PDGF and the progression of renal disease.

54. Noh H, Kim HJ, Yu MR et al. Heat shock protein 90 inhibitor attenuates renal fibrosis through degradation of transforming growth factor-β type II receptor. Lab Invest 2012; 92: 1583–1596 55. Zeisberg M, Hanai J, Sugimoto H et al. BMP-7 counteracts TGF-beta1induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 2003; 9: 964–968

56. Trachtman H, Fervenza FC, Gipson DS et al. A phase 1, single-dose study of fresolimumab, an anti-TGF-β antibody, in treatment-resistant primary focal segmental glomerulosclerosis. Kidney Int 2011; 79: 1236–1243 Received for publication: 22.3.2013; Accepted in revised form: 26.4.2013

Nephrol Dial Transplant (2014) 29: i45–i54 doi: 10.1093/ndt/gft273

PDGF and the progression of renal disease

1

Department of Nephrology, RWTH University of Aachen, Aachen, Germany, 2Institute of Pathology, RWTH University of Aachen, Aachen,

Germany and 3Institute of Molecular Biomedicine, Comenius University, Bratislava, Slovakia

Correspondence and offprint requests to: Peter Boor; E-mail: [email protected]

Progressive renal diseases represent a global medical problem, in part because we currently lack effective treatment strategies. Inhibition of platelet-derived growth factors (PDGFs) might represent one such novel strategy. PDGFs are required for normal kidney development by the recruitment of mesenchymal cells to both glomeruli and the interstitium. PDGFs are expressed in renal mesenchymal cells and, upon injury, in epithelial and infiltrating cells. They exert autocrine and paracrine effects on PDGF receptor-bearing mesenchymal cells, i.e. mesangial cells, fibroblasts and vascular smooth-muscle cells, which are crucially involved in progressive renal diseases. Proliferation but also migration and activation of these mesenchymal cells are the major effects mediated by PDGFs. These actions predefine the major roles of PDGFs in renal pathology, particularly in mesangioproliferative glomerulonephritis and interstitial fibrosis. Whereas for the former, the role of PDGFs is very well described and established, the latter is increasingly better documented as well. An involvement of PDGFs in other renal diseases, e.g. acute kidney injury, vascular injury and hypertensive as well as diabetic nephropathy, is less well established or presently unknown. Nevertheless, PDGFs represent a promising therapeutic option for progressive renal diseases, especially those characterized by mesangial cell proliferation and interstitial fibrosis. Clinical studies are eagerly awaited, in particular, since several drugs inhibiting PDGF signalling are available for clinical testing. © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Keywords: chronic kidney disease, fibroblasts, fibrosis, mesangial cells, platelet-derived growth factors

INTRODUCTION Some epidemiological studies have suggested a prevalence of moderate-to-advanced chronic kidney disease (CKD) of >10% in the general population [1]. The uncovering of molecular mechanisms which would allow both a specific treatment of the primary renal disease as well as of the common processes promoting CKD is therefore of great interest. Such common processes include, in particular, renal fibrosis, i.e. an essential process of wound healing, probably even in the kidneys which becomes pathological if left unchecked [2]. Blocking renal fibrosis is a highly attractive therapy for CKD patients and has raised considerable interest from pharmaceutical companies, especially since antifibrotic therapies may, of course, have implications far beyond the kidney. Unfortunately, however, the translation of new treatment options has been rather poor in nephrology, the reasons being manifold [3]. In this review, we discuss the role of the platelet-derived growth factor (PDGF) family of proteins in renal diseases, with a particular focus on progressive renal diseases.

PDGFS & PDGF RECEPTORS PDGF was first described by Ross et al. in 1974 as a ‘a plateletdependent serum factor that stimulates the proliferation of i45

FULL REVIEW

A B S T R AC T

Downloaded from http://ndt.oxfordjournals.org/ at University of Glasgow on October 5, 2014

Peter Boor1,2,3, Tammo Ostendorf1 and Jürgen Floege1

P. Boor et al.

FULL REVIEW

receptor binding, i.e. -BB and -DD and -AA and -CC, have different roles or can substitute for each other. In fact, using genomic and proteomic approaches, we have shown that PDGF-BB and -DD in mesangial cells and -AA and -CC in renal fibroblasts exerted nearly identical effects [15, 16]. Several factors influencing PDGF signalling have been described. These include the proteases activating PDGF-CC and -DD (described above), proteases cleaving the extracellular matrix retention motive in ‘classical’ PDGF isoforms or proteases degrading PDGF-BB, e.g. factor VII-activating protease. Molecules like SPARC (secreted protein, acidic and rich in cysteine/ BM40/osteonectin) were shown to inhibit PDGFR binding. Integrins may act as co-receptors and G-protein-coupled receptor as transactivators of PDGFR signalling [5, 12]. Other endogenous PDGF antagonists might be the nephroblastoma overexpressed (NOV, CCN3) or Dickkopf-related protein 1 (Dkk-1), see below.

RENAL PDGF AND PDGFR EXPRESSION Renal expression of PDGFs and their receptors is well documented by several studies and has been reviewed in detail by us previously [11]. As in other organs, kidney mesenchymal cells, i.e. glomerular mesangial cells, interstitial fibroblasts and vascular smooth-muscle cells, constitutively express both PDGFR-α and -β (Figure 2). PDGFR-β is even being used as a marker for these mesenchymal cells. The PDGFR expression is maintained in vitro and renders these cells responsive to PDGFs. Epithelial cells, such as podocytes and tubular cells, do not express PDGF receptors in normal nor in pathological conditions. Some focal expression of PDGFR-β was described on parietal epithelial cells. PDGFRs were also not observed on glomerular endothelial cells in vivo. However, we found that in vitro glomerular endothelial cells expressed PDGFR-α and were responsive to PDGF-CC [17]. These data are in line with reports of low PDGFR expression on the microvascular endothelium [18]. It remains to be shown whether PDGFRs are expressed in vivo on the renal endothelium of peritubular capillaries (Figure 2). It also remains unclear whether resident macrophages or dendritic cells of the kidney express PDGFR. The expression of the PDGFR ligands is less well characterized. This mainly relates to difficulties and some variability in the immunohistochemical detection of PDGFs, species differences and lack of reporter mice. Vascular smooth-muscle and mesangial cells seem to express all PDGF isoforms, although the data are somewhat variable between species and diseases [11]. PDGF-DD is expressed by podocytes, and focally by parietal epithelial cells, in humans, but mainly by mesangial cells in mice [19]. PDGF-CC was also observed in parietal epithelial cells in humans and in the developing mesangium [20]. In the tubulointerstitium, PDGF-AA, -CC and -DD were described to be expressed in some tubular cells and collecting ducts. Upon injury, PDGF-BB and -DD are highly and in part de novo expressed in tubular cells [11, 21–23], whereas PDGF-CC seems to be mainly expressed in infiltrating macrophages [21, 24]. Whether PDGF isoforms are expressed in renal endothelial cells, and if so in which ones, remains largely unclear.

