial Transpl 5 : 123-129 E1 Nahas AM, Le Carpentier JE, Bassett AH (1990b) Effects of growth hormone deficiency on the development of glomerulosclerosis in rats [Abstract]. Kidney Int 37 : 504 E1 Nahas AM, Bassett AH, Cope GH, Le Carpentier JE (1991) Role of growth hormone in the development of experimental renal scarring. Kidney Int 40: 29-34 Engstr6m W, Lindham S, Schofield PN (1988) Wiedemann-Beckwith syndrome. Eur J Pediatr 147: 450-457 Fagin JA, Melmed S (1987) Relative increase in insulin-like growth factor I messenger ribonucleic acid levels in compensatory renal hypertrophy. Endocrinology 120:718-724 Fagin JA, Roberts CT, LeRoith D, Brown AT (1989) Coordinate decrease of tissue insulinlike growth factor I posttranscriptional alternative mRNA transcripts in diabetes mellitus. Diabetes 38:428-434 Fine L (1986) The biology of renal hypertrophy. Kidney Int 29: 619-634 Flyvbjerg A, Thorlacius O, Naeraa R, Ingerslev J, Orskov H (1988) Kidney tissue somatomedin C and initial renal growth in diabetic and uninephrectomized rats. Diabetologia 31:310-314 Flyvbjerg A, Frystyk J, Thorlacius-Ussing O, Orskov H (1989) Somatostatin analogue administration prevents increase in kidney somatomedin C and initial renal growth in diabetic and uninephrectomized rats. Diabetologia 32:261-265 Flyvbjerg A, Orskov H (1990) Kidney tissue insulin-like growth factor I and initial growth in diabetic rats: relation to severity of diabetes. Acta Endocrinol (Copenh) 122:374-378 Flyvbjerg A, Bornfeldt KE, Marshall SM, Arnqvist HJ, Orskov H (1990a) Kidney IGF-I mRNA in initial renal hypertrophy in experimental diabetes in rats. Diabetologia 33:334-338 Flyvbjerg A, Frystyk J, Marshall SM (1990b) Additive increase in kidney insulin-like growth factor I and initial enlargement in uninephrectomized-diabetic rats. Horm Metab Res 22:516520 Flyvbjerg A, Nielsen S, Sheikh MI, Orskov H, Christensen El (1991) Luminal and basolateral receptor binding and uptake of IGF-I in renal proximal tubules [Abstract]. Program of the 2nd International Symposium on Insulin-like Growth Factors/ Somatomedins, January 12-16th 1991, San Francisco (USA), p 144 Flyvbjerg A, Marshall SM, Frystyk J, Hansen KW, Osterby R, Harris AG, Orskov H (1992) Six months octreotide treatment

217 in diabetic rats: effects on kidney growth and urinary albumin excretion. Kidney Int (in press) Gansler T, Allen KD, Burant CF, Inabnett T, Scott A, Buse M, Sens DA, Garvin AJ (1988) Detection of type 1 insulin-like growth factor (IGF) receptors in Wilms' tumors. Am J Pathol 130:431-435 Gansler T, Furlanetto R, Gramling TS, Robinson KA, Blocker N, Buse MG, Sens DA, Garvin AJ (1989) Antibody to type I insulin-like growth factor receptor inhibits growth of Wilms' tumor in culture and in athymic mice. Am J Pathol 135:961966 Gillespie C, Read LC, Bagley CJ, Ballard FJ (1991) Enhanced potency of truncated insulin-like growth factor-I (des(1-3)IGFI) relative to IGF-I in lit~lit mice. J Endocrinol 127:401-405 Goldberg A, Trivedi B, Delmez J, Harter H, Daughaday W (1982) Uraemia reduced insulin-like growth factor I, increases insulinlike growth factor II, and modifies their serum protein binding. J Clin Endocrinol Metab 55:1040-1045 Goldstein S, Phillips LS (1991) Extraction and nutritional/hormonal regulation of tissue insulin-like growth factor 1 activity. J Biol Chem 266:14725-14731 Gray RW, Garthwaite TL (1985) Activation of renal 1,25-dihydroxyvitamin D 3 synthesis by phosphate deprivation: evidence for a role of growth hormone. Endocrinology 116 : 189-193 Gray R (1987) Evidence that somatomedins mediate the effect of hypophosphatemia to increase serum 1,25-dihydroxyvitamin D3 levels in rats. Endocrinology 121:504-512 Gruner M, Guillaume A, Montagne JP, Faure C (1981) Nephroblastome et syndrome de Beckwith-Wiedemann. Ann