Relaxin in cardiovascular and renal disease
2006; Elsevier BV; Volume: 69; Issue: 9 Linguagem: Inglês
10.1038/sj.ki.5000264
ISSN1523-1755
AutoresChrishan S. Samuel, Tim D. Hewitson,
Tópico(s)Pregnancy-related medical research
ResumoFibrosis (organ scarring) is a hallmark of many forms of cardiovascular and renal disease, and causes organ dysfunction and structural changes when normal tissue is replaced with scar tissue; the accumulation of scar tissue being a leading cause of death around the world. Despite deep organ scarring potentially existing in many forms (including myocardial and vascular sclerosis, renal interstitial fibrosis, and glomerulosclerosis), current therapies have only had limited success in delaying end-stage disease. The peptide hormone relaxin is emerging as a potent antifibrotic therapy with rapid-occurring efficacy. Recent studies have demonstrated the antifibrotic actions of relaxin in experimental models of cardiac and renal disease in vivo, and the various levels at which relaxin acts to inhibit fibroblast-induced collagen overproduction leading to fibrosis, in vitro. Separate studies using relaxin gene-knockout mice have demonstrated the significance of endogenous relaxin as a naturally occurring and protective moderator of collagen turnover, while the therapeutic potential of relaxin has been enhanced by its ability to promote vasodilation and renal hyperfiltration. This review will summarize these coherent findings as a means of highlighting the clinical potential of relaxin in cardiovascular and renal disease. Fibrosis (organ scarring) is a hallmark of many forms of cardiovascular and renal disease, and causes organ dysfunction and structural changes when normal tissue is replaced with scar tissue; the accumulation of scar tissue being a leading cause of death around the world. Despite deep organ scarring potentially existing in many forms (including myocardial and vascular sclerosis, renal interstitial fibrosis, and glomerulosclerosis), current therapies have only had limited success in delaying end-stage disease. The peptide hormone relaxin is emerging as a potent antifibrotic therapy with rapid-occurring efficacy. Recent studies have demonstrated the antifibrotic actions of relaxin in experimental models of cardiac and renal disease in vivo, and the various levels at which relaxin acts to inhibit fibroblast-induced collagen overproduction leading to fibrosis, in vitro. Separate studies using relaxin gene-knockout mice have demonstrated the significance of endogenous relaxin as a naturally occurring and protective moderator of collagen turnover, while the therapeutic potential of relaxin has been enhanced by its ability to promote vasodilation and renal hyperfiltration. This review will summarize these coherent findings as a means of highlighting the clinical potential of relaxin in cardiovascular and renal disease. A growing body of evidence suggests that relaxin is both an endogenous regulator of fibrosis and a potential antifibrotic therapy for both developing and established fibrosis. Relaxin is a small peptide hormone, structurally related to the insulin family of peptides and is primarily produced by the ovary and/or placenta in pregnancy and the prostate of mammals.1Sherwood O.D. Relaxin's physiological roles and other diverse actions.Endocr Rev. 2004; 25: 205-234Crossref PubMed Scopus (422) Google Scholar, 2Bathgate R.A.D. Hsueh A.J. Sherwood O.D. Physiology and molecular biology of the relaxin peptide family.in: Neill J.D. The Physiology of Reproduction. 