0013-7227/90/1261-0273$02.00/0 Endocrinology Copyright © 1990 by The Endocrine Society
Vol. 126, No. 1 Printed in U.S.A.
Tumor Necrosis Factor and Interleukin-1 May Regulate Renin Secretion* I. ANTONIPILLAI, Y. WANG, AND R. HORTON University of Southern California Medical Center, Section of Endocrinology, Los Angeles, California 90033
ABSTRACT. Cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1) are not only immunoregulatory polypeptides, but may have endocrine functions. We have studied the direct effects of recombinant and purified TNF and IL-1 on renln secretion using both static incubations and perifusions of rat renal cortical slices. Ultrapure human IL-1 (hIL-1) at concentrations as low as 5 U/ml (3 x 10~12 M) significantly stimulated renin secretion (control, 98 ± 4%; hIL-1, 153 ± 13%; P < 0.01). TNF similarly induced renin release [control, 97 ± 6%; TNF (10 U/ml), 151 ± 13%; P < 0.005]. TNF and recombinant human 1L-1/3 (rhlL-i^S) also blocked the inhibitory actions of angiotensin-II (All) on renin release [control, 100 ± 3%; All (2 x 10"7 M), 80 ± 5%; All plus TNF (20 U/ml), 102 ± 7%; All plus rhIL/3 (10 U/ml), 106 ± 6%; both P < 0.02 vs. All]. A cyclooxy-
M
ONOCYTES and activated macrophages release a group of factors that influence inflammation and tissue regulation. Tumor necrosis factor (TNF) and interleukin-1 (IL-1), two major cytokines, are part of this group of factors which mediate a variety of actions important in host defense, inflammation, and autoimmunity (1-4). Although unrelated to each other in their amino acid sequences and known to recognize separate receptors, TNF and IL-1 are surprisingly similar in many of their actions (2). Both stimulate IL-1 synthesis in monocytes or endothellal cells as well as induce IL-2 receptors, activate T, B, and natural killer cells, and stimulate synthesis of IL-6 (2, 5, 6). In addition, TNF and IL-1 have hormone-like actions that extend beyond the immune system. For instance, IL-1 can participate not only in the stress response by increasing ACTH and cortisol levels when injected into mice (7), but can also directly stimulate the secretion of hypothalamlc CRF as well as ACTH, LH, GH, and TSH from the pituitary (8, 9). Similarly, TNF can alter thyroid hormone metabo-
genase (CO) blocker, meclofenamate (M), which does not significantly alter basal renin release, attenuated the TNF- and rhlL10-induced renin secretion [TNF (20 U/ml), 132 ± 11%; TNF plus M (5 x 10-B M), 100 ± 3% (P < 0.01); rhIL-1/3 (10 U/ml), 135 ± 9%; rhIL-1/3 plus M, 105 ± 10% (P < 0.05)]. The stimulatory effects of TNF and IL-1 on renin were reversible. These results suggest that IL-1 and TNF are renin secretagogues and can also block the inhibitory actions of All on renin. Since the effect of TNF and IL-1 on renin can be blocked by a (CO) inhibitor, the studies indicate a role of prostaglandins in their action. Therefore, locally produced TNF and IL-1 may play an important paracrine role in regulation of the renin-anglotensin system. {Endocrinology 126: 273-278, 1990)
lism (10), follicular steroidogenesis (11), and ovarian function (12). IL-1 can also modulate glucose-dependent insulin release from isolated rat islets (13). Both TNF and IL-1 can act directly on vascular endothelial and smooth muscle cells to increase the secretion of prostacyclin (PGI2) (14-16). Juxtaglomerular (JG) cells of the kidney are modified vascular smooth muscle cells (17). Since PGI2 is a potent renin secretogogue in these cells (18-20), there is a possibility that TNF and IL-1 may play a role in the regulation of renin secretion. No studies of the effects of TNF and IL-1 on the renin-angiotensin system have been described. The recent availability of highly purified and recombinant IL-1 and -2 as well as TNF prompted us to examine their effects on renin release. Materials and Methods Recombinant human TNFa/cachectin (SA, 107 U/mg protein) was obtained from Amgen Biological (Thousand Oaks, CA). Ultrapure human IL-1 (hIL-1; SA, 108 U/mg protein), recombinant human IL-1/3 (rhIL-i/3; SA, 108 U/mg protein), and recombinant IL-2 (SA, 3 x 106 U/mg protein) were purchased from Genzyme Corp. (Boston, MA). Pentex BSA (fatty acid-free fraction V) was obtained from Miles Laboratories (Naperville, IL). Meclofenamate (M) was a gift from Warner Lambert Co. (Ann Arbor, MI). Male Sprague-Dawley rats (150-250 g) were killed by decapitation. The superficial slices from the dorsal and ventral sides
Received August 1,1989. Address requests for reprints to: Dr. Indra Antonipillai, Section of Endocrinology, University of Southern California, 2025 Zonal Avenue, Los Angeles, California 90033. * This work was supported by NiH First Award DK-39204 (to LA.) and Research Grant HL-21112 (to R.H.). Presented in part in abstract form at the 71st Annual Meeting of The Endocrine Society, Seattle, WA, 1989.