Radiol (Paris) 24: 39-42 Guler HP, Zapf J, Scheiwiller E, Froesch ER (1988) Recombinant human insulin-like growth factor I stimulates growth and has distinct effects on organ size in hypophysectomized rats. Proc Natl Acad Sci USA 85:4889-4893 Guler HP, Eckardt KU, Zapf J, Bauer C, Froesch ER (1989a) Insulin-like growth factor I increases glomerular filtration rate and renal plasma flow in man. Acta Endocrinol (Copenh) 121 : 101-106 Guler HP, Schmid C, Zapf J, Froesch ER (1989 b) Effect of recombinant insulin-like growth factor I on insulin secretion and renal function in normal human subjects. Proc Natl Acad Sci USA 86 : 2868-2872 Halloran BP, Spencer EM (1988) Dietary phosphorus and 1,25dihydroxyvitamin D 3 metabolism: influence of insulin-like growth factor I. Endocrinology 123:1225-1229 Hammerman MR, Gavin III JR (1984) Binding of insulin-like growth factor II and multiplication-stimulating activity-stimulated phosphorylation in basolateral membranes from dog kidney. J Biol Chem 259:13511-13517 Hammerman MR, Gavin III JR (1986) Binding of IGF I and IGF I-stimulated phosphorylation in canine renal basolateral membranes. Am J Physiol 251 :E32-E41 Hammerman MR, Rogers S (1987) Distribution of IGF receptors in the plasma membrane of proximal tubular cells. Am J Physiol 253 : F841-F847 Hammerman MR (1989) The growth hormone-insulin-like growth factor axis in kidney. Am J Physiol 257:F503-F514 Han VKM, D'Ercole AJ, Lund PK (1987) Cellular localization of somatomedin (insulin-like growth factor) messenger RNA in human fetus. Science 236:193-197 Han VKM, Lund PK, Lee DC, D'Ercole AJ (1988a) Expression of somatomedin/insulin-like growth factor messenger ribonucleic acids in the human fetus: identification, characterization, and tissue distribution. J Clin Endocrinol Metab 66:422-429 Han VKM, Hill D J, Strain A J, Towle AC, Lauder JM, Underwood LE, D'Ercole AJ (1988b) Identification of somatomedin/insulinlike growth factor immunoreactive cells in the human fetus. Pediatr Res 22: 245-249 Hart VKM, Hill DJ (1992) The involvement of Insulin-like growth factors in embryonic and fetal development. In: Schofield PN (ed). The Insulin-like growth factors; structure and biological functions. Oxford University Press, Oxford, pp 178 220

Hansson HA, Nilsson A, Isgaard J, Billig H, Isaksson O, Skottner A, Andersson IK, Rozell B (1988) Immunohistochemical localization of insulin-like growth factor I in the adult rat. Histochemistry 89: 403-410 Haselbacher GK, Irminger JC, Zapf J, Ziegler WH, Humbel RE (1987) Insulin-like growth factor II in human adrenal pheochromocytomas and Wilms' tumors: Expression at the mRNA and protein level. Proc Natl Acad Sci USA 84:1104-1106 Haskell JF, Pillion DJ, Meezan E (1988) Specific, high affinity receptors for insulin-like growth factor II in the rat kidney glomerulus. Endocrinology 123:774-780 Hauguel-de Mouzon S, Kahn CR (1991) Insulin-like growth factormediated phosphorylation and protooncogene induction in Madin-Darby canine kidney cells. Mol Endocrinol 5:51-60 Haylor J, Singh I, Fey R, E1 Nahas AM (1990) Nitro-arginine methyl ester on insulin growth factor and compensatory growth in the kidney [Abstract]. Arch Pharm Int Ther 305:252 Henry I, Bonaiti-Pellie C, Chehensse V, Beldjord C, Schwartz C, Utermann G, Junien C (1991) Unilateral paternal disomy in a genetic cancer-predisposing syndrome. Nature 351:665-667 Hill D J, Clemmons DR, Wilson S, Han VKM, Strain A J, Milner RDG (1989) Immunological distribution of one form of insulinlike growth factor (IGF)-binding protein and IGF peptides in human fetal tissues. J Mol Endocrinol 2:31-38 Hintz RL, Bock S, Thorsson AV, Bovens J, Powell DR, Jakse G, Petrides PE (1991) Expression of the insulin-like growth factor-binding protein 3 (IGFBP-3) gene is increased