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Relaxin and renal fibrosis
Kidney International, Vol. 59 (2001), pp. 1184–1185
EDITORIAL
Relaxin and renal fibrosis There is now widespread recognition that tubulointerstitial fibrosis is an important component in almost all forms of progressive renal disease. This excessive accumulation of interstitial connective tissue, principally collagen, has led to a search for therapeutic strategies directed at this process. Indirect strategies aimed at inhibiting fibrosis by reducing glomerular hyperfiltration and the effects of proteinuria on the tubule, through control of hypertension, angiotensin blockade, low protein diet, control of hyperglycaemia, and to a lesser extent control of hyperlipidemia have been proved both experimentally and clinically. A more direct strategy would be to inhibit the process at the level of the tubule and the interstitial fibrogenic cell, the fibroblast, including maneuvers that interfere with the major fibrogenic cytokine produced by the tubular cell transforming growth factor-1 (TGF-1), or reduce the direct stimulatory effect of angiotensin on the fibroblast by angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockade [1]. In this issue of Kidney International, Garber et al [2] present experimental work suggesting that the hormone relaxin may also be an antifibrotic agent, acting at this final common pathway of progressive renal failure. Relaxin was first described in 1926, when injections of serum from pregnant guinea pigs or rabbits were shown to relax the interpubic ligament of female guinea pigs [3]. Normally excreted into the bloodstream by the corpus luteum, decidua, and placenta, the hormone has since been demonstrated to have many important roles in pregnancy, including not only softening effects on connective tissue, but also reducing uterine contractility and control of mammary gland growth and differentiation [3]. Structurally, relaxin is a multipolypeptide hormone of about 6 kD with homology to insulin and insulin-like growth factors. Two molecular forms, designated H1 and H2, have been described, with H2 being the main form found in the bloodstream [3]. With the production of recombinant H2 relaxin, clinical applications of this polypeptide are being investigated. The possibility of utilizing the antifibrotic effects clinically has been the subject of speculation since studies in the late 1950s suggested that porcine relaxin induced transient improvements in patients with scleroderma [3]. 2001 by the International Society of Nephrology
Experimentally, relaxin has been demonstrated to inhibit pulmonary [4] and dermal fibrosis [5]. Recently, infusion of 25 but not 100 g/kg/day of relaxin over 24 weeks has been shown to produce a reduction in skin thickening in patients with scleroderma [6]. In this issue of Kidney International, Garber et al [2] demonstrate that relaxin reduces renal fibrosis in an acute experimental model of bromoethylamine-induced papillary necrosis, where corticomedullary fibrosis is prominent [7]. They demonstrated that continuous subcutaneous infusion of relaxin commenced 1 week after injury dramatically reduced corticomedullary scarring. Importantly, in this model with minimal glomerular changes, the glomerular filtration rate (GFR) was also markedly preserved in the relaxin-treated group, implying that reduction in interstitial fibrosis was responsible for preservation of renal function. The mechanism by which relaxin attenuates this fibrosis is not clear. Garber et al [2] showed reduced immunohistochemical staining for TGF-1 and reduced cellular infiltration. At a cellular level, relaxin has previously been shown to reduce collagen synthesis by dermal fibroblasts [5], enhance the effects of interferon gamma [8], inhibit TGF-1 and interleukin-1 (IL-1)–induced collagen expression [9], and increase secretion of collagenase [4]. It has also been demonstrated that relaxin increases nitric oxide production [3], with consequent vasodilatory properties [10]. Recombinant relaxin therapy currently has significant disadvantages, not the least of which is the requirement for continuous subcutaneous infusion [2, 6]. A better understanding of the molecular and cellular interactions responsible for the many effects of this polypeptide may lead to more practical analogues. In the meantime, applications clinically and experimentally will necessarily address fibrosing processes occurring over weeks not years. Accordingly, studies of clinically relevant experimental models such as crescentic glomerulonephritis and obstructive nephropathy will be of great interest. In this context, an initial report has suggested that relaxin improves both functional and structural outcomes in experimental anti-glomerular basement membrane nephritis (abstract; McDonald et al, J Am Soc Nephrol 10:576A, 1999), with reduced serum creatinine and proteinuria as well as attenuated glomerular sclerosis and interstitial fibrosis. The universal biology of scarring indicates that strate-