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of the kidney (0.5 mm thick) were used for static incubation and perifusion experiments (Endotronics Acusyst S Perifusion System, Marietta, OH). For static incubations, slices (15-30 mg) were washed with Krebs-Ringer bicarbonate with glucose (KRBG) medium containing 0.1 BSA. Slices were then preincubated in a metabolic shaker, saturated with 95% O2-5% CO2 at 37 C for 30 min, and incubated for two consecutive 1-h incubation periods. Each slice was incubated for a 1-h baseline period, after which various agents were added. The response to an agent was observed for the next 1-h period, thus enabling each slice to serve as its own control (20). The standard KRBG medium contained (in millimolar concentrations): 120 NaCl, 4.7 KC1,1.2 MgSO4, 2.5 CaCl2, 1.2 KH2P04, 26.8 NaHCO3, and 10 glucose, pH 7.4. For perifusions, slices were placed in culture chambers and perifused with KRBG buffer at a flow rate of 0.5 ml/ml, as described previously (21). After an initial 60-min stabilization period, 5-min fractions were collected. After a 30min baseline sampling, the agents were dissolved in 30 ml KRBG buffer and perifused over a 30-min period. This was followed by a control KRBG buffer for a period of 40 min. TNF, IL-1, and IL-2 were dissolved in KRBG buffer with 0.1% BSA and freshly prepared on ice just before use, whereas M was dissolved in ethanol. The final concentration of ethanol in KRBG medium was 0.05%. This concentration of ethanol was also added to control incubations not exposed to test compounds and did not influence the release of renin. Renin activity in the supernatant of the incubations or perifusion medium was determined by a RIA that measures the generation of angiotensin-I (AI) by the method of Haber et al. as described previously (20-22).In the static incubation model, renin release during the second hour of incubation was expressed as the percentage of basal release in the same slice during the first 1h period, in the perifusion experiments renin release during each collection period was expressed as the percentage of basal release in the same chamber during the first collection period (0-10 min). Statistical significance was determined with analysis of variance, unpaired t tests, and a multiple comparison method (using either Duncan's or Dunnett's test wherever appropriate), as previously described (20-22).
Results Effects of TNF and IL on renin release Renin secretion by the cortical slices was relatively stable during two consecutive 1-h periods (first hour, 100%; second hour, 94 ± 4%). The absolute levels of renin release exhibited considerable variation between incubations even when corrected for slice weight, as indicated previously by us (22) as well as others (23), but values within the same slice did not greatly differ. This finding emphasizes the importance of using each slice as its own control. In static incubations, TNF (1 and 5 U/ml) increased renin slightly at 1 h (Fig. 1), but 10 U/ml (or 1000 pg/ ml) TNF significantly increased renin release compared with that in control slices (control, 97 ± 6%; TNF, 151
Endo • 1990 Vol 126 • No 1
180
160
140
120
100
CONTROL
1(0.1)
5(0.5)
10(1)
50(5)
TNF Units (ng)/ml
FIG. 1. Dose-related stimulatory action of TNF on renin release by rat renal cortical slices. The effect of TNF is expressed as a percentage of baseline at 1 h. Each value represents the mean ± SEM of five to seven separate sets of experiments. *, P < 0.005 vs. control.
± 13%; P < 0.005). A higher concentration (50 U/ml) did not further stimulate renin release (179 ± 24%). Ultrapure hIL-1 also markedly stimulated renin secretion. As little as 5 U/ml (or 50 pg/ml) significantly stimulated renin release to 153 ± 13% of the control value (P < 0.01; Fig. 2) compared to TNF, which at a concentration of 1000 pg/ml induced similar increases in renin secretion. Similar effects were observed using recombinant hIL-1/3 [control, 100 ± 5%; rnIL-1/? (10 U/ ml), 135 ± 9%]. In contrast to the effects of IL-1, IL-2 at concentrations from 2-25 U/ml had no effect on basal renin release [control, 93 ± 9%; IL-2 (25 U/ml), 100 ± 8%). To fully evaluate the more definitive roles of TNF, perifusion studies were performed. Renin release in control slices was relatively stable over the 100-min period (Fig. 3). TNF caused a sustained increase in renin secretion over the control slices after 20 min (Fig. 3). Reversibility of the effects of TNF on JG cell function In separate experiments, when slices were exposed to TNF (50 U/ml) for 1 h, there was stimulation of renin release (140 ±7%). When these same slices were washed twice with KRBG buffer (wash period) and then reincubated, renin secretion returned to control levels (111 ±2%). When TNF (10 U/ml) was then added after a
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release to 80 ± 5% of the control value (P < 0.01). Both TNF (20 U/ml; 1.2 X 1010 M) and rhIL-1/3 (10 U/ml; 6 X 10"12 M) blocked the All inhibition of renin release (All plus TNF, 102 ± 7%; All plus rhIL-1/3, 106 ± 10%; P < 0.02; Fig. 4).