i46


arterial smooth-muscle cells in vitro’ [4]. Since then, tremendous progress has been made in our understanding of the role of PDGFs, which reaches far beyond the role in vascular smoothmuscle cell proliferation [5]. PDGFs are involved in the embryonic development of many organs including the brain, lungs, vasculature and kidneys (see below) [6]. Proliferation, differentiation and migration of mesenchymal cells, which are the major PDGF receptor (PDGFR)-bearing cells, are the main processes regulated by PDGFs both during development and adulthood and in both physiological and pathological processes. Best characterized is the role of PDGFs in the vascular system. PDGFs are essential for physiological angiogenesis by the recruitment of perivascular cells, e.g. pericytes, but they are also involved in the regulation of vascular tone and platelet aggregation [5]. PDGFs play crucial roles in cardiovascular diseases, e.g. during vessel remodelling or atherosclerosis. Both latter processes are also important factors in progressive renal diseases of native or transplanted kidneys. We will not cover these processes within this review, in part because hardly any data exist specifically for the kidneys [7]. PDGFs were also shown to be involved in tumourigenesis, by direct pro-oncogenic effects but also by indirect effects on tumour angiogenesis and tumour stroma. Finally, PDGFs are involved in wound healing and its pathological counterpart, organ fibrosis [8, 9]. PDGFs comprise five dimers (PDGF-AA, -AB, -BB, -CC and -DD) with distinct binding affinity to three dimeric PDGFRs with tyrosine-kinase activity (PDGFR-αα, -αβ and -ββ). PDGFR-αα-specific ligands include PDGF-AA and -CC, the latter being a low-affinity ligand for -αβ receptor as well. PDGF-BB and -AB bind to all three receptor dimers. PDGFDD is the only specific high-affinity ligand for PDGFR-ββ, and, as PDGF-CC, a low-affinity ligand for the αβ receptor (Figure 1). The binding of PDGFs to the PDGFRs induces downstream signalling involving several well-known pathways, e.g. Ras-MAPK, PI3K, PLC-γ pathways and others (Figure 1). For more detailed description of these downstream pathways, we refer the readers to several excellent review articles [5, 10–12]. Historically, the first described isoforms were the ‘classical’ PDGFs -AA, -BB and -AB. PDGF-CC and -DD were described >20 years later, in 2000 and 2001, respectively. PDGFCC and -DD differ from the ‘classical’ PDGF isoforms in that they are secreted in an inactive form containing an N-terminal CUB domain, and they lack a C-terminal basic sequence involved in binding to extracellular matrix in ‘classical’ PDGF isoforms. Proteolytic cleavage of the CUB domain is required for receptor binding. Proteases identified in the CUB domain cleavage include tissue plasminogen activator (tPA) for PDGF-CC, urokinase plasminogen activator (uPA) for PDGFDD and plasmin for both isoforms (Figure 1) [13]. CUB domains are found on various proteins, e.g. complement, and exert various functions, e.g. calcium binding and interaction with various ligands [14]. To date, we have no data on the role of CUB domains in the kidneys, neither in those derived from PDGFs nor from others. The function of the PDGF-AB isoform and the receptor αβ also remains largely unknown. This is mainly due to methodological difficulties in specifically dissecting their role from the other isoforms. It also remains largely unclear whether the isoforms with overlapping

FULL REVIEW


F I G U R E 1 : PDGF–PDGFR signalling and interactions. PDGF-AA, -AB and -BB are secreted in an active form. PDGF-CC and -DD are

secreted with a CUB domain, i.e. inactive. Proteolytical cleavage of the CUB domains by tPA or plasmin (PDGF-CC) and uPA or plasmin (PDGF-DD) is required for PDGFR binding and activation. The binding of PDGFs to the PDGFRs induces autophosphorylation of the PDGFR cytoplasmic tyrosine kinase domain and subsequent recruitment of adaptor proteins carrying SH2 and SH3 domains. Main downstream signalling is mediated via the Jak/STAT-, PI3K-, PLC-γ- or RAS-MAPK pathways. This results in expression of genes involved in cell proliferation, migration and survival. Several factors are involved in cross-talk with PDGF signalling, e.g. the integrin signalling is important for PDGF signalling. Other factors involve NHERFs, which were shown to enhance PDGF signalling via the linking of PDGFR-β with focal adhesion kinase and the cortical actin cytoskeleton. For simplification purposes, several other regulatory processes of PDGF signalling were not included. Akt/PKB, protein kinase B; CUB, complement C1r/C1s, Uegf, Bmp1; ECM, extracellular matrix; FAK, focal adhesion kinase; JAK, Janus kinase, JNK, c-Jun amino-terminal kinase; MAPK, mitogen-activated protein kinase; MERM, merlin and ezrin/radixin/moezin family of cytoskeletal linkers; NHERF, Na+/H+ exchanger regulatory factor; p70S6K, ribosomal protein S6 kinase beta-1; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; PI3K, phosphatidyl-inositol-3-kinase; PKC, protein kinase C; PLC-γ, phospholipase C-γ; RAS, rat sarcoma; STAT, signal transducers and activators of transcription; tPA, tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator. Taken and modified from [12] with kind permission from Springer Science and Business Media.

Endothelial-specific ablation of PDGF-BB documented the importance of endothelium-derived PDGF-BB for glomerular development [25]. Glomerular endothelial cells in mice express PDGF-CC [23], and our study suggested paracrine and autocrine effects of PDGF-CC in glomerular endothelial cells [17]. Some studies suggested endothelial expression of both PDGFAA and -CC [11]. It is conceivable that, as in other organs, PDGFs are expressed in the renal endothelium and might be involved in renal angiogenesis, being physiological or pathological. Taken together, renal mesenchymal cells are the main

i47

PDGFR-bearing cells and also the main PDGF effector cells via paracrine and autocrine signalling. The expression of PDGFs in endothelial and epithelial cells remains less well characterized.