1184
Editorial
gies to directly reduce fibrosis in the kidney will have implications for chronic fibrosing conditions in other organs, although the long-term consequences of inhibiting growth factor activity and collagen metabolism are unknown, particularly with respect of normal healing. The increasing ability to inhibit fibrosis, as evidenced by Garber et al [2], suggests that potential strategies are within reach, at least in the more rapidly progressive diseases. Gavin J. Becker and Tim D. Hewitson Melbourne, Australia Correspondence to Professor Gavin Becker, M.D., Department of Nephrology, The Royal Melbourne Hospital, Victoria, NSW 3050, Australia. E-mail: [email protected]
REFERENCES 1. Becker GJ, Hewitson TD: The role of tubulointerstitial injury in chronic renal failure. Curr Opin Nephrol Hypertension 9:133–148, 2000
1185
2. Garber SL, Mirochnik Y, Brecklin CS, et al: Relaxin decreases renal interstitial fibrosis and slows progression of renal disease. Kidney Int 59:876–882, 2000 3. Bani D: Relaxin: A pleiotropic hormone. Gen Pharmac. 28:13–22, 1997 4. Unemori EN, Pickford LB, Salles AL, et al: Relaxin induces an extracellular matrix degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo. J Clin Invest 98:2739–2745, 1996 5. Unemori EN, Beck LS, Lee WP, et al: Human relaxin decreases collagen accumulation in vivo in two rodent models of fibrosis. J Invest Dermatol 101:280–285, 1993 6. Seibold JR, Korn JH, Simms R: Recombinant human relaxin in the treatment of scleroderma: A randomized, double-blind, placebocontrolled trial. Ann Intern Med 132:871–879, 2000 7. Garber SL, Mirochnik Y, Desai SS, et al: Angiotensin-converting enzyme inhibition reduces the effect of bromoethylamine-induced papillary necrosis and renal fibrosis. J Am Soc Nephrol 9:1052– 1059, 1998 8. Unemori EN, Bauer EA, Amento EP: Relaxin alone and in conjunction with interferon-gamma decreases collagen synthesis by cultured human scleroderma fibroblasts. J Invest Dermatol 99:337– 342, 1992 9. Unemori EN, Amento EP: Relaxin modulates synthesis and secretion of procollagenase and collagen by human dermal fibroblasts. J Biol Chem 265:10681–10685, 1990 10. Danielson LA, Sherwood OD, Conrad KP: Relaxin is a potent renal vasodilator in conscious rats. J Clin Invest 103:525–533, 1999
EDITORIAL
Relaxin and renal fibrosis There is now widespread recognition that tubulointerstitial fibrosis is an important component in almost all forms of progressive renal disease. This excessive accumulation of interstitial connective tissue, principally collagen, has led to a search for therapeutic strategies directed at this process. Indirect strategies aimed at inhibiting fibrosis by reducing glomerular hyperfiltration and the effects of proteinuria on the tubule, through control of hypertension, angiotensin blockade, low protein diet, control of hyperglycaemia, and to a lesser extent control of hyperlipidemia have been proved both experimentally and clinically. A more direct strategy would be to inhibit the process at the level of the tubule and the interstitial fibrogenic cell, the fibroblast, including maneuvers that interfere with the major fibrogenic cytokine produced by the tubular cell transforming growth factor-1 (TGF-1), or reduce the direct stimulatory effect of angiotensin on the fibroblast by angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockade [1]. In this issue of Kidney International, Garber et al [2] present experimental work suggesting that the hormone relaxin may also be an antifibrotic agent, acting at this final common pathway of progressive renal failure. Relaxin was first described in 1926, when injections of serum from pregnant guinea pigs or rabbits were shown to relax the interpubic ligament of female guinea pigs [3]. Normally excreted into the bloodstream by the corpus luteum, decidua, and placenta, the hormone has since been demonstrated to have many important roles in pregnancy, including not only softening effects on connective tissue, but also reducing uterine contractility and control of mammary gland growth and differentiation [3]. Structurally, relaxin is a multipolypeptide hormone of about 6 kD with homology to insulin and insulin-like growth factors. Two molecular forms, designated H1 and H2, have been described, with H2 being the main form found in the bloodstream [3]. With the production of recombinant H2 relaxin, clinical applications of this polypeptide are being investigated. The possibility of utilizing the antifibrotic effects clinically has been the subject of speculation since studies in the late 1950s suggested that porcine relaxin induced transient improvements in patients with scleroderma [3]. 2001 by the International Society of Nephrology