180
160
Effects of M, a cyclooxygenase (CO) blocker, on TNF and IL-induced renin release
140
120
100
CONTROL
1(10)
2.5(25)
5(50)
10(100)
To study the potential regulatory role of prostaglandins in TNF and IL-1 action, the CO blocker M was used, since indomethacin may have some nonspecific inhibitory actions (24, 25). M (50 /uM) had no significant effect by itself on basal renin release (control, 100 ± 4%; M, 111 ± 5%), but significantly blocked the stimulatory effects of both TNF and rhIL-1,8 on renin release (TNF, 132 ± 11%; TNF plus M, 100 ± 3%; rhIL-1/3, 135 ± 9%; rhIL-1/3 plus M, 105 ± 10%; both P < 0.05; Fig. 5).
hlL-1 Unit* (pg)/ml
FIG. 2. Effects of hIL-1 on renin release by rat renal cortical slices at 1 h. Values (percentage of control) are the mean ± SEM, representing five to eight experiments. *, P < 0.01 vs. control. 180r
140
100
0
I
20
40
60
TNF (10 u/ml)
FIG. 3. Effects of TNF on renin secretion in perifused rat renal cortical slices. Perifusions were performed as indicated in the text. Results are expressed as the percentage of each basal renin release during the first 0-10 min. Values represent the mean ± SEM of five to six experiments. TNF significantly stimulated renin release after 20 min. *, P < 0.05.
Discussion The list of target tissues for the monokines IL-1 and TNF continues to expand. Endocrine tissues appear particularly sensitive to these cytokines. In the present report evidence is presented that both TNF and IL-1 exert a stimulatory effect on JG cell renin release. This increase occurs in a dose-related manner over a range of 10-i2_10-io M T h e g e c o n c e n t r a t i o n s o f TNF and IL-1 are similar to the concentrations that induce other well established in vitro effects, such as induction of PGI2 synthesis in human vascular endothelial cells (16) or FSH-induced aromatase activity in cultured granulosa cells (12). In our studies we used both purified natural hIL-1 and rhIL-10 (an IL with a pi of 7.0), an isoform known to show some of the major effects of IL-1 (26). 1201-
wash period, there was another increase in renin release (155 ± 5%). Similarly, when isoproterenol (106 M) was added after a wash period, TNF-treated slices responded in a manner similar to slices that were exposed to isoproterenol alone. With isoproterenol (106 M), renin release was stimulated at 1 h to 186 ± 13% and at 2 h to 159 ± 7% of control values. Sequential addition of TNF and isoproterenol stimulated renin release to 158 ± 13% at 1 h and to 172 ± 12% of the basal value at 2 h. Similar results (data not shown) were obtained using hIL-1. CONTROL
Effects of TNF and IL-1 on All-mediated renin release The roles of TNF and IL-1 were also evaluated in Allinduced renin inhibition. All (2 X 10'7 M) decreased renin
All (2x10'7M)
rhlL-1p 10M/ITII
FIG. 4. Effects of TNF and rhIL-1/3 on All-mediated renin inhibition by rat renal cortical slices. The results are expressed as the mean ± SEM, representing five to seven experiments. *, P < 0.02 vs. All.
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276 160 r
(5x10-5 M)
FIG. 5. Effects of a CO blocker, M, on TNF- and rhIL-l/3-induced renin secretion. Values represent the mean ± SEM of five to eight experiments. *,P< 0.05 us. TNF or rhIL-1/3.
Both preparations similarly increased renin release. These effects of IL-l/TNF were seen not only in a static incubation system, but also in a perifusion system, which is considered more physiological, since products from slices and medium are constantly washed out, and the contents of the medium are kept constant. The stimulation of renin release by TNF/IL-1 was completely reversible after removal of TNF. Furthermore, the renin response to another secretogogue, such as isoproterenol, was intact, suggesting that these effects are notcytotoxic and that TNF/IL-1 can produce reversible stimulation of renin without general damage to the JG cell. Similarly, stimulation of insulin release in rat islets (27) or PGE2 production by lung fibroblasts (28) is reversible after TNF or IL-1 removal. TNF and IL-1 in concentrations as little as 10"12-10"10 M blocked the inhibitory effects of All on renin, suggesting that these two monokines might act in vivo to block or alter angiotensin feedback. These studies are consistent with those made by our group on adrenal zona glomerulosa cells, where both TNF and IL-1 also block the All-induced aldosterone secretion (29). Arachidonic acid products, specifically prostaglandins, have been shown to play a role in induction of TNF and IL-1 actions in vivo as well as in vitro in a variety of cell types (1416). In the present studies a CO inhibitor, M, at doses that have been shown to markedly inhibit prostaglandin formation (25) significantly attenuated both TNF- and IL-1-induced renin release. These studies suggest that, like many other systems, prostaglandin action may be an important step in TNF/IL-1-induced renin secretion. The cellular mechanisms by which these cytokines act