PDGFS AND THEIR RECEPTORS IN RENAL D E V E LO P M E N T PDGFs are essential for kidney development by the recruitment of mesenchymal cells. Mice with genetic deletion of

PDGF in renal diseases

PDGFR-β, PDGF-BB or endothelium-derived PDGF-BB showed a similar renal phenotype with failure to develop a glomerular mesangium [25–28]. PDGF-AA-deficient mice showed no obvious renal phenotype [29]. On the other hand, PDGFR-α and combined PDGF-AA- and -CC-deficient mice exhibited similar renal phenotypes with failure to develop an interstitium [30]. PDGF-CC-deficient mice develop a complete cleft palate [31], however, if bred on different genetic backgrounds (e.g. C57Bl6) they are viable and show no obvious renal phenotype, at least until early adulthood ([24] unpublished observations). PDGF-DD-deficient mice were not yet described, but preliminary experiments showed that these mice are viable and have no obvious renal phenotype (own unpublished results). These latter observations suggest that other isoforms can compensate for an ontogenetic lack of PDGF-CC and -DD. Both PDGF-BB and -AA induced chemotaxis of metanephric mesenchyme, and interestingly, the PDGF-BB signal seemed to

P. Boor et al.

inhibit that of PDGF-AA [32]. Taken together, during development, the PDGFR-β–PDGF-BB axis is essential for the recruitment of mesangial cells and PDGFR-α as well as PDGF-AA and -CC for the recruitment of interstitial cells. Apart from their role in embryogenesis, potential roles of PDGFs in physiological processes in the adult kidney remain elusive. Long-term deletion of PDGFR-β in adult mice resulted in reduced ageing-dependent mesangial expansion but also in defective adaptation to glomerular hypertrophy [33], suggesting a potential role in mesangial homeostasis.

P D G F S I N R E N A L P AT H O LO G Y Several studies analysed the role of PDGFs in animal models of renal diseases, in particular regarding mesangial proliferation and interstitial fibrosis.

i48

FULL REVIEW


F I G U R E 2 : Both PDGFR chains -α and -β are expressed and up-regulated in a rat model of mesangioproliferative glomerulonephritis (GN). Expression of PDGFR-α (A) and -β (B) on Day 5 after induction of mesangioproliferative (anti-Thy1.1) GN in rats. The left panels show the appropriate PDGFR stainings, both mainly confined to an expanded mesangium in glomeruli (arrows). Expression in the interstitial space, most likely on fibroblasts, is also seen around the glomeruli (arrowheads). The right panels show a double immunostaining of the PDGFRs in red and endothelial marker JG12 in blue in the same rats with mesangioproliferative GN. Both stainings are largely exclusive, PDGFRs being expressed in mesangium and JG12 showing an expected endothelial staining pattern. Only rare, very small areas of overlapping staining were found (arrows). These findings might be in line with the data showing very low levels of PDGFR expression on the microvascular endothelium [18]. All pictures are in original magnifications ×400; inserts magnified digitally.

F I G U R E 3 : Inhibition of PDGF-DD in progressive mesangioproliferative glomerulonephritis (GN)-reduced glomerular and tubulointerstitial

damage and fibrosis. Significantly reduced fibrosis was observed after treatment with PDGF-DD-neutralizing antibody, even when the treatment was initiated late in the course of the disease, i.e. with already established interstitial fibrosis. Pictures show immunohistochemistry for collagen type III, vimentin and α-smooth-muscle actin (α-SMA) in IgG-treated control animals (upper panels) versus anti-PDGF-DD-treated rats (lower panels) with progressive mesangioproliferative GN. Anti-PDGF-DD-treated animals had reduced deposition of extracellular matrix protein collagen type III, reduced tubular injury and expansion of interstitial (myo-)fibroblasts (vimentin, arrow points to tubular expression of vimentin) and reduced interstitial but also glomerular myofibroblasts as indicated by α-SMA staining (the glomeruli are outlined by dashed circles). Magnification ×100. Taken and modified from [38] with kind permission from Oxford University Press.

i49


FULL REVIEW

The role of PDGF-AA remains unclear, but given the receptor binding that is similar to PDGF-CC, it likely has little to no relevant effect on mesangial proliferation in vivo. In a cDNA screen of PDGF-BB-stimulated mesangial cells, we have identified the nephroblastoma overexpressed gene (NOV, CCN3) as an endogenous PDGF antagonist, limiting mesangial proliferation [42, 43]. CCN3 belongs to the CCN protein family (Cyr61/CTGF/NOV), which is a group of matricellular proteins regulating cell proliferation, migration and differentiation. After stimulation of mesangial cells with PDGF-BB and -DD, CCN3 was the most prominently downregulated gene, and it diminished PDGF-induced mesangial proliferation [43]. In normal kidneys, the CCN3 expression pattern somewhat resembled that of PDGF, namely being expressed in podocytes, vascular smooth-muscle cells, cells of the medullary interstitium and in collecting ducts. A de novo mesangial expression was observed after induction of mesangioproliferative GN in rats [43]. Systemic overexpression of CCN3 significantly reduced mesangial proliferation and also had beneficial effects on long-term progression in mesangioproliferative GN [42]. Interestingly, CCN3 also exhibited proangiogenic effects in the early phase of mesangioproliferative GN [42]. Our data thus identified CCN3 as a potent endogenous inhibitor of PDGF-BB and -DD in mesangial cells and mesangial proliferation. The effects of CCN3 might not be limited to dampening the PDGF-driven effects. In vitro in mesangial cells, CCN3 was also shown to limit the profibrotic effects of CCN2 [connective tissue growth factor (CTGF)] [44]. Growth arrest-specific protein-1 might be another factor that acts as an endogenous inhibitor of mesangial cell proliferation and potentially constitutes another in vivo PDGF antagonist [45].


Mesangioproliferative glomerulonephritis and mesangial sclerosis PDGFR-β and its ligands PDGF-BB and -DD are crucial mediators of mesangial cell proliferation. This is the best described role of PDGFs in renal diseases and several lines of evidence support this [11, 34]. First, the receptor (Figure 2) and its ligands are overexpressed in mesangioproliferative diseases [11]. Secondly, both ligands potently induce mesangial cell proliferation in vitro [11, 34, 35]. Thirdly, overexpression of both ligands systemically or of PDGF-DD in podocytes in healthy mice, was sufficient to induce mesangioproliferative glomerulonephritis (GN) [22, 36]. Fourthly, neutralization of both ligands effectively blocked the development of mesangial proliferation in animal models [11, 34, 35, 37]. Finally, neutralization of both ligands reduced the progressive course and sequelae in progressive mesangioproliferative GN models [38–40] (Figure 3). The activation of mesangial cells towards a profibrotic (or ‘prosclerotic’) phenotype was also reduced in the above-mentioned interventional studies. Taken together, a large body of evidence supports the role of the PDGFR-β– PDGF-BB and -DD axis in mesangial cell proliferation and mesangial sclerosis. We found no major differences in mesangial cells stimulated with PDGF-BB (ligand for both PDGFR-α and -β) versus PDGF-DD (PDGFR-β-specific ligand) [16]. Mesangial cells express PDGFR-α and are responsive to PDGF-CC in vitro. Furthermore, PDGF-CC is de novo expressed in podocytes in IgA nephropathy [20, 41]. However, in vivo, the PDGFR-α–PDGF-CC axis does not seem to play a role in mesangial proliferation [17]. Similarly, in nephrogenesis (see above) there is no indication that the PDGFR-α–PDGF-CC axis participates in the development of the mesangium [11].