Experimentally, relaxin has been demonstrated to inhibit pulmonary [4] and dermal fibrosis [5]. Recently, infusion of 25 but not 100 g/kg/day of relaxin over 24 weeks has been shown to produce a reduction in skin thickening in patients with scleroderma [6]. In this issue of Kidney International, Garber et al [2] demonstrate that relaxin reduces renal fibrosis in an acute experimental model of bromoethylamine-induced papillary necrosis, where corticomedullary fibrosis is prominent [7]. They demonstrated that continuous subcutaneous infusion of relaxin commenced 1 week after injury dramatically reduced corticomedullary scarring. Importantly, in this model with minimal glomerular changes, the glomerular filtration rate (GFR) was also markedly preserved in the relaxin-treated group, implying that reduction in interstitial fibrosis was responsible for preservation of renal function. The mechanism by which relaxin attenuates this fibrosis is not clear. Garber et al [2] showed reduced immunohistochemical staining for TGF-1 and reduced cellular infiltration. At a cellular level, relaxin has previously been shown to reduce collagen synthesis by dermal fibroblasts [5], enhance the effects of interferon gamma [8], inhibit TGF-1 and interleukin-1 (IL-1)–induced collagen expression [9], and increase secretion of collagenase [4]. It has also been demonstrated that relaxin increases nitric oxide production [3], with consequent vasodilatory properties [10]. Recombinant relaxin therapy currently has significant disadvantages, not the least of which is the requirement for continuous subcutaneous infusion [2, 6]. A better understanding of the molecular and cellular interactions responsible for the many effects of this polypeptide may lead to more practical analogues. In the meantime, applications clinically and experimentally will necessarily address fibrosing processes occurring over weeks not years. Accordingly, studies of clinically relevant experimental models such as crescentic glomerulonephritis and obstructive nephropathy will be of great interest. In this context, an initial report has suggested that relaxin improves both functional and structural outcomes in experimental anti-glomerular basement membrane nephritis (abstract; McDonald et al, J Am Soc Nephrol 10:576A, 1999), with reduced serum creatinine and proteinuria as well as attenuated glomerular sclerosis and interstitial fibrosis. The universal biology of scarring indicates that strate-
1184
Editorial
gies to directly reduce fibrosis in the kidney will have implications for chronic fibrosing conditions in other organs, although the long-term consequences of inhibiting growth factor activity and collagen metabolism are unknown, particularly with respect of normal healing. The increasing ability to inhibit fibrosis, as evidenced by Garber et al [2], suggests that potential strategies are within reach, at least in the more rapidly progressive diseases. Gavin J. Becker and Tim D. Hewitson Melbourne, Australia Correspondence to Professor Gavin Becker, M.D., Department of Nephrology, The Royal Melbourne Hospital, Victoria, NSW 3050, Australia. E-mail: [email protected]
REFERENCES 1. Becker GJ, Hewitson TD: The role of tubulointerstitial injury in chronic renal failure. Curr Opin Nephrol Hypertension 9:133–148, 2000
1185
2. Garber SL, Mirochnik Y, Brecklin CS, et al: Relaxin decreases renal interstitial fibrosis and slows progression of renal disease. Kidney Int 59:876–882, 2000 3. Bani D: Relaxin: A pleiotropic hormone. Gen Pharmac. 28:13–22, 1997 4. Unemori EN, Pickford LB, Salles AL, et al: Relaxin induces an extracellular matrix degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo. J Clin Invest 98:2739–2745, 1996 5. Unemori EN, Beck LS, Lee WP, et al: Human relaxin decreases collagen accumulation in vivo in two rodent models of fibrosis. J Invest Dermatol 101:280–285, 1993 6. Seibold JR, Korn JH, Simms R: Recombinant human relaxin in the treatment of scleroderma: A randomized, double-blind, placebocontrolled trial. Ann Intern Med 132:871–879, 2000 7. Garber SL, Mirochnik Y, Desai SS, et al: Angiotensin-converting enzyme inhibition reduces the effect of bromoethylamine-induced papillary necrosis and renal fibrosis. J Am Soc Nephrol 9:1052– 1059, 1998 8. Unemori EN, Bauer EA, Amento EP: Relaxin alone and in conjunction with interferon-gamma decreases collagen synthesis by cultured human scleroderma fibroblasts. J Invest Dermatol 99:337– 342, 1992 9. Unemori EN, Amento EP: Relaxin modulates synthesis and secretion of procollagenase and collagen by human dermal fibroblasts. J Biol Chem 265:10681–10685, 1990 10. Danielson LA, Sherwood OD, Conrad KP: Relaxin is a potent renal vasodilator in conscious rats. J Clin Invest 103:525–533, 1999