3rd edn. Raven Press, New York2006: 701-790Crossref Scopus (68) Google Scholar Humans (and higher primates) have three relaxin genes, designated H1, H2, and H3 relaxin while rodents have two genes, relaxin (equivalent to H2 relaxin) and relaxin-3 (equivalent to H3 relaxin). H2 relaxin or relaxin (in rodents) are the major source of circulating relaxin, while the primary relaxin receptor was recently identified as a G protein-coupled receptor, called the leucine-rich repeat containing G protein-coupled receptor-7.3Hsu S.Y. Nakabayashi K. Nishi S. et al.Activation of orphan receptors by the hormone relaxin.Science. 2002; 295: 671-673Crossref PubMed Scopus (658) Google Scholar Leucine-rich repeat containing G protein-coupled receptor-7 is part of a subgroup (type C) of leucine-rich repeat containing G protein-coupled receptors, that include receptors for follicle-stimulating hormone, luteinizing hormone and thyroid-stimulating hormone.2Bathgate R.A.D. Hsueh A.J. Sherwood O.D. Physiology and molecular biology of the relaxin peptide family.in: Neill J.D. The Physiology of Reproduction. 3rd edn. Raven Press, New York2006: 701-790Crossref Scopus (68) Google Scholar, 3Hsu S.Y. Nakabayashi K. Nishi S. et al.Activation of orphan receptors by the hormone relaxin.Science. 2002; 295: 671-673Crossref PubMed Scopus (658) Google Scholar Normally associated with reproduction, relaxin has been implicated in a number of pregnancy-related functions including softening the cervix and vagina at delivery.1Sherwood O.D. Relaxin's physiological roles and other diverse actions.Endocr Rev. 2004; 25: 205-234Crossref PubMed Scopus (422) Google Scholar, 2Bathgate R.A.D. Hsueh A.J. Sherwood O.D. Physiology and molecular biology of the relaxin peptide family.in: Neill J.D. The Physiology of Reproduction. 3rd edn. Raven Press, New York2006: 701-790Crossref Scopus (68) Google Scholar These actions are due in a large part to relaxin's ability to reduce collagen synthesis and increase collagen degradation via stimulation of collagenase activity. It is now becoming increasingly recognized that relaxin has a number of functions outside reproduction, with numerous reports suggesting therapeutic applications in non-reproductive processes such as fibrosis, wound healing, cardiac protection, and allergic responses.1Sherwood O.D. Relaxin's physiological roles and other diverse actions.Endocr Rev. 2004; 25: 205-234Crossref PubMed Scopus (422) Google Scholar, 2Bathgate R.A.D. Hsueh A.J. Sherwood O.D. Physiology and molecular biology of the relaxin peptide family.in: Neill J.D. The Physiology of Reproduction. 3rd edn. Raven Press, New York2006: 701-790Crossref Scopus (68) Google Scholar, 4Samuel C.S. Mookerjee I. Lekgabe E.D. Actions of relaxin in non-reproductive tissues.Curr Med Chem-Immunol Endocr Metab Agents. 2005; 5: 391-402Crossref Scopus (4) Google Scholar Not only are these actions surprisingly diverse, but unlike its actions in reproductive biology, occur in both males and females. For the purposes of this review, we will concentrate on the effect of relaxin on cardiovascular and renal disease (Table 1).Table 1Summary of the main effects of relaxin in the heart and kidneyTissueActions/effectsReferencesHeartAntifibrotic1Sherwood O.D. Relaxin's physiological roles and other diverse actions.Endocr Rev. 2004; 25: 205-234Crossref PubMed Scopus (422) Google Scholar, 2Bathgate R.A.D. Hsueh A.J. Sherwood O.D. Physiology and molecular biology of the relaxin peptide family.in: Neill J.D. The Physiology of Reproduction. 3rd edn. Raven Press, New York2006: 701-790Crossref Scopus (68) Google Scholar, 4Samuel C.S. Mookerjee I. Lekgabe E.D. Actions of relaxin in non-reproductive tissues.Curr Med Chem-Immunol Endocr Metab Agents. 2005; 5: 391-402Crossref Scopus (4) Google Scholar, 7Du X.J. Samuel C.S. Gao X.M. et al.Increased myocardial collagen and ventricular diastolic dysfunction in relaxin deficient mice: a gender-specific phenotype.Cardiovasc Res. 2003; 57: 395-404Crossref PubMed Scopus (139) Google Scholar, 8Samuel C.S. Unemori E.N. Mookerjee I. et al.Relaxin modulates cardiac fibroblast proliferation, differentiation, and collagen production and reverses cardiac fibrosis in vivo.Endocrinology. 2004; 145: 4125-4133Crossref PubMed Scopus (234) Google Scholar, 15Lekgabe E.D. Kiriazis H. Zhao C. et al.Relaxin reverses cardiac and renal fibrosis in spontaneously hypertensive rats.Hypertension. 2005; 46: 412-418Crossref PubMed Scopus (150) Google ScholarChronotropic1Sherwood O.D. Relaxin's physiological roles and other diverse actions.Endocr Rev. 2004; 25: 205-234Crossref PubMed Scopus (422) Google Scholar, 2Bathgate R.A.D. Hsueh A.J. Sherwood O.D. Physiology and molecular biology of the relaxin peptide family.in: Neill J.D. The Physiology of Reproduction. 3rd edn. Raven Press, New York2006: 701-790Crossref Scopus (68) Google Scholar, 4Samuel C.S. Mookerjee I. Lekgabe E.D. Actions of relaxin in non-reproductive tissues.Curr Med Chem-Immunol Endocr Metab Agents. 2005; 5: 391-402Crossref Scopus (4) Google ScholarInotropic1Sherwood O.D. Relaxin's physiological roles and other diverse actions.Endocr Rev. 2004; 25: 205-234Crossref PubMed Scopus (422) Google Scholar, 2Bathgate R.A.D. Hsueh A.J. Sherwood O.D. Physiology and molecular biology of the relaxin peptide family.in: Neill J.D. The Physiology of Reproduction. 3rd edn. Raven Press, New York2006: 701-790Crossref Scopus (68) Google Scholar, 4Samuel C.S. Mookerjee I. Lekgabe E.D. Actions of relaxin in non-reproductive tissues.Curr Med Chem-Immunol Endocr Metab Agents. 2005; 5: 391-402Crossref Scopus (4) Google Scholar, 9Kompa A.R. Samuel C.S. Summers R.J. Inotropic responses to human gene 2 (B29) relaxin in a rat model of myocardial infarction (MI): effect of pertussis toxin.Br J Pharmacol. 2002; 137: 710-718Crossref PubMed Scopus (59) Google ScholarVasodilatory1Sherwood O.D. Relaxin's physiological roles and other diverse actions.Endocr Rev. 2004; 25: 205-234Crossref PubMed Scopus (422) Google Scholar, 2Bathgate R.A.D. Hsueh A.J. Sherwood O.D. Physiology and molecular biology of the relaxin peptide family.in: Neill J.D. The Physiology of Reproduction. 3rd edn. Raven Press, New York2006: 701-790Crossref Scopus (68) Google Scholar, 4Samuel C.S. Mookerjee I. Lekgabe E.D. Actions of relaxin in non-reproductive tissues.Curr Med Chem-Immunol Endocr Metab Agents. 2005; 5: 391-402Crossref Scopus (4) Google Scholar, 11Dschietzig T. Richter C. Bartsch C. et al.The pregnancy hormone relaxin is a player in human heart failure.FASEB J. 2001; 15: 2187-2195Crossref PubMed Scopus (176) Google Scholar, 22Bani-Sacchi T. Bigazzi M. Bani D. et al.Relaxin induced increased coronary flow through stimulation of nitric oxide production.Br J Pharmacol. 1995; 116: 1589-1594Crossref PubMed Scopus (141) Google Scholar, 25Dschietzig T. Bartsch C. Richter C. et al.Relaxin, a pregnancy hormone, is a functional endothelin-1 antagonist: attenuation of endothelin-1-mediated vasoconstriction by stimulation of endothelin type-B receptor expression via ERK-1/2 and nuclear factor-kB.Circ Res. 2003; 92: 32-40Crossref PubMed Scopus (140) Google ScholarAngiogenic1Sherwood O.D. Relaxin's physiological roles and other diverse actions.Endocr Rev. 2004; 25: 205-234Crossref PubMed Scopus (422) Google Scholar, 2Bathgate R.A.D. Hsueh A.J. Sherwood O.D. Physiology and molecular biology of the relaxin peptide family.in: Neill J.D. The Physiology of Reproduction. 3rd edn. Raven Press, New York2006: 701-790Crossref Scopus (68) Google Scholar, 4Samuel C.S. Mookerjee I. Lekgabe E.D. Actions of relaxin in non-reproductive tissues.Curr Med Chem-Immunol Endocr Metab Agents. 2005; 5: 391-402Crossref Scopus (4) Google Scholar, 24Jeyabalan A. Novak J. Danielson L.A. et al.Essential role for vascular gelatinase activity in relaxin-induced renal vasodilation, hyperfiltration, and reduced myogenic reactivity of small renal arteries.Circ Res. 2003; 93: 1249-1257Crossref PubMed Scopus (124) Google Scholar, 25Dschietzig T. Bartsch C. Richter C. et al.Relaxin, a pregnancy hormone, is a functional endothelin-1 antagonist: attenuation of endothelin-1-mediated vasoconstriction by stimulation of endothelin type-B receptor expression via ERK-1/2 and nuclear factor-kB.Circ Res. 2003; 92: 32-40Crossref PubMed Scopus (140) Google ScholarWound healing1Sherwood O.D. Relaxin's physiological roles and other diverse actions.Endocr Rev. 2004; 25: 205-234Crossref PubMed Scopus (422) Google Scholar, 2Bathgate R.A.D. Hsueh A.J. Sherwood O.D. Physiology and molecular biology of the relaxin peptide family.in: Neill J.D. The Physiology of Reproduction. 3rd edn. Raven Press, New York2006: 701-790Crossref Scopus (68) Google Scholar, 4Samuel C.S. Mookerjee I. Lekgabe E.D. Actions of relaxin in non-reproductive tissues.Curr Med Chem-Immunol Endocr Metab Agents. 2005; 5: 391-402Crossref Scopus (4) Google Scholar, 24Jeyabalan A. Novak J. Danielson L.A. et al.Essential role for vascular gelatinase activity in relaxin-induced renal vasodilation, hyperfiltration, and reduced myogenic reactivity of small renal arteries.Circ Res. 2003; 93: 1249-1257Crossref PubMed Scopus (124) Google Scholar, 25Dschietzig T. Bartsch C. Richter C. et al.Relaxin, a pregnancy hormone, is a functional endothelin-1 antagonist: attenuation of endothelin-1-mediated vasoconstriction by stimulation of endothelin type-B receptor expression via ERK-1/2 and nuclear factor-kB.Circ Res. 2003; 92: 32-40Crossref PubMed Scopus (140) Google ScholarCardioprotective1Sherwood O.D. Relaxin's physiological roles and other diverse actions.Endocr Rev. 2004; 25: 205-234Crossref PubMed Scopus (422) Google Scholar, 2Bathgate R.A.D. Hsueh A.J. Sherwood O.D. Physiology and molecular biology of the relaxin peptide family.in: Neill J.D. The Physiology of Reproduction. 3rd edn. Raven Press, New York2006: 701-790Crossref Scopus (68) Google Scholar, 4Samuel C.S. Mookerjee I. Lekgabe E.D. Actions of relaxin in non-reproductive tissues.Curr Med Chem-Immunol Endocr Metab Agents. 2005; 5: 391-402Crossref Scopus (4) Google ScholarKidneyAntifibrotic1Sherwood O.D. Relaxin's physiological roles and other diverse actions.Endocr Rev. 2004; 25: 205-234Crossref PubMed Scopus (422) Google Scholar, 2Bathgate R.A.D. Hsueh A.J. Sherwood O.D. Physiology and molecular biology of the relaxin peptide family.in: Neill J.D. The Physiology of Reproduction. 3rd edn. Raven Press, New York2006: 701-790Crossref Scopus (68) Google Scholar, 4Samuel C.S. Mookerjee I. Lekgabe E.D. Actions of relaxin in non-reproductive tissues.Curr Med Chem-Immunol Endocr Metab Agents. 2005; 5: 391-402Crossref Scopus (4) Google Scholar, 6Samuel C.S. Zhao C. Bond C.P. et al.Relaxin-1-deficient mice develop an age-related progression of renal fibrosis.Kidney Int. 2004; 65: 2054-2064Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 12Garber S.L. Mirochnik Y. Brecklin C.S. et al.Relaxin decreases renal interstitial fibrosis and slows progression of renal disease.Kidney Int. 2001; 59: 876-882Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, 13Garber S.L. Mirochnik Y. Brecklin C. et al.Effect of relaxin in two models of renal mass reduction.Am J Nephrol. 2003; 23: 8-12Crossref PubMed Scopus (61) Google Scholar, 14Mcdonald G.A. Sarkar P. Rennke H. et al.Relaxin increases ubiquitin-dependent degradation of fibronectin in vitro and ameliorates renal fibrosis in vivo.Am J Physiol Renal Physiol. 2003; 285: F59-F67Crossref PubMed Scopus (58) Google Scholar, 15Lekgabe E.D. Kiriazis H. Zhao C. et al.Relaxin reverses cardiac and renal fibrosis in spontaneously hypertensive rats.Hypertension. 2005; 46: 412-418Crossref PubMed Scopus (150) Google Scholar, 16Masterson R. Hewitson T.D. Kelynack K. et al.Relaxin down-regulates renal fibroblast function and promotes matrix remodelling in vitro.Nephrol Dial Transplant. 2004; 19: 544-552Crossref PubMed Scopus (80) Google