Other glomerular diseases Increased expression of both PDGFR-β and PDGF-BB in cells of glomerular crescents was demonstrated previously in human renal biopsies [49, 50]. In rats with anti-GBM nephritis, both PDGFR-β and PDGF-BB were overexpressed in the crescents [51, 52]. The expression of PDGFR-α and of the other ligands in crescentic GN is yet unknown. There are some interventional studies that used non-specific inhibitors that also affect PDGF signalling in models of crescentic GN [53–55]. Both trapidil, and more recently also imatinib, ameliorated the course of the crescentic GN models, the latter most likely via reduced macrophage influx. These studies are promising but they could not distinguish to what extent the beneficial effects were mediated specifically via inhibition of PDGF signalling. This is, however, a general problem of studies using non-specific and multi-kinase inhibitors such as imatinib (see below). Some data showed that the expression of both ‘classical’ PDGFs and PDGFRs were increased in humans and animals with lupus nephritis [49, 56]. Two studies showed that treatment with imatinib reduced the severity of nephritis in animal models [57, 58]. It is not clear, whether these were direct effects on the kidney or whether imatinib acted primarily on the immune response. Interestingly, serum PDGF-DD was significantly reduced in patients with lupus nephritis compared with both healthy controls and patients with other glomerular diseases [46]. The importance of this finding remains completely unclear. In a mouse model of mixed cryoglobulinaemia with associated membranoproliferative GN, the expression of PDGF-BB and PDGFR-β was increased and imatinib treatment ameliorated the disease [59, 60]. Scarce or no data exist on the potential role of PDGFs in other glomerular diseases. For example, patients with membranous nephropathy expressed PDGF-CC de novo in podocytes [20]. Mesangial proliferation and activation is observed in all of the above-mentioned glomerular diseases. Whether PDGFs play a role in these glomerular diseases beyond their effects on mesangial cell proliferation remains unclear.

P. Boor et al.

PDGF-CC was shown to be pro-angiogenic [61]. We have recently shown that PDGF-CC accelerated capillary healing in mesangioproliferative GN, and its inhibition aggravated renal injury in both rat mesangioproliferative GN and in a murine model of thrombotic microangiopathy [17]. These effects were VEGF-independent and were mediated by the direct effects on glomerular endothelial cells and by paracrine effects mediated via macrophages but also via mesangial cells. Although PDGFCC or its inhibition did not alter mesangial cell proliferation, it altered the expression of pro-angiogenic factors by mesangial cells. Hence, PDGF-CC appears to be a novel angiogenic factor for the glomerular endothelium. Hypertensive and diabetic nephropathy PDGF seems to be involved in pulmonary hypertension by acting on vascular smooth-muscle cells and pulmonary vascular remodelling [62, 63]. Although many of the data were generated using imatinib, i.e. a non-specific tyrosine-kinase inhibitor (TKI), first clinical phase II and III trials suggested a prolonged efficacy of imatinib treatment in patients with severe pulmonary hypertension [63]. PDGFs may also play a role in systemic (arterial) hypertension [7]. In rats, PDGF-BB, but not PDGF-AA or -AB, exerted hypotensive effects mediated via nitric oxide (NO) [64]. In two different rat models with malignant hypertension imatinib reduced renal damage but had no effect on blood pressure [65, 66]. It was also shown that PDGF-AA inhibition reduced renal injury in spontaneously hypertensive stroke-prone rats without affecting the blood pressure [67]. Thus, PDGFs are essential factors involved in atherosclerosis, vessel remodelling and kidney damage in hypertension, whereas effects on systolic blood pressure itself seem to be limited [7]. PDGFs are also up-regulated in diabetic nephropathy [11, 68]. Imatinib and postnatal genetic deletion of PDGFR-β both reduced renal injury, in particular mesangial expansion, in different murine models of diabetic nephropathy [69, 70]. Recently, PDGFR-α signalling was shown to be essential for maintenance of proliferation of insulin-producing pancreatic β-cells [71]; it is, therefore, possible that PDGFs might be involved in diabetic nephropathy and diabetes even beyond the role in mesangial expansion. Interstitial fibrosis Both PDGF receptors and all ligands are up-regulated in fibrosis [11, 20, 21, 23, 41]. A number of studies analysed the role of PDGF inhibition in progressive models of mesangioproliferative, crescentic or other glomerular diseases (see above). Some studies initiated the treatment late after induction of the disease, i.e. at a time when glomerular disease had progressed to tubulointerstitial injury [38]. However, none of these studies could clearly distinguish between effects of PDGF inhibition in glomeruli versus the tubulointerstitium. Few experimental studies have addressed the role of PDGF in models of tubulointerstitial fibrosis. One week of high-dose PDGF-BB injections induced proliferation of interstitial fibroblasts and their differentiation to myofibroblasts and fibrosis, but also apoptosis of these cells was observed [72]. Interestingly, PDGF-AA injections had no such effects [72]. However,

i50


FULL REVIEW

In a rat model of mesangioproliferative GN, serum PDGFDD increased up to 1000-fold [35]. This prompted us to analyse serum levels of PDGF-DD in patients with mesangioproliferative (IgA) nephropathy. Compared with healthy controls and patients with various types of GN, serum PDGF-DD was specifically increased in patients with IgA nephropathy [46]. The increase was by far not as robust as in the animal model, and it is unlikely that serum PDGF-DD would become an effective diagnostic biomarker in IgA nephropathy. Still, increased PDGF-DD was also found in children with IgA nephropathy [47]. Taken together, elevated serum levels of PDGF-DD in IgA nephropathy might serve as a biomarker in IgA nephropathy that can potentially guide therapy. Interestingly, none of the four analysed single-nucleotide polymorphisms of PDGF-BB showed an association with the severity of IgA nephropathy [48].

Translation to the clinic Two clinical phase I studies showed that PDGF-DD neutralizing antibody in healthy subjects [81] or a highly specific PDGFR TKI in patients with advanced solid tumours were well tolerated [82]. A PDGFR-β antibody fragment resulted in increased fluid retention in a small study of patients with advanced ovarian or colorectal cancer [83]. To date, no other clinical studies with specific PDGF inhibitors, like antibodies,

i51

CONCLUSIONS The major and best described functions of PDGFs, in particular of PDGFR-β/PDGF-BB and -DD, are their mitogenic role for mesangial cells. The role of PDGF in mesangial activation towards a profibrotic phenotype, i.e. in mesangial sclerosis, was suggested by several interventional studies, but is less well established. Mesangial hypercellularity and sclerosis are found in many glomerular diseases including IgA nephropathy, lupus, diabetes, membranoproliferative GN and hypertension. This can on the one hand explain the renoprotective effects of PDGF inhibition in these diseases (although mostly shown for imatinib), and on the other hand this supports a possible broad clinical applicability of PDGF inhibition. Whether PDGF inhibition has specific effects in glomerular diseases beyond the effects on mesangial cell proliferation and activation remains unclear. PDGFR-α/PDGF-AA and -CC seem to play a role in glomerular capillary healing and angiogenesis and thus lend themselves to studies in thrombotic microangiopathy and other renal conditions characterized by widespread endothelial damage. The other major role of PDGFs seems to be a profibrotic action and thus, PDGF antagonism may become a target in any progressive CKD. Both PDGF receptors -α and -β seem to be involved in proliferation and activation of interstitial fibroblasts. Surprisingly, however, this is far less well described compared with the role of PDGF in mesangial proliferation. Apart from PDGF-CC, PDGF-specific intervention studies in renal fibrosis are missing. Clarification of the role of PDGFs in