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on renin release were not assessed here. In other systems TNF and/or IL-1 can induce changes in intracellular cAMP (6, 30), activate phospholipase-A2 and -C (31, 32), initiate hydrolysis of phosphoinosltide (13) production of diacylglycerol (31, 33), as well as involve subcellular redistribution and activation of protein kinase-C systems (34). It is well known that in addition to cAMP and calcium, which play an important second messenger role in renin release (22, 35, 36), all of the above events directly or indirectly can induce changes in renin secretory processes (35-38). Although actions of prostaglandins on renin have been linked to adenylate cyclase systems (39), both cAMP and calcium can act in a concerted fashion (25, 35, 36, 38). TNF and IL-1 can bind specifically to endothelium (40) and initiate a wide variety of changes on vascular smooth muscle and endothelial cells (2, 41) For example, both induce the synthesis of PGI2 in endothelial cells (15). In addition, IL-1 is a potent inhibitor of vascular smooth muscle contractility (41). Since the cells that make renin are derived from vessel cells, bear a close anatomical relationship with endothelium, and respond to PGI2 by increasing renin secretion, it is not surprising that TNF and IL-1 have stimulatory actions. The effects of these cytokines on renin are acute (minutes) and are, therefore, not due to mitogenesis (or growth). In some other systems, such as progesterone production by ovarian follicles (11) or FSH-induced aromatase activity (12), a lag period of 24 h or longer is required for TNF action. The rapid effects of these cytokines on renin release suggests that they act either by inducing direct secretion of stored renin or by converting inactive to active renin (42). This latter action would be via activating a protease (42). An action on a tissue protease (plasminogen inhibitor) has been observed with IL-1 (43). These effects probably also include an action via prostaglandin formation, since the action of IL-1 and TNF on renin was blocked by M. It is interesting to consider the physiological relevance of these observations. IL-1 is synthesized by virtually every nucleated cell type (4), and although concentrations of TNF are low under normal circumstances, serum concentrations of both TNF and IL-1 can markedly increase when animals are exposed to endotoxin (44, 45). The concept that these macrophage-monocyte-derived soluble products influence hormone secretion is not new (8-13). It is interesting to note that Zipser et al. (46) described a syndrome of hyperreninemic hypoaldosteronism in critically ill patients. Patients with this syndrome have increased levels of renin with inappropriately low concentrations of plasma aldosterone. Although no known regulators of renin-AII-aldosterone could explain this phenomenon, major infections and septicemia were common underlying illnesses. Recent reports indicate
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CYTOKINES AND RENIN SECRETION that levels of these cytokines are markedly increased in septisemla (1-4, 47). Since the kidney not only possesses high affinity receptors for TNF (48), and renal glomeruli synthesize and respond to a number of cytokines, including IL-1 (49, 50), increased local glomerular production of TNF along with IL-1 may have contributed to the altered renin-AII-aldosterone axis in hyperreninemlc hypoaldosteronism. In summary, our study demonstrates that TNF and IL-1 are extremely potent as renin secretogogues and have the ability to block the action of All on renin secretion. These paracrine factors may be involved in states where a discrepancy exists between renin-angiotensin levels and aldosterone secretion.
17. 18. 19. 20. 21. 22. 23.
Acknowledgments
24.
We thank Michael Halim for the technical assistance and Jenny Yang for typing the manuscript.
25.
References
26.
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and TNF on induction of prostacycl in synthesis in human vascular endothelial cells. Biochem Biophys Res Commun 156:1007 Barajas L 1979 Anatomy of the juxtaglomerular apparatus. Am J Physiol 237:F333 Oates JA, Whorton R, Gerkers JF, Branch RA, Hollifield JW, Frolich JC 1979 The participation of prostaglandlns in the control of renin release. Fed Proc 38:72 McGiff JC, Spokas EG, Wong PYK 1982 Stimulation of renin release by 6-oxoPGEi and prostacycl in. Br J Pharmacol 75:137 Antonipillai I, Nadler J, Robin EC, Horton R 1987 The inhibitory role of 12 and 15 lipoxygenase products on renin release. Hypertension 10:61 Antonipillai I, Nadler J, Horton R 1988 Angiotensin feedback inhibition on renin is expressed via the lipoxygenase pathway. Endocrinology 122:1277 Antonipillai I, Horton R 1985 Role of extra and intracellular calcium and calmodul in on renin release from rat kidney. Endocrinology 117:601 Naftilan AJ, Oparil S 1982 The role of calcium in the control of renin release. Hypertension 4:670 Kojima I, Kojima K, Rasmussen H 1985 Possible role of phospholipase A2 action and arachidonic acid metaoblism in angiotensin II-mediated aldosterone secretion. Endocrinology 117:1057 Churchil PC, Savoy-Moore RT, Churchill MC 1983 Lack of relationship between prostaglandin E2 release and renin secretion in rat renal corticol slices. J Pharmacol Exp Ther 226:46 Bendtzen K, Mandrup-Poulsen T, Nerup J, Nielsen JH, Dinarello CA, Svenson M 1986 Cytotoxicity of human PI 7 interleukin 1 for pancreatic islets of Langerhams. Science 232:1545 Rabinovitch A, Pukel C, Baquerizo H 1988 IL-1 inhibits glucosemediated insulin and glucagon secretion in rat islet monolayer cultures. Endocrinology 122:2393 Elias JA, Custilo K, Baeder W, Freudich B 1987 Synergistic stimulation of fibroblast