in human renal carcinomas. J Urol 146:1160-1163 Hirschberg R, Kopple JD (1988) Increase in renal plasma flow and glomerular filtration rate during growth hormone treatment may be mediated by insulin-like growth factor I. Am J Nephrol 8: 249-253 Hirschberg R, Kopple JD (1989 a) Evidence that insulin-like growth factor I increases renal plasma flow and glomerular filtration rate in fasted rats. J Clin Invest 83:326-330 Hirschberg R, Kopple JD (1989 b) Effects of growth hormone and IGF-I on renal function. Kidney Int 36:$20-$26 Hirschberg R, Rabb H, Bergamo R, Kopple JD (1989) The delayed effect of growth hormone on renal functions in humans. Kidney Int 35:865-870 Hirschberg R, Tucker BJ, Blantz R, Kopple JD (1990) The acute effects of IGF-I on nephron dynamics in food-deprived rats [Abstract]. Kidney Int 37:370 Hirschberg R, Kopple JD, Blantz RC, Tucker BJ (1991) Effects of recombinant human insulin-like growth factor I on glomerular dynamics in the rat. J Clin Invest 87:1200-1206 Hirvonen H, Sandberg M, Kalimo H, Hukkanen V, Vuorio E, Salmi T, Alitalo K (1989) The N-myc protooncogene and IGFII growth factor mRNA are expressed by distinct cells in fetal kidneys and brain. J Cell Biol 108:1093-1104 Hokken-Koelega ACS, Hackeng WHL, Stijnen T, Wit JM, KeizerSchrama SMPF, Drop SLS (1990) Twenty-four-hour plasma growth hormone (GH) profiles, urinary GH excretion, and plasma insulin-like growth factor-I and -II levels in prepubertal children with chronic renal insufficiency and severe growth retardation. J Clin Endocrinol Metab 71:688-695 Humbel RE (1990) Insulin-like growth factors I and II (review). Eur J Biochem 190: 445-462 Irminger JC, Rosen KM, Humbel RE, Villa-Komaroff L (1987) Tissue-specific expression of insulin-like growth factor II mRNAs with distinct 5' untranslated regions. Proc Natl Acad Sci USA 84:6330-6334 Irminger JC, Schoenle EJ, Briner J, Humbel RE (1989) Structural alterations at the insulin-like growth factor II gene in Wilms' tumour. Eur J Pediatr 148:620-623 Izumi T, White MF, Kadowaki T, Takaku F, Akunuma Y, Kasuga M (1987) Insulin-like growth factor I rapidly stimulates tyrosine phosphorylation of a Mr 185,000 protein in intact cells. J Biol Chem 262:1282-1287 Kawaguchi H, Itoh K, Mori H, Hayashi Y, Makino S (1991) Renal pathology in rats bearing tumour-secreting growth hormone. Pediatr Nephrol 5: 533-538

218 Kiefer MC, Masiarz FR, Bauer DM, Zapf J (1991a) Identification and molecular cloning of two new 30-kDa insulin-like growth factor binding proteins isolated from adult human serum. J Biol Chem 266: 9043-9049 Kiefer MC, Ioh RS, Bauer DM, Zapf J (1991b) Molecular cloning of a new human insulin-like growth factor binding protein. Biochem Biophys Res Commun 176:219-225 Knecht A, Fine LG, Norman JT (1990) A unique, paracrine relationship between inner medullary collecting duct (IMCD) epithelium and interstitial fibroblasts. An explanation for initiation of tubulo-interstitial nephropathy? [Abstract]. Kidney lnt 37:198 Kobayashi S, Venkatachalam MA, Roy AK, Stein JH (1991) Work load induced by furosemide increases IGF-I and IGF-BP-I in rat distal nephron [Abstract]. Program of the 2nd International Symposium on Insulin-like Growth Factors/Somatomedins, January 12-16th 1991, San Francisco (USA), p 141 Kopple JD, Hirschberg R (1990) Physiological effects of growth hormone and insulin-like growth factor I on the kidney. Miner Electrolyte Metab 16: 82-88 Koufos A, Grundy P, Morgan K, Aleck KA, Hadro T, Lampkin BC, Kalbakji A, Cavenee WC (1989) Familial Beckwith-Wiedemann syndrome and a second Wilms' tumour locus both map to 11p15.5. Am J Hum Genet 44:711 719 Kovacs G, Worgall S, Mall G, Rosivall L, Klaus G, Mehls O (1991) Effects of growth hormone (rhGH) and insulin-like growth factor-1 (rhIGF-1) on kidney growth and