FULL REVIEW

Acute kidney injury To date, only one study has suggested a potential renal side-effect of PDGF inhibition. Treatment with either the nonspecific anti-platelet agent trapidil or a multi-kinase inhibitor aggravated renal damage in a model of acute kidney injury [80]. It is unclear whether these effects were indeed mediated by inhibition of PDGFs. Tubular cells do not express PDGFRs which might rather argue against such effects. Indeed, imatinib or neutralizing antibodies to both PDGFRs reduced renal fibrosis in a mouse model of ischaemia-reperfusion injury [21]. However, formal studies are required to exclude that PDGF antagonism interferes with renal recovery in acute kidney injury.

soluble receptors or aptamers, have been published. Considering the data available on TKIs such as imatinib, PDGF-related side-effects could involve defective wound-healing, myelosuppression, fluid retention and cardiovascular and bone toxicity [83–86]. Several pharmaceutical companies have developed or are developing specific PDGF/PDGFR inhibitors mainly for cancer indications [21, 87]. There are a number of established and clinically used TKIs that (also) target PDGFRs, one prototype being imatinib. Imatinib was developed as an inhibitor of the c-abl kinase and is being used successfully for the treatment of chronic myeloic leukaemia. Imatinib is, as the majority of the currently used TKIs, rather non-specific, and inhibits c-kit, PDGFR and c-fms tyrosine kinases. Experimental studies have shown the renoprotective role of imatinib in various models of renal diseases (see above). However, in general it remains unclear to what extent the observed effects can be attributed to the inhibition of PDGFR tyrosine kinase and to what extent these might even be systemic effects [9, 88]. However, the treatment of most renal diseases will require a long-term application which might be hampered by the side-effects of imatinib or similar TKIs (see above). For example, a high number of adverse effects including a new onset of proteinuria were recorded in a phase I/IIa study of 1-year treatment with imatinib in patients with systemic sclerosis-associated interstitial lung disease [89]. This suggests that more targeted therapeutic approaches may be necessary.


no such effects were observed during adenoviral hepatic overexpression or infusion of PDGF-BB [22, 73]. At least in vitro PDGF-DD acted as a mitogen for renal fibroblasts [38]. As for many other diseases, the role of PDGF-AA in tubulointerstitial fibrosis remains unknown. However, mice with a PDGFR-α-activating mutation developed widespread fibrosis in various organs including the kidneys [74]. We showed that both genetic PDGF-C deficiency and neutralizing antibodies to PDGF-CC significantly blunted the development of fibrosis in murine obstructive nephropathy [24]. This effect seems to be kidney specific, since we found no such effects in models of liver fibrosis [75]. At first glance, the profibrotic role of PDGFCC appears inconsistent with its pro-angiogenic activity, since there is considerable evidence that the loss of peritubular capillaries accompanies renal fibrosis and that pro-angiogenic factors, such as VEGF-121, can rescue progressive interstitial damage [76]. Therefore, our own ongoing studies will attempt to assess the relative importance of both processes in renal fibrosis. One elegant study showed that PDGFR-α- and -β-neutralizing antibodies as well as imatinib ameliorated ischaemia and obstruction-induced tubulointerstitial fibrosis in mice; combination treatment with both antibodies was not additive [21]. Another recent study identified Dickkopf-related protein 1 (Dkk-1), an inhibitor of the WNT/β-catenin signalling pathway, as a significant inhibitor of PDGF-BB-induced proliferation of renal pericytes or perivascular fibroblasts in vitro. Dkk-1 was antifibrotic in models of interstitial fibrosis, and also antagonized profibrotic effects of CTGF and TGF-β [77]. Suramin, a non-specific inhibitor of several growth factors including PDGFs, also inhibited renal fibrosis in various models of renal fibrosis [78, 79]. But as with other such molecules it remains unclear to what extent these effects were mediated via PDGF. Taken together, there is mounting evidence that antagonism of PDGFs, in particular PDGF-CC and PDGFR-α, may represent attractive antifibrotic targets.

ischaemia-reperfusion injury and tubular regeneration deserves further studies. Clinical trials are feasible, since various tools to manipulate PDGF signalling have been or are being developed. AC K N O W L E D G E M E N T S This study was supported by financial research grants from the Deutsche Forschungsgemeinschaft to P.B., T.O. and J.F. (SFB TRR57: P25, P17 and Q1) and P.B. (BO 3755/2-1). C O N F L I C T O F I N T E R E S T S TAT E M E N T None declared.

FULL REVIEW

1. Coresh J, Selvin E, Stevens LA et al. Prevalence of chronic kidney disease in the United States. JAMA 2007; 298: 2038–2047 2. Boor P, Ostendorf T, Floege J. Renal fibrosis: novel insights into mechanisms and therapeutic targets. Nat Rev Nephrol 2010; 6: 643–656 3. Samuels JA, Molony DA. Randomized controlled trials in nephrology: state of the evidence and critiquing the evidence. Adv Chronic Kidney Dis 2012; 19: 40–46 4. Ross R, Glomset J, Kariya B et al. A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci USA 1974; 71: 1207–1210 5. Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 1999; 79: 1283–1316 6. Betsholtz C. Insight into the physiological functions of PDGF through genetic studies in mice. Cytokine Growth Factor Rev 2004; 15: 215–228 7. Raines EW. PDGF and cardiovascular disease. Cytokine Growth Factor Rev 2004; 15: 237–254 8. Bonner JC. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev 2004; 15: 255–273 9. Boor P, Floege J. Chronic kidney disease growth factors in renal fibrosis. Clin Exp Pharmacol Physiol 2011; 38: 391–400 10. Tallquist M, Kazlauskas A. PDGF signaling in cells and mice. Cytokine Growth Factor Rev 2004; 15: 205–213 11. Floege J, Eitner F, Alpers CE. A new look at platelet-derived growth factor in renal disease. J Am Soc Nephrol 2008; 19: 12–23 12. Ostendorf T, Eitner F, Floege J. The PDGF family in renal fibrosis. Pediatr Nephrol 2012; 27: 1041–1050 13. Fredriksson L, Li H, Eriksson U. The PDGF family: four gene products form five dimeric isoforms. Cytokine Growth Factor Rev 2004; 15: 197–204 14. Gaboriaud C, Gregory-Pauron L, Teillet F et al. Structure and properties of the Ca(2+)-binding CUB domain, a widespread ligand-recognition unit involved in major biological functions. Biochem J 2011; 439: 185–193 15. Seikrit C, Henkel C, van Roeyen CR et al. Biological responses to PDGFAA versus PDGF-CC in renal fibroblasts. Nephrol Dial Transplant 2013; 28: 889–900 16. van Roeyen CR, Ostendorf T, Denecke B et al. Biological responses to PDGF-BB versus PDGF-DD in human mesangial cells. Kidney Int 2006; 69: 1393–1402 17. Boor P, van Roeyen CR, Kunter U et al. PDGF-C mediates glomerular capillary repair. Am J Pathol 2010; 177: 58–69 18. Li X, Tjwa M, Moons L et al. Revascularization of ischemic tissues by PDGF-CC via effects on endothelial cells and their progenitors. J Clin Invest 2005; 115: 118–127 19. Liu G, Changsirikulchai S, Hudkins KL et al. Identification of plateletderived growth factor D in human chronic allograft nephropathy. Hum Pathol 2008; 39: 393–402