prostaglandin production by recombinant IL1 and TNF. J Immunol 138:3812 Horton R, Antonipillai I, Natarajan R, Nadler J 1989 The effect of tumor necrosis factor and interleukin-1 on the renin-angiotensin system. Clin Res 37:532A (Abstract) Baud L, Perez J, Frienlander G, Ardaillou 1988 TNF stimulates prostaglandin production and cAMP levels in rat cultured mesangial cells. FEBS Lett 239:50 Kester M, Simonson MS, Mene P, Sedor JR 1988 IL-1 generates transmenbrane signals from phosphollplds through novel pathways in cultured rat mesangial cells. J Clin invest 83:718 Godfrey PW, Johnson WJ, Newman T, Hoffstein ST 1988 IL-1 and TNF are not synergistic for human synovial fibroblast PLA2 activation and PGE2 production. Prostaglandin 35:107 Rosoff PM, Savage N, Dinarello CA 1988 IL-1 stimulates diacylglycerol production in T lymphocytes by a novel mechanism. Cell 54:73 Levine L, Xiao DM 1985 The stimulation of arachidonic acid metabolism by recombinant murine IL-1 and tumor promotors or l-oleoyl-2-acetyl-glycerol are synergistic. J immunol 135:3430 Keeton TK, Campbell WB 1981 The pharmacologic alteration of renin release. Pharmacoi Rev 32:81 Churchill PC 1985 Second messenger in renin secretion. Am J Physiol 249:F175 Kurtz A, Pefilschifter J, Hutter A, Buhrle C, Nobiling R, Taugner R, Hackenthal E, Bauuer C 1986 Role of protein kinase C in inhibition of renin release by vasoconstrictors. Am J Physiol 250:C563 Fray JCS, Park CS, Valentine ANP 1987 Calcium and the control of renin secretion. Endocr Rev 8:53 Campbell WB, Graham RM, Jackson EK 1979 Role of renal prostaglandin in sympathetically mediated renin release in rat. J Clin Invest 64:448 Kull Jr FC, Jacobs S, Cuatrecasas P 1985 Cellular receptor for 1251-labeled TNF: specific binding affinity labeling and relationships to sensitivity. Proc Natl Acad Sci 82:5756 Beasley D, Cohen RA, Levinsky NG 1989 IL-1 inhibits contraction of vascular smooth muscle. J Clin Invest 83:331 Sealey JE, Atlas SA, Laragh JH 1980 Prorenin and other large
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molecular weight forms of renin. Endocr Rev 1:365 43. Emeis JJ, Koolstra T 1986 Interleukin-1 and lipopolysaccharide induce an inhibitor of tissue type plasminogen activator in vivo and in vitro in cultured endothelial cells. J Exp Med 163:1260 44. Michie HR, Manogue KR, Spriggs DR, Revhaug A, O'Dwyer S, Dinarello CA, Ceraml A, Wolfes SM, Wilmore DW 1988 Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 318:1481 45. Neta R, Oppenheim JJ 1988 Why should internists be interested in IL-1. Intern Med 109:1 46. Zipser RD, Davenport MW, Mantin KL, Tuck ML, Warner NE, Swinney RR, Davis CL, Horton R 1981 Hyperreninemic hypoaldosteronism in the critically ill: a new entity. J Clin Endocrinol
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Metab 53:867 47. Giarardin E, Grau GE, Dayer JM, Roux P, Lombard PR 1988 The J5 study group and P.H. Lambert TNF and IL-1 in the serum of children with severe infectious purpura. N Engl J Med 319:397 48. Beutler B, Mahoney J, Letrang N, Pekala P, Ceraml A 1985 Purification of cachectln, a lipoprotein lipase suppressing hormone secreted by endotoxin induced RAW 264.7 cell. J Exp Med 161:984 49. Schlondoroff D 1987 The glomerular mesangial cell: an expanding role for a specialized perlcyte. FASEB J 1:272 50. Werber HI, Emancipator SN, Tykoclnskl, Sedor JR 1987 The IL1 gene is expressed by rat glomerular mesangial cells and is augmented in immune complex glomerulonephritis. Immunology 138:3207
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Vol. 126, No. 1 Printed in U.S.A.
Tumor Necrosis Factor and Interleukin-1 May Regulate Renin Secretion* I. ANTONIPILLAI, Y. WANG, AND R. HORTON University of Southern California Medical Center, Section of Endocrinology, Los Angeles, California 90033
ABSTRACT. Cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1) are not only immunoregulatory polypeptides, but may have endocrine functions. We have studied the direct effects of recombinant and purified TNF and IL-1 on renln secretion using both static incubations and perifusions of rat renal cortical slices. Ultrapure human IL-1 (hIL-1) at concentrations as low as 5 U/ml (3 x 10~12 M) significantly stimulated renin secretion (control, 98 ± 4%; hIL-1, 153 ± 13%; P < 0.01). TNF similarly induced renin release [control, 97 ± 6%; TNF (10 U/ml), 151 ± 13%; P < 0.005]. TNF and recombinant human 1L-1/3 (rhlL-i^S) also blocked the inhibitory actions of angiotensin-II (All) on renin release [control, 100 ± 3%; All (2 x 10"7 M), 80 ± 5%; All plus TNF (20 U/ml), 102 ± 7%; All plus rhIL/3 (10 U/ml), 106 ± 6%; both P < 0.02 vs. All]. A cyclooxy-
M
ONOCYTES and activated macrophages release a group of factors that influence inflammation and tissue regulation. Tumor necrosis factor (TNF) and interleukin-1 (IL-1), two major cytokines, are part of this group of factors which mediate a variety of actions important in host defense, inflammation, and autoimmunity (1-4). Although unrelated to each other in their amino acid sequences and known to recognize separate receptors, TNF and IL-1 are surprisingly similar in many of their actions (2). Both stimulate IL-1 synthesis in monocytes or endothellal cells as well as induce IL-2 receptors, activate T, B, and natural killer cells, and stimulate synthesis of IL-6 (2, 5, 6). In addition, TNF and IL-1 have hormone-like actions that extend beyond the immune system. For instance, IL-1 can participate not only in the stress response by increasing ACTH and cortisol levels when injected into mice (7), but can also directly stimulate the secretion of hypothalamlc CRF as well as ACTH, LH, GH, and TSH from the pituitary (8, 9). Similarly, TNF can alter thyroid hormone metabo-