kidney function. Pediatr Nephrol 5:F86 Krett NL, Heaton JH, Gelehrter TD (1986) Madin-Darby canine kidney cells display type I and type II insulin-like growth factor (IGF) receptors. Biochem Biophys Res Commun 134:120-127 Lajara R, Rotwein P, Bortz JD, Hansen VA, Sadow JL, Betts CR, Rogers SA, Hammerman MR (1989) Dual regulation of insulin-like growth factor I expression during renal hypertrophy. Am J Physiol 257: F252-F261 Le Carpentier JE, Hill DJ, Nahas EL (1989) Role of insulin-like growth factor-I (IGF-I) in compensatory renal growth (CRG) in dwarf rats [Abstract]. Kidney Int 35 : 315 Lee PDK, Hintz R, Sperry J, Baxter R, Powell D (1989) IGF binding proteins in growth-retarded children with chronic renal failure. Pediatr Res 26:308-315 Lee WH, Evan AP, Summurlin PB, Henry DP (1991) Immunocytochemical localization of insulin-like growth factor (IGF-II) in adult rat kidney [Abstract]. Program of the 2nd International Symposium on Insulin-like Growth Factors/Somatomedins, January 12-16th 1991, San Francisco (USA), p 140 Lee YL, Hintz RL, James PM, Lee PDK, Shively JE, Powell DR (1988) Insulin-like growth factor (IGF) binding protein complementary deoxyribonucleic acid from human Hep G2 hepatoma cells: predicted protein sequence suggests an IGF binding domain different from those of the IGF-I and IGF-II receptors. Mol Endocrinol 2:404411 Little MH, Ablett G, Smith PJ (1987) Enhanced expression of insulin-like growth factor II is not a necessary event in Wilms' tumour progression. Carcinogenesis 8 : 865-868 Little M, Van Heyningen V, Hastie N (1991) Dads and disomy and disease. Nature 351:609-610 Liu F, Powell DR, Hintz L (1990) Characterization of insulin-like growth factor-binding proteins in human serum from patients with chronic renal failure. J Clin Endocrinol Metab 70: 620-628 Lowe WL Jr, Adamo M, Werner H, Roberts CT Jr, LeRoith D (1989) Regulation by fasting of rat insulin-like growth factor I and its receptor. Effects on gene expression and binding. J Clin Invest 84:619 626 Marshall SM, Korsgaard L, Flyvbjerg A, Frystyk J, Orskov H (1990) Renal insulin-like growth factor I binding in experimental diabetes. Diabetologia 33 :A148 Marshall SM, Flyvbjerg A, Frokioer J, Orskov H (1991) Insulinlike growth factor-1 and renal growth following ureteral obstruction in the rat. Nephron 58:219-224 Martin AA, Tomas FM, Knowles SE, Owens PC, Read LC, Ballard FJ (1991) Effects of insulin-like growth factor-I (IGF-I) on

growth in rats with renal failure [Abstract]. Program of the 2nd International Symposium on Insulin-like Growth Factors/ Somatomedins, January 12-16th 1991, San Francisco (USA), p 142 Mathews LS, Hammer RE, Behringer RR, D'Ercole A J, Bell GI, Brinster RL, Palmiter RD (1988) Growth enhancement of transgenic mice expressing human insulin-like growth factor I. Endocrinology 123:2827-2833 McCusker RH, Clemmons DR (1992) The Insulin-like growth factor binding proteins: structure and biological functions. In: Schofield PN (ed) The Insulin-like growth factors; structure and biological functions. Oxford University Press, Oxford, pp 110-150 Mehls O, Ritz E, Hunziker EB, Eggli P, Heinrich U, Zapf J (1988) Improvement of growth and food utilization by human recombinant growth hormone in uraemia. Kidney Int 33:45-52 Mehls O, Ritz E, Kovacs G, Worgall S, Schaefer F, Mall G (1991) Effects of growth hormone (rhGH) and insulin-like growth factor (rhIGF-I) on function and growth of kidney of healthy and uremic rats [Abstract]. Program of the 2nd International Symposium on Insulin-like Growth Factors/Somatomedins, January 12-16th 1991, San Francisco (USA), p 137 Mellas J, Gavin III JR, Hammerman MR (1986) Multiplication stimulating activity-induced alkalinization of canine renal proximal tubular cells. J Biol Chem 261:14437 14442 Miller