P. Boor et al.

i52


REFERENCES

20. Eitner F, Ostendorf T, Kretzler M et al. PDGF-C expression in the developing and normal adult human kidney and in glomerular diseases. J Am Soc Nephrol 2003; 14: 1145–1153 21. Chen YT, Chang FC, Wu CF et al. Platelet-derived growth factor receptor signaling activates pericyte-myofibroblast transition in obstructive and post-ischemic kidney fibrosis. Kidney Int 2011; 80: 1170–1181 22. Hudkins KL, Gilbertson DG, Carling M et al. Exogenous PDGF-D is a potent mesangial cell mitogen and causes a severe mesangial proliferative glomerulopathy. J Am Soc Nephrol 2004; 15: 286–298 23. Taneda S, Hudkins KL, Topouzis S et al. Obstructive uropathy in mice and humans: potential role for PDGF-D in the progression of tubulointerstitial injury. J Am Soc Nephrol 2003; 14: 2544–2555 24. Eitner F, Bucher E, van Roeyen C et al. PDGF-C is a proinflammatory cytokine that mediates renal interstitial fibrosis. J Am Soc Nephrol 2008; 19: 281–289 25. Bjarnegard M, Enge M, Norlin J et al. Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development 2004; 131: 1847–1857 26. Hellstrom M, Kalen M, Lindahl P et al. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 1999; 126: 3047–3055 27. Lindahl P, Hellstrom M, Kalen M et al. Paracrine PDGF-B/PDGF-Rbeta signaling controls mesangial cell development in kidney glomeruli. Development 1998; 125: 3313–3322 28. Leveen P, Pekny M, Gebre-Medhin S et al. Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev 1994; 8: 1875–1887 29. Bostrom H, Willetts K, Pekny M et al. PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell 1996; 85: 863–873 30. Ding H, Wu X, Bostrom H et al. A specific requirement for PDGF-C in palate formation and PDGFR-alpha signaling. Nat Genet 2004; 36: 1111–1116 31. Li X, Ponten A, Aase K et al. PDGF-C is a new protease-activated ligand for the PDGF alpha-receptor. Nat Cell Biol 2000; 2: 302–309 32. Ricono JM, Wagner B, Gorin Y et al. PDGF receptor-{beta} modulates metanephric mesenchyme chemotaxis induced by PDGF AA. Am J Physiol Renal Physiol 2009; 296: F406–F417 33. Nakagawa T, Izumino K, Ishii Y et al. Roles of PDGF receptor-beta in the structure and function of postnatal kidney glomerulus. Nephrol Dial Transplant 2011; 26: 458–468 34. Floege J, van Roeyen C, Boor P et al. The role of PDGF-D in mesangioproliferative glomerulonephritis. Contrib Nephrol 2007; 157: 153–158 35. Ostendorf T, van Roeyen CR, Peterson JD et al. A fully human monoclonal antibody (CR002) identifies PDGF-D as a novel mediator of mesangioproliferative glomerulonephritis. J Am Soc Nephrol 2003; 14: 2237–2247 36. van Roeyen CR, Eitner F, Boor P et al. Induction of progressive glomerulonephritis by podocyte-specific overexpression of platelet-derived growth factor-D. Kidney Int 2011; 80: 1292–1305 37. Nakamura H, Isaka Y, Tsujie M et al. Electroporation-mediated PDGF receptor-IgG chimera gene transfer ameliorates experimental glomerulonephritis. Kidney Int 2001; 59: 2134–2145 38. Boor P, Konieczny A, Villa L et al. PDGF-D inhibition by CR002 ameliorates tubulointerstitial fibrosis following experimental glomerulonephritis. Nephrol Dial Transplant 2007; 22: 1323–1331 39. Ostendorf T, Kunter U, Grone HJ et al. Specific antagonism of PDGF prevents renal scarring in experimental glomerulonephritis. J Am Soc Nephrol 2001; 12: 909–918 40. Ostendorf T, Rong S, Boor P et al. Antagonism of PDGF-D by human antibody CR002 prevents renal scarring in experimental glomerulonephritis. J Am Soc Nephrol 2006; 17: 1054–1062 41. Eitner F, Ostendorf T, Van Roeyen C et al. Expression of a novel PDGF isoform, PDGF-C, in normal and diseased rat kidney. J Am Soc Nephrol 2002; 13: 910–917 42. van Roeyen CR, Boor P, Borkham-Kamphorst E et al. A novel, dual role of CCN3 in experimental glomerulonephritis: pro-angiogenic and antimesangioproliferative effects. Am J Pathol 2012; 180: 1979–1990