genase (CO) blocker, meclofenamate (M), which does not significantly alter basal renin release, attenuated the TNF- and rhlL10-induced renin secretion [TNF (20 U/ml), 132 ± 11%; TNF plus M (5 x 10-B M), 100 ± 3% (P < 0.01); rhIL-1/3 (10 U/ml), 135 ± 9%; rhIL-1/3 plus M, 105 ± 10% (P < 0.05)]. The stimulatory effects of TNF and IL-1 on renin were reversible. These results suggest that IL-1 and TNF are renin secretagogues and can also block the inhibitory actions of All on renin. Since the effect of TNF and IL-1 on renin can be blocked by a (CO) inhibitor, the studies indicate a role of prostaglandins in their action. Therefore, locally produced TNF and IL-1 may play an important paracrine role in regulation of the renin-anglotensin system. {Endocrinology 126: 273-278, 1990)
lism (10), follicular steroidogenesis (11), and ovarian function (12). IL-1 can also modulate glucose-dependent insulin release from isolated rat islets (13). Both TNF and IL-1 can act directly on vascular endothelial and smooth muscle cells to increase the secretion of prostacyclin (PGI2) (14-16). Juxtaglomerular (JG) cells of the kidney are modified vascular smooth muscle cells (17). Since PGI2 is a potent renin secretogogue in these cells (18-20), there is a possibility that TNF and IL-1 may play a role in the regulation of renin secretion. No studies of the effects of TNF and IL-1 on the renin-angiotensin system have been described. The recent availability of highly purified and recombinant IL-1 and -2 as well as TNF prompted us to examine their effects on renin release. Materials and Methods Recombinant human TNFa/cachectin (SA, 107 U/mg protein) was obtained from Amgen Biological (Thousand Oaks, CA). Ultrapure human IL-1 (hIL-1; SA, 108 U/mg protein), recombinant human IL-1/3 (rhIL-i/3; SA, 108 U/mg protein), and recombinant IL-2 (SA, 3 x 106 U/mg protein) were purchased from Genzyme Corp. (Boston, MA). Pentex BSA (fatty acid-free fraction V) was obtained from Miles Laboratories (Naperville, IL). Meclofenamate (M) was a gift from Warner Lambert Co. (Ann Arbor, MI). Male Sprague-Dawley rats (150-250 g) were killed by decapitation. The superficial slices from the dorsal and ventral sides
Received August 1,1989. Address requests for reprints to: Dr. Indra Antonipillai, Section of Endocrinology, University of Southern California, 2025 Zonal Avenue, Los Angeles, California 90033. * This work was supported by NiH First Award DK-39204 (to LA.) and Research Grant HL-21112 (to R.H.). Presented in part in abstract form at the 71st Annual Meeting of The Endocrine Society, Seattle, WA, 1989.
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of the kidney (0.5 mm thick) were used for static incubation and perifusion experiments (Endotronics Acusyst S Perifusion System, Marietta, OH). For static incubations, slices (15-30 mg) were washed with Krebs-Ringer bicarbonate with glucose (KRBG) medium containing 0.1 BSA. Slices were then preincubated in a metabolic shaker, saturated with 95% O2-5% CO2 at 37 C for 30 min, and incubated for two consecutive 1-h incubation periods. Each slice was incubated for a 1-h baseline period, after which various agents were added. The response to an agent was observed for the next 1-h period, thus enabling each slice to serve as its own control (20). The standard KRBG medium contained (in millimolar concentrations): 120 NaCl, 4.7 KC1,1.2 MgSO4, 2.5 CaCl2, 1.2 KH2P04, 26.8 NaHCO3, and 10 glucose, pH 7.4. For perifusions, slices were placed in culture chambers and perifused with KRBG buffer at a flow rate of 0.5 ml/ml, as described previously (21). After an initial 60-min stabilization period, 5-min fractions were collected. After a 30min baseline sampling, the agents were dissolved in 30 ml KRBG buffer and perifused over a 30-min period. This was followed by a control KRBG buffer for a period of 40 min. TNF, IL-1, and IL-2 were dissolved in KRBG buffer with 0.1% BSA and freshly prepared on ice just before use, whereas M was dissolved in ethanol. The final concentration of ethanol in KRBG medium was 0.05%. This concentration of ethanol was also added to control incubations not exposed to test compounds and did not influence the release of renin. Renin activity in the supernatant of the incubations or perifusion medium was determined by a RIA that measures the generation of angiotensin-I (AI) by the method of Haber et al. as described previously (20-22).In the static incubation model, renin release during the second hour of incubation was expressed as the percentage of basal release in the same slice during the first 1h period, in the perifusion experiments renin release during each collection period was expressed as the percentage of basal release in the same chamber during the first collection period (0-10 min). Statistical significance was determined with analysis of variance, unpaired t tests, and a multiple comparison method (using either Duncan's or Dunnett's test wherever appropriate), as previously described (20-22).