SB, Hansen VA, Hammerman MR (1990a) Effects of growth hormone and IGF-I on renal function in rats with normal and reduced renal mass. Am J Physiol 259:747-751 Miller SB, Rotwein P, Bortz JD, Bechtel PJ, Hansen VA, Rogers SA, Hammerman MR (1990b) Renal expression of IGF I in hypersomatotropic states. Am J Physiol 259:F251-F257 Mitchell CD (1991) Recessive oncogenes, antioncogenes and tumour suppression. Br Med Bull 47:136-156 Moore T, Haig D (1991) Genomic imprinting in mammalian development; a parental tug of war. Trends Genet 7:45-49 Moxham C, Jacobs S (1992) Insulin-like growth factor receptors. In: Schofield PN (ed) The Insulin-like growth factors; structure and biological functions. Oxford University Press, Oxford, pp 80-109 Mulroney SE, Haramati A, Roberts CT Jr, LeRoith D (1991) Renal IGF-1 mRNA levels are enhanced following unilateral nephrectomy in immature but not adult rats. Endocrinology 128:26602662 Murphy LJ, Bell GI, Friesen HG (1987a) Tissue distribution of insulin-like growth factor I and II messenger ribonucleic acid in the adult rat. Endocrinology 120:1279 1282 Murphy LJ, Bell G, Friesen H (1987b) Growth hormone stimulates sequential induction of c-myc and insulin-like growth factor expression in vivo. Endocrinology 120 : 1806-1812 Murphy LJ, Seneviratne C, Ballejo G, Croze F, Kennedy TG (1990) Identification and characterization of a rat decidual insulin-like growth factor-binding protein complementary DNA. Mol Endocrinol 4:329-336 Murray BM, Campos S, MacGillvray MH (1991) Role of the growth hormone-insulin like growth factor I (GH-IGF-I) axis in renal hypertrophy induced by a high protein diet [Abstract]. Program of the 2nd International Symposium on Insulin-like Growth Factors/Somatomedins, January 12-16th 1991, San Francisco (USA), p 143 Norman JT, Kleinman KS, Bacay A, Fine LG (1989) Renal tubular epithelial cells release factors which modulate fibroblast function: implication for pathogenesis of interstitial nephritis [Abstract]. Kidney Int 35:179 Nystr6m A, Engstr6m W, Cheetham J, Schofield PN (1992a) Molecular analysis of patients with Wiedemann-Beckwith syndrome. I. Gene dosage on the short arm of chromosome 11. Eur J Pediatr 151:504-510 Nystr6m A, Cheetham JE, Engstr6m W, Schofield PN (1992b) Molecular analysis of patients with Wiedemann-Beckwith syndrome. II. Paternally derived disomies of chromosome 11. Eur J Pediatr 151 : 511-514 Oemar BS, Rosenzweig SA, Bedell A, Kacinski BM, Foellmer HG

219 (1990) Analysis of insulin and insulin-like growth factor-I binding to mesangial cells derived from diabetic mice [Abstract]. Kidney Int 37:201 Ohashi H, Attawia M, King GL (1991) Receptors for insulin-like growth factor II (IGF-II) and binding proteins in the cultured bovine glomerular endothelial cells [Abstract]. Program of the 2nd International Symposium on Insulin-like Growth Factors/ Somatomedins, January 12-16th 1991, San Francisco (USA), p 145 Orlowski CC, Chernausek SD (1988) Discordance of serum and tissue somatomedin levels in growth hormone-stimulated growth in the rat. Endocrinology 122:44-49 Orlowski CC, Brown AL, Ooi GT, Yang YWH, Tseng LYH, Rechler M M (1990) Tissue, developmental, and metabolic regulation of messenger ribonucleic acid encoding a rat insulin-like growth factor-binding protein. Endocrinology 126:644-652 Paik S, Rosen N, Jung W, You JM, Lippman ME, Perdue JF, Yee D (1989) Expression of insulin-like growth factor-II mRNA in fetal kidney and Wilms' Tumor. An in situ hybridization study. Lab Invest 61 : 522-526 Pekonen F, Partanen S, Rutanen EM (1989) Binding of epidermal growth factor and insulin-like growth factor I in renal carcinoma and adjacent normal kidney tissue. Int J Cancer 43:10291033 Perfetti R, Conti FC, Elliott SE, Striker LJ, Striker GE (1989) Mouse glomerular