FULL REVIEW

i53

66. Graciano ML, Mitchell KD. Imatinib ameliorates renal morphological changes in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension. Am J Physiol Renal Physiol 2012; 302: F60–F69 67. Kishioka H, Fukuda N, Wen-Yang H et al. Effects of PDGF A-chain antisense oligodeoxynucleotides on growth of cardiovascular organs in strokeprone spontaneously hypertensive rats. Am J Hypertens 2001; 14(5 Pt 1): 439–445 68. Uehara G, Suzuki D, Toyoda M et al. Glomerular expression of plateletderived growth factor (PDGF)-A, -B chain and PDGF receptor-alpha, -beta in human diabetic nephropathy. Clin Exp Nephrol 2004; 8: 36–42 69. Lassila M, Jandeleit-Dahm K, Seah KK et al. Imatinib attenuates diabetic nephropathy in apolipoprotein E-knockout mice. J Am Soc Nephrol 2005; 16: 363–373 70. Suzuki H, Usui I, Kato I et al. Deletion of platelet-derived growth factor receptor-beta improves diabetic nephropathy in Ca(2)(+)/calmodulin-dependent protein kinase IIalpha (Thr286Asp) transgenic mice. Diabetologia 2011; 54: 2953–2962 71. Chen H, Gu X, Liu Y et al. PDGF signalling controls age-dependent proliferation in pancreatic beta-cells. Nature 2011; 478: 349–355 72. Tang WW, Ulich TR, Lacey DL et al. Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast formation and tubulointerstitial fibrosis. Am J Pathol 1996; 148: 1169–1180 73. Floege J, Eng E, Young BA et al. Infusion of platelet-derived growth factor or basic fibroblast growth factor induces selective glomerular mesangial cell proliferation and matrix accumulation in rats. J Clin Invest 1993; 92: 2952–2962 74. Olson LE, Soriano P. Increased PDGFRalpha activation disrupts connective tissue development and drives systemic fibrosis. Dev Cell 2009; 16: 303–313 75. Martin IV, Borkham-Kamphorst E, Zok S et al. Platelet-derived growth factor (PDGF)-C neutralization reveals differential roles of PDGF receptors in liver and kidney fibrosis. Am J Pathol 2013; 182: 107–117 76. Kang DH, Hughes J, Mazzali M et al. Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J Am Soc Nephrol 2001; 12: 1448–1457 77. Ren S, Johnson BG, Kida Y et al. LRP-6 is a coreceptor for multiple fibrogenic signaling pathways in pericytes and myofibroblasts that are inhibited by DKK-1. Proc Natl Acad Sci USA 2013; 110: 1440–1445 78. Liu N, Tolbert E, Pang M et al. Suramin inhibits renal fibrosis in chronic kidney disease. J Am Soc Nephrol 2011; 22: 1064–1075 79. Liu N, Tolbert E, Ponnusamy M et al. Delayed administration of suramin attenuates the progression of renal fibrosis in obstructive nephropathy. J Pharmacol Exp Ther 2011; 338: 758–766 80. Nakagawa T, Sasahara M, Haneda M et al. Role of PDGF B-chain and PDGF receptors in rat tubular regeneration after acute injury. Am J Pathol 1999; 155: 1689–1699 81. Hawthorne T, Giot L, Blake L et al. A phase I study of CR002, a fullyhuman monoclonal antibody against platelet-derived growth factor-D. Int J Clin Pharmacol Ther 2008; 46: 236–244 82. Lewis NL, Lewis LD, Eder JP et al. Phase I study of the safety, tolerability, and pharmacokinetics of oral CP-868,596, a highly specific plateletderived growth factor receptor tyrosine kinase inhibitor in patients with advanced cancers. J Clin Oncol 2009; 27: 5262–5269 83. Jayson GC, Parker GJ, Mullamitha S et al. Blockade of platelet-derived growth factor receptor-beta by CDP860, a humanized, PEGylated di-Fab’, leads to fluid accumulation and is associated with increased tumor vascularized volume. J Clin Oncol 2005; 23: 973–981 84. Margolis DJ, Morris LM, Papadopoulos M et al. Phase I study of H5.020CMV.PDGF-beta to treat venous leg ulcer disease. Mol Ther 2009; 17: 1822–1829 85. Kerkela R, Grazette L, Yacobi R et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006; 12: 908–916 86. Berman E, Nicolaides M, Maki RG et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med 2006; 354: 2006–2013 87. Shen J, Vil MD, Prewett M et al. Development of a fully human antiPDGFRbeta antibody that suppresses growth of human tumor xenografts


43. van Roeyen CR, Eitner F, Scholl T et al. CCN3 is a novel endogenous PDGF-regulated inhibitor of glomerular cell proliferation. Kidney Int 2008; 73: 86–94 44. Riser BL, Najmabadi F, Perbal B et al. CCN3 (NOV) is a negative regulator of CCN2 (CTGF) and a novel endogenous inhibitor of the fibrotic pathway in an in vitro model of renal disease. Am J Pathol 2009; 174: 1725–1734 45. van Roeyen CR, Zok S, Pruessmeyer J et al. Growth arrest-specific protein 1 is a novel endogenous inhibitor of glomerular cell activation and proliferation. Kidney Int 2013; 83: 251–263 46. Boor P, Eitner F, Cohen CD et al. Patients with IgA nephropathy exhibit high systemic PDGF-DD levels. Nephrol Dial Transplant 2009; 24: 2755–2762 47. Rong ZH, Wang C, Hao J et al. Expression and clinical implication of platelet-derived growth factor-D and platelet-derived growth factor-beta in childhood IgA nephropathy. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2008; 20: 275–278 48. Bicanski B, Wenderdel M, Mertens PR et al. PDGF-B gene single-nucleotide polymorphisms are not predictive for disease onset or progression of IgA nephropathy. Clin Nephrol 2007; 67: 65–72 49. Matsuda M, Shikata K, Makino H et al. Gene expression of PDGF and PDGF receptor in various forms of glomerulonephritis. Am J Nephrol 1997; 17: 25–31 50. Waldherr R, Noronha IL, Niemir Z et al. Expression of cytokines and growth factors in human glomerulonephritides. Pediatr Nephrol 1993; 7: 471–478 51. Fujigaki Y, Sun DF, Fujimoto T et al. Mechanisms and kinetics of Bowman’s epithelial-myofibroblast transdifferentiation in the formation of glomerular crescents. Nephron 2002; 92: 203–212 52. Fujigaki Y, Sun DF, Fujimoto T et al. Cytokines and cell cycle regulation in the fibrous progression of crescent formation in antiglomerular basement membrane nephritis of WKY rats. Virchows Arch 2001; 439: 35–45 53. Iyoda M, Shibata T, Kawaguchi M et al. Preventive and therapeutic effects of imatinib in Wistar-Kyoto rats with anti-glomerular basement membrane glomerulonephritis. Kidney Int 2009; 75: 1060–1070 54. Shinkai Y, Cameron JS. Trial of platelet-derived growth factor antagonist, trapidil, in accelerated nephrotoxic nephritis in the rabbit. Br J Exp Pathol 1987; 68: 847–852 55. Iyoda M, Shibata T, Wada Y et al. Long- and short-term treatment with imatinib attenuates the development of chronic kidney disease in experimental anti-glomerular basement membrane nephritis. Nephrol Dial Transplant 2013; 28: 576–584 56. Gesualdo L, Di Paolo S, Milani S et al. Expression of platelet-derived growth factor receptors in normal and diseased human kidney. An immunohistochemistry and in situ hybridization study. J Clin Invest 1994; 94: 50–58 57. Zoja C, Corna D, Rottoli D et al. Imatinib ameliorates renal disease and survival in murine lupus autoimmune disease. Kidney Int 2006; 70: 97–103 58. Sadanaga A, Nakashima H, Masutani K et al. Amelioration of autoimmune nephritis by imatinib in MRL/lpr mice. Arthritis Rheum 2005; 52: 3987–3996 59. Iyoda M, Hudkins KL, Becker-Herman S et al. Imatinib suppresses cryoglobulinemia and secondary membranoproliferative glomerulonephritis. J Am Soc Nephrol 2009; 20: 68–77 60. Taneda S, Hudkins KL, Cui Y et al. Growth factor expression in a murine model of cryoglobulinemia. Kidney Int 2003; 63: 576–590 61. Li X, Kumar A, Zhang F et al. VEGF-independent angiogenic pathways induced by PDGF-C. Oncotarget 2010; 1: 309–314 62. Antoniu SA. Targeting PDGF pathway in pulmonary arterial hypertension. Expert Opin Ther Targets 2012; 16: 1055–1063 63. ten Freyhaus H, Dumitrescu D, Berghausen E et al. Imatinib mesylate for the treatment of pulmonary arterial hypertension. Expert Opin Investig Drugs 2012; 21: 119–134 64. Ikeda M, Morita C, Mizuno M et al. PDGF-BB decreases systolic blood pressure through an increase in macrovascular compliance in rats. Am J Physiol 1997; 273(4 Pt 2): H1719–H1726 65. Schellings MW, Baumann M, van Leeuwen RE et al. Imatinib attenuates end-organ damage in hypertensive homozygous TGR(mRen2)27 rats. Hypertension 2006; 47: 467–474