Results Effects of TNF and IL on renin release Renin secretion by the cortical slices was relatively stable during two consecutive 1-h periods (first hour, 100%; second hour, 94 ± 4%). The absolute levels of renin release exhibited considerable variation between incubations even when corrected for slice weight, as indicated previously by us (22) as well as others (23), but values within the same slice did not greatly differ. This finding emphasizes the importance of using each slice as its own control. In static incubations, TNF (1 and 5 U/ml) increased renin slightly at 1 h (Fig. 1), but 10 U/ml (or 1000 pg/ ml) TNF significantly increased renin release compared with that in control slices (control, 97 ± 6%; TNF, 151
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160
140
120
100
CONTROL
1(0.1)
5(0.5)
10(1)
50(5)
TNF Units (ng)/ml
FIG. 1. Dose-related stimulatory action of TNF on renin release by rat renal cortical slices. The effect of TNF is expressed as a percentage of baseline at 1 h. Each value represents the mean ± SEM of five to seven separate sets of experiments. *, P < 0.005 vs. control.
± 13%; P < 0.005). A higher concentration (50 U/ml) did not further stimulate renin release (179 ± 24%). Ultrapure hIL-1 also markedly stimulated renin secretion. As little as 5 U/ml (or 50 pg/ml) significantly stimulated renin release to 153 ± 13% of the control value (P < 0.01; Fig. 2) compared to TNF, which at a concentration of 1000 pg/ml induced similar increases in renin secretion. Similar effects were observed using recombinant hIL-1/3 [control, 100 ± 5%; rnIL-1/? (10 U/ ml), 135 ± 9%]. In contrast to the effects of IL-1, IL-2 at concentrations from 2-25 U/ml had no effect on basal renin release [control, 93 ± 9%; IL-2 (25 U/ml), 100 ± 8%). To fully evaluate the more definitive roles of TNF, perifusion studies were performed. Renin release in control slices was relatively stable over the 100-min period (Fig. 3). TNF caused a sustained increase in renin secretion over the control slices after 20 min (Fig. 3). Reversibility of the effects of TNF on JG cell function In separate experiments, when slices were exposed to TNF (50 U/ml) for 1 h, there was stimulation of renin release (140 ±7%). When these same slices were washed twice with KRBG buffer (wash period) and then reincubated, renin secretion returned to control levels (111 ±2%). When TNF (10 U/ml) was then added after a
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release to 80 ± 5% of the control value (P < 0.01). Both TNF (20 U/ml; 1.2 X 1010 M) and rhIL-1/3 (10 U/ml; 6 X 10"12 M) blocked the All inhibition of renin release (All plus TNF, 102 ± 7%; All plus rhIL-1/3, 106 ± 10%; P < 0.02; Fig. 4).
180
160
Effects of M, a cyclooxygenase (CO) blocker, on TNF and IL-induced renin release
140
120
100
CONTROL
1(10)
2.5(25)
5(50)
10(100)
To study the potential regulatory role of prostaglandins in TNF and IL-1 action, the CO blocker M was used, since indomethacin may have some nonspecific inhibitory actions (24, 25). M (50 /uM) had no significant effect by itself on basal renin release (control, 100 ± 4%; M, 111 ± 5%), but significantly blocked the stimulatory effects of both TNF and rhIL-1,8 on renin release (TNF, 132 ± 11%; TNF plus M, 100 ± 3%; rhIL-1/3, 135 ± 9%; rhIL-1/3 plus M, 105 ± 10%; both P < 0.05; Fig. 5).
hlL-1 Unit* (pg)/ml
FIG. 2. Effects of hIL-1 on renin release by rat renal cortical slices at 1 h. Values (percentage of control) are the mean ± SEM, representing five to eight experiments. *, P < 0.01 vs. control. 180r
140
100
0
I
20
40
60
TNF (10 u/ml)
FIG. 3. Effects of TNF on renin secretion in perifused rat renal cortical slices. Perifusions were performed as indicated in the text. Results are expressed as the percentage of each basal renin release during the first 0-10 min. Values represent the mean ± SEM of five to six experiments. TNF significantly stimulated renin release after 20 min. *, P < 0.05.
Discussion The list of target tissues for the monokines IL-1 and TNF continues to expand. Endocrine tissues appear particularly sensitive to these cytokines. In the present report evidence is presented that both TNF and IL-1 exert a stimulatory effect on JG cell renin release. This increase occurs in a dose-related manner over a range of 10-i2_10-io M T h e g e c o n c e n t r a t i o n s o f TNF and IL-1 are similar to the concentrations that induce other well established in vitro effects, such as induction of PGI2 synthesis in human vascular endothelial cells (16) or FSH-induced aromatase activity in cultured granulosa cells (12). In our studies we used both purified natural hIL-1 and rhIL-10 (an IL with a pi of 7.0), an isoform known to show some of the major effects of IL-1 (26). 1201-
wash period, there was another increase in renin release (155 ± 5%). Similarly, when isoproterenol (106 M) was added after a wash period, TNF-treated slices responded in a manner similar to slices that were exposed to isoproterenol alone. With isoproterenol (106 M), renin release was stimulated at 1 h to 186 ± 13% and at 2 h to 159 ± 7% of control values. Sequential addition of TNF and isoproterenol stimulated renin release to 158 ± 13% at 1 h and to 172 ± 12% of the basal value at 2 h. Similar results (data not shown) were obtained using hIL-1. CONTROL
Effects of TNF and IL-1 on All-mediated renin release The roles of TNF and IL-1 were also evaluated in Allinduced renin inhibition. All (2 X 10'7 M) decreased renin
All (2x10'7M)
rhlL-1p 10M/ITII
FIG. 4. Effects of TNF and rhIL-1/3 on All-mediated renin inhibition by rat renal cortical slices. The results are expressed as the mean ± SEM, representing five to seven experiments. *, P < 0.02 vs. All.