mesangial cells in culture produce insulinlike growth factor-I binding proteins [Abstract]. Program of the 71st Annual Meeting of the Endocrine Society, Seattle, WA, p 275 Phillips LS, Pennisi A J, Belosky DC, Uittenbogaart C, Ettenger RB, Malekzadeh MH, Fine RN (1978) Somatomedin activity and inorganic sulfate in children undergoing hemodialysis. J Clin Endocrinol 46:165 168 Phillips LS, Kopple JD (1981) Circulating somatomedin activity and sulphate levels in adults with normal and impaired kidney function. Metabolism 30:1091-1095 Phillips LS, Fusco AC, Untermann TG, del Greco F (1984) Somatomedin inhibitor in uraemia. J Clin Endocrinol Metab 59:764772 Pillion DJ, Haskell JF, Meezan E (1988) Distinct receptors for insulin-like growth factor I in rat renal glomeruli and tubules. Am J Physiol 255:E504-E512 Polychronakos C, Guyda HJ, Posner BI (1985) Increase in the type 2 insulin-like growth factor receptors in the rat kidney during compensatory growth. Biochem Biophys Res Commun 132 : 418-423 P6voa G, Enberg G, J6rnvall H, Hall K (1984) Isolation and characterization of a somatomedin-binding protein from mid-term human amniotic fluid. Eur J Biochem 144:199-204 Powell D, Rosenfeld R, Baker B, Liu F, Hintz R (1986) Serum somatomedin levels in adults with chronic renal failure: the importance of measuring insulin-like growth factor 1 (IGF l) and IGF 2 in acid-chromatographed uremic serum. J Clin Endocrinol Metab 63 : 1186-1192 Powell DR, Rosenfeld RG, Sperry JB, Baker BK, Hintz RL (1987) Serum concentrations of insulin-like growth factor (IGF)-I, IGF-2 and unsaturated somatomedin carrier proteins in children with chronic renal failure. Am J Kidney Dis 4:287-292 Powell D, Lee P, Baxter R, Correa J, Burch W (1989) Insulin-like growth factor binding proteins (IGFBPs) are increased in serum of children with chronic renal failure (CRF) and inhibit cartilage growth in vitro [Abstract]. Kidney Int 35:436 Quaife CJ, Mathews LS, Pinkert CA, Hammer RE, Brinster RL, Palmiter RD (1989) Histopathology associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic mice. Endocrinology 124:40-48 Quigley R, Baum M (1991) Effects of growth hormone and insulinlike growth factor I on rabbit proximal convoluted tubule transport. J Clin Invest 88:368-374 Reeve AE, Eccles MR, Wilkins RJ, Bell GI, Millow LJ (1985) Expression of insulin-like growth factor-II transcripts in Wilms' tumor. Nature 317:258-260

Reeve AE, Sih SA, Raizis AM, Feinberg AP (1989) Loss of allelic heterozygosity at a second locus on chromosome 11 in sporadic Wilms' tumour cells. Mol Cell Biol 9:1799-1803 Rogers SA, Hammerman MR (1988) Insulin-like growth factor II stimulates production of inositol triphosphate in proximal tubular basolateral membranes from canine kidney. Proc Natl Acad Sci USA 85:40374041 Rogers SA, Hammerman MR (1989a) Mannose-6-phosphate potentiates IGF-II stimulated inositol triphosphate production in proximal tubular basolateral membranes [Abstract]. Kidney Int 35:181 Rogers SA, Hammerman MR (1989b) Growth hormone directly stimulates gluconeogenesis in canine renal proximal tubule. Am J Physiol 257:E751-E756 Rogers SA, Miller SB, Hammerman MR (1990) Growth hormone stimulates IGF I gene expression in isolated rat renal collecting duct. Am J Physiol 259: F474-F479 Rogers SA, Miller SB, Hammerman MR (1991a) Insulin-like growth factor I gene expression in isolated rat renal collecting duct is stimulated by epidermal growth factor. J Clin Invest 87:347-351 Rogers SA, Ryan G, Hammerman MR (1991 b) Insulin-like growth factor-I and factor-II are produced in the metanephros and are required for growth and development in vitro. J Cell Biol 113 : 1447-1454 Rosendahl W, Wetzel D, Blum W (1991) The role of IGF-I and IGF-II in compensatory kidney growth (CKG) in infantile (IR) and adult rats (AR): interpretation of immunocytochemical findings. Pediatr Nephrol 5:F85 Rotwein P (1986) Two insulin-like growth factor I messenger RNAs are expressed in human liver. Proc Natl Acad Sci USA 83:7781 Saenger P, Wiedemann E, Schwartz E, Korth-Schutz S, Lewy JE, Riggio RR, Rubin AL, Stenzel KH, New M (1974) Somatomedin and growth after renal transplantation. Pediatr Res 8 : 163169 Schabel F, Fritsch H, Spencer G (1980) Raised somatomedin associated with normal growth hormone. A cause of Beckwith-Wiedemann syndrome. Arch Dis Child 55:151-153 Schofield PN, Tate VE (1987) Regulation of human IGF-II transcription in human fetal and adult tissues. Development 101 : 793-803 Schofield PN, Lindham S, Engstr6m W (1989) Analysis of gene dosage on chromosome 11 in children suffering from BeckwithWiedemann syndrome. Eur J Pediatr 148:320-324 Schofield PN (1991) Developmental tumours. Br Med Bull 47:227232 Schofield PN, Lee A, Cheetham JE, James D, Hill DJ, Stewart C (1991) Tumour suppression associated with expression of human insulin-like growth factor II. Br J Cancer 63:687-692 Schwalbe SL, Betts PR, Rayner PH, Rudd BT (1977) Somatomedin in growth disorders and chronic renal insufficiency in children. Br Med J 1 : 679-682 Schwander J, Schmid C, Mary JL, Schlapfer I, Boeni-Schnetzler M, Froesch ER (1991) IGFBP-3 in tissues and primary cell cultures of the rat [Abstract]. Program of the 2nd International Symposium on Insulin-like Growth Factors/Somatomedins, January 12-16th 1991, San Francisco (USA), p 235 Scott J, Cowell ME, Robertson ME, Priestly LM, Wadey R, Hopkins B, Bell GI, Rall LB, Graham CF, Knott TJ (1985) Insulinlike growth factor II in Wilms' tumors and embryonic tissues. Nature 317: 260-262 Shimasaki S, Koba A, Mercado M, Shimonaka M, Ling N (1989) Complementary DNA structure of the high molecular weight rat insulin-iike growth factor binding protein (IGF-BP3) and tissue distribution of its mRNA. Biochem Biophys Res Commun 165:907-912 Shimasaki S, Uchiyama F, Shimonaka M, Ling N (1990) Molecular cloning of the cDNAs encoding a novel insulin-like growth factor-binding protein from rat and human. Mol Endocrinol 4:1451-1458

220 Shimasaki S, Shimonaka M, Zhang HP, Ling N (1991) Identification of five different insulin-like growth factor binding proteins (IGFBPs) from adult rat serum and molecular cloning of a novel IGFBP-5 in rat and human. J Biol Chem 266:1064610653 Sklar MM, Kiess W, Thomas CL, Nissley SP (1989) Developmental regulation of the tissue insulin-like growth factor-II/mannose-6-phosphate receptor in the rat. J Biol Chem 258:90339036 Skottner A, Clark RG, Fryklund L, Robinson ICAF (1989) Growth responses in a mutant dwarf rat to human growth hormone and recombinant human insulin-like growth factor I. Endocrinology 124: 2519-2526 Spencer GS, Schabel F, Frisch H (1980) Raised somatomedin associated with normal growth hormone. A cause for BeckwithWiedemann syndrome? Arch Dis Child 55:151-153 Spencer GS (1981) Somatomedin C in the Beckwith-Wiedemann syndrome. Arch Dis Child 56:77-78 Spritz RA, Mager D, Pauli M, Laxova R (1986) Normal dosage of the insulin and IGF-II genes in patients with Beckwith-Wiedemann syndrome. Am J Hum Genet 39:265-273 Stiles AD, Sosenko IRS, D'Ercole J, Smith BT (1985) Relation of kidney tissue somatomedin-C/insulin-like growth factor I to postnephrectomy renal growth in the rat. Endocrinology 117:2397-2401 Still W, Corteza Q, Mantzouris NM, Hise MK (1990) Regulation of the insulin-like growth factor-I (ILGF-I) receptor in the diabetic rat kidney [Abstract]. Kidney Int 37:522 Strewler G J, Spencer EM, Nissenson RA, Leung SC, Pelle-Day G, Williams RD (1985) Human renal carcinoma cells secrete an insulin-like growth factor [Abstract]. The Endocrine Society, p 203 Stylianopoulou F, Efstratiadis A, Herbert J, Pintar J (1988) Pattern of the insulin-like growth factor II gene expression during rat embryogenesis. Development 103:497-506 Szabo L, Mottershead DG, Ballard FJ, Wallace JC (1988) The bovine insulin-like growth factor (IGF) binding protein purified from conditioned medium requires the N-terminal tripeptide in IGF-I for binding. Biochem Biophys Res Commun 151:207214 Taylor JE, Scott CD, Baxter RC (1987) Comparison of receptors for insulin-like growth factor II from various rat tissues. J Endocrinol 115 : 35-41 Thomas BR, Spencer EM (1990) Acute effect of IGF-1 on l-alpha hydroxylase activity in the isolated perfused rat kidney [Abstract]. J Bone Min Res 5:$265 T6nshoff B, Mehls O, Schauer A, Heinrich U, Blum W, Ranke M (1989) Improvement of uremic growth failure by recombinant human growth hormone. Kidney Int 36:$201-$204 T6nshoff B, Mehls O, Heinrich U, Blum WF, Ranke MB, Schauer A (1990) Growth-stimulating effects of recombinant human growth hormone in children with end-stage renal disease. J Pediatr 116: 561-566

Troyer DA, Gonzalez OF (1989) Effect of insulin-like growth factor (IGF-1) on glomerular mesangial (MS) cell lipids [Abstract]. Kidney Int 35:185 Valentino KL, Pham H, Ocrant I, Rosenfeld RG (1988) Distribution of insulin-like growth factor II receptor immunoreactivity. Endocrinology 122:2753-2763 van Buul-Offers S, Ueda I, van den Brande JL (1986) Biosynthetic somatomedin C (SM-C/IGF I) increases the length and weight of snell dwarf mice. Pediatr Res 20: 825-827 Van den Brande JL (1992) Structure of the human Insulin-like growth factors: relationship to function. In: Schofield PN (ed). The Insulin-like growth factors; structure and biological functions. Oxford University Press, Oxford, pp 12-44 Ward A, Elliss CJ (1992) The Insulin-like growth factor genes. In: Schofield PN (ed) The Insulin-like growth factors; structure and biological functions. Oxford University Press, Oxford, pp 45-79 Watanabe MA, Haverty TP, Ziyadeh FN, Blazer-Yost BL (1990) Insulin and insulin-like growth factor 1 (IGF 1) effects on growth of a murine proximal tubular cell line [Abstract]. Kidney Int 37:380 Weninger M, Lischka A, Pollak A, Vergesslich C, Ogris E, Frisch H (1984) Somatomedin Aktivit/it bei Beckwith-Wiedemann Syndrom. Monatsschr Kinderheilk 32:900-903 Werner H, Shen-Orr Z, Stannard B, Burguera B, Roberts CT, Le Roith D (1990) Experimental diabetes increases insulin-like growth factor I and II receptor concentration and gene expression in kidney. Diabetes 39:1490-1497 Wilkins R J, Molenaar A J, Ohlsson R, Reeve AR, Yun K, Beechroft DMO (1989) Wilms' tumourigenesis: insulin-like growth factor II gene expression and blocked differentiation. In: Furth M, Greaves M (eds) Cancer cells 7 : Molecular Diagnosis of Human Cancer. Cold Spring Harbour, New York Yang YWH, Brown AL, Orlowski CC, Graham DE, Tseng LYH, Romanus JA, Rechler MM (1990) Identification of rat cell lines that preferentially express insulin-like growth factor binding proteins rlGFBP-1, -2 or -3. Mol Endocrinol 4:29-38 Zapf J, Kiefer M, Merryweather J, Masiarz F, Bauer F, Bauer D, Born W, Fischer JA, Froesch ER (1990) Isolation from adult human serum of four insulin-like growth factor (IGF) binding proteins and molecular cloning of one of them that is increased by IGF I administration and in extrapancreatic tumor hypoglycemia. J Biol Chem 265 : 14892-14898 Zhang G, Ichimura T, Wallin A, Kan M, Stevens JL (1991) Regulation of rat proximal tubule epithelial cell growth by fibroblast growth factors, insulin-like growth factor-1 and transforming growth factor-/3, and analysis of fibroblast growth factors in rat kidney. J Cell Physiol 148:295-305 Zumkeller W, Hall K (1990) Immunoreactive insulin-like growth factor II in urine. Acta Endocrinol (Copenh) 123:499-503