and enhances antitumor activity of an anti-VEGFR2 antibody. Neoplasia 2009; 11: 594–604 88. Boor P, Sebekova K, Ostendorf T et al. Treatment targets in renal fibrosis. Nephrol Dial Transplant 2007; 22: 3391–3407 89. Khanna D, Saggar R, Mayes MD et al. A one-year, phase I/IIa, open-label pilot trial of imatinib mesylate in the treatment of systemic sclerosis-

associated active interstitial lung disease. Arthritis Rheum 2011; 63: 3540–3546

Received for publication: 19.4.2013; Accepted in revised form: 13.5.2013

Nephrol Dial Transplant (2014) 29: i54–i62 doi: 10.1093/ndt/gft342

Ana B. Sanz1,2, M. Concepcion Izquierdo1,2, Maria Dolores Sanchez-Niño2,3, Alvaro C. Ucero1,2, Jesus Egido1,4,5, Marta Ruiz-Ortega1,2,4, Adrián Mario Ramos1,2, Chaim Putterman6,* and Alberto Ortiz1,2,4,5,* Dialysis Unit, IIS-Fundacion Jimenez Diaz, Madrid, Spain, 2REDinREN, Madrid, Spain, 3IDIPAZ, Madrid, Spain, 4Universidad Autonoma de

FULL REVIEW

1

Madrid, Madrid, Spain, 5IRSIN, Madrid, Spain and 6Albert Einstein College of Medicine, New York, USA

Correspondence and offprint requests to: Alberto Ortiz; E-mail: [email protected] * Contributed equally.

A B S T R AC T Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) activates the fibroblast growth factor-inducible-14 (Fn14) receptor. TWEAK has actions on intrinsic kidney cells and on inflammatory cells of potential pathophysiological relevance. The effects of TWEAK in tubular cells have been explored in most detail. In cultured murine tubular cells TWEAK induces the expression of inflammatory cytokines, downregulates the expression of Klotho, is mitogenic, and in the presence of sensitizing agents promotes apoptosis. Similar actions were observed on glomerular mesangial cells. In vivo TWEAK actions on healthy kidneys mimic cell culture observations. Increased expression of TWEAK and Fn14 was reported in human and experimental acute and chronic kidney injury. The role of TWEAK/Fn14 in kidney injury has been demonstrated in non-inflammatory compensatory renal growth, acute kidney injury and chronic kidney disease of immune and non-immune origin, including hyperlipidaemic nephropathy, lupus nephritis (LN) and antiGBM nephritis. The nephroprotective effect of TWEAK or Fn14 targeting in immune-mediated kidney injury is the result of protection from TWEAK-induced injury of renal © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

intrinsic cells, not from interference with the immune response. A phase I dose-ranging clinical trial demonstrated the safety of anti-TWEAK antibodies in humans. A phase II randomized placebo-controlled clinical trial exploring the efficacy, safety and tolerability of neutralizing anti-TWEAK antibodies as a tissue protection strategy in LN is ongoing. The eventual success of this trial may expand the range of kidney diseases in which TWEAK targeting should be explored. Keywords: apoptosis, clinical trials, fibrosis, inflammation, necroptosis, proteinuria

INTRODUCTION Tumour necrosis factor-like weak inducer of apoptosis [TWEAK, Apo3L, tumour necrosis factor superfamily (TNFSF)12] is a cytokine that belongs to the TNFSF that activates Fibroblast growth factor-inducible-14 (Fn14, TWEAK receptor, TNFRSF12A, CD266), a TNF receptor superfamily (TNFRSF) protein [1–4]. In recent years, evidence has accumulated supporting a role for TWEAK activation of intrinsic renal cell Fn14 receptors in the pathogenesis of acute and chronic kidney injury, glomerular and tubulointerstitial damage and non-immune and i54


TWEAK and the progression of renal disease: clinical translation

Vascular endothelin and renal disease progression.

Sulodexide and glycosaminoglycans in the progression of renal disease.

Targeting CTGF, EGF and PDGF pathways to prevent progression of kidney disease.

Hyperuricemia after orthotopic liver transplantation: divergent associations with progression of renal disease, incident end-stage renal disease, and mortality.

A possible mechanism for the progression of chronic renal disease and congestive heart failure.

PDGF-AA and PDGF-BB biosynthesis: proprotein processing in the Golgi complex and lysosomal degradation of PDGF-BB retained intracellularly.

The association between acute kidney injury in renal infarction and progression to chronic kidney disease.

Temporal profile of the renal transcriptome of HIV-1 transgenic mice during disease progression.

Synaptic plasticity and PDGF signaling defects underlie clinical progression in multiple sclerosis.

Protein restriction and the progression of renal insufficiency.

Association of Renal Elasticity and Renal Function Progression in Patients with Chronic Kidney Disease Evaluated by Real-Time Ultrasound Elastography.

Shape of the relationship between hypertension and the rate of progression of renal failure in autosomal dominant polycystic kidney disease.

Sustained uremic toxin control improves renal and cardiovascular outcomes in patients with advanced renal dysfunction: post-hoc analysis of the Kremezin Study against renal disease progression in Korea.

FoxO3a and disease progression.

Expression of platelet-derived growth factor (PDGF) and PDGF receptor genes in the developing rat brain.

TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression.

GFOD1 and peejar are promising markers for clear-cell renal cell carcinoma disease progression.

Progression of chronic renal failure in man.

Effect of receptor kinase inactivation on the rate of internalization and degradation of PDGF and the PDGF beta-receptor.

Progression of Parkinson's disease.

The axis of progression of disease.

Progression of scleral disease.

Renal Interstitial Fibrosis: An Imperfect Predictor of Kidney Disease Progression in Some Patient Cohorts.

Lipids in the progression of chronic renal failure.