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276 160 r
(5x10-5 M)
FIG. 5. Effects of a CO blocker, M, on TNF- and rhIL-l/3-induced renin secretion. Values represent the mean ± SEM of five to eight experiments. *,P< 0.05 us. TNF or rhIL-1/3.
Both preparations similarly increased renin release. These effects of IL-l/TNF were seen not only in a static incubation system, but also in a perifusion system, which is considered more physiological, since products from slices and medium are constantly washed out, and the contents of the medium are kept constant. The stimulation of renin release by TNF/IL-1 was completely reversible after removal of TNF. Furthermore, the renin response to another secretogogue, such as isoproterenol, was intact, suggesting that these effects are notcytotoxic and that TNF/IL-1 can produce reversible stimulation of renin without general damage to the JG cell. Similarly, stimulation of insulin release in rat islets (27) or PGE2 production by lung fibroblasts (28) is reversible after TNF or IL-1 removal. TNF and IL-1 in concentrations as little as 10"12-10"10 M blocked the inhibitory effects of All on renin, suggesting that these two monokines might act in vivo to block or alter angiotensin feedback. These studies are consistent with those made by our group on adrenal zona glomerulosa cells, where both TNF and IL-1 also block the All-induced aldosterone secretion (29). Arachidonic acid products, specifically prostaglandins, have been shown to play a role in induction of TNF and IL-1 actions in vivo as well as in vitro in a variety of cell types (1416). In the present studies a CO inhibitor, M, at doses that have been shown to markedly inhibit prostaglandin formation (25) significantly attenuated both TNF- and IL-1-induced renin release. These studies suggest that, like many other systems, prostaglandin action may be an important step in TNF/IL-1-induced renin secretion. The cellular mechanisms by which these cytokines act
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on renin release were not assessed here. In other systems TNF and/or IL-1 can induce changes in intracellular cAMP (6, 30), activate phospholipase-A2 and -C (31, 32), initiate hydrolysis of phosphoinosltide (13) production of diacylglycerol (31, 33), as well as involve subcellular redistribution and activation of protein kinase-C systems (34). It is well known that in addition to cAMP and calcium, which play an important second messenger role in renin release (22, 35, 36), all of the above events directly or indirectly can induce changes in renin secretory processes (35-38). Although actions of prostaglandins on renin have been linked to adenylate cyclase systems (39), both cAMP and calcium can act in a concerted fashion (25, 35, 36, 38). TNF and IL-1 can bind specifically to endothelium (40) and initiate a wide variety of changes on vascular smooth muscle and endothelial cells (2, 41) For example, both induce the synthesis of PGI2 in endothelial cells (15). In addition, IL-1 is a potent inhibitor of vascular smooth muscle contractility (41). Since the cells that make renin are derived from vessel cells, bear a close anatomical relationship with endothelium, and respond to PGI2 by increasing renin secretion, it is not surprising that TNF and IL-1 have stimulatory actions. The effects of these cytokines on renin are acute (minutes) and are, therefore, not due to mitogenesis (or growth). In some other systems, such as progesterone production by ovarian follicles (11) or FSH-induced aromatase activity (12), a lag period of 24 h or longer is required for TNF action. The rapid effects of these cytokines on renin release suggests that they act either by inducing direct secretion of stored renin or by converting inactive to active renin (42). This latter action would be via activating a protease (42). An action on a tissue protease (plasminogen inhibitor) has been observed with IL-1 (43). These effects probably also include an action via prostaglandin formation, since the action of IL-1 and TNF on renin was blocked by M. It is interesting to consider the physiological relevance of these observations. IL-1 is synthesized by virtually every nucleated cell type (4), and although concentrations of TNF are low under normal circumstances, serum concentrations of both TNF and IL-1 can markedly increase when animals are exposed to endotoxin (44, 45). The concept that these macrophage-monocyte-derived soluble products influence hormone secretion is not new (8-13). It is interesting to note that Zipser et al. (46) described a syndrome of hyperreninemic hypoaldosteronism in critically ill patients. Patients with this syndrome have increased levels of renin with inappropriately low concentrations of plasma aldosterone. Although no known regulators of renin-AII-aldosterone could explain this phenomenon, major infections and septicemia were common underlying illnesses. Recent reports indicate
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CYTOKINES AND RENIN SECRETION that levels of these cytokines are markedly increased in septisemla (1-4, 47). Since the kidney not only possesses high affinity receptors for TNF (48), and renal glomeruli synthesize and respond to a number of cytokines, including IL-1 (49, 50), increased local glomerular production of TNF along with IL-1 may have contributed to the altered renin-AII-aldosterone axis in hyperreninemlc hypoaldosteronism. In summary, our study demonstrates that TNF and IL-1 are extremely potent as renin secretogogues and have the ability to block the action of All on renin secretion. These paracrine factors may be involved in states where a discrepancy exists between renin-angiotensin levels and aldosterone secretion.
17. 18. 19. 20. 21. 22. 23.
Acknowledgments
24.
We thank Michael Halim for the technical assistance and Jenny Yang for typing the manuscript.
25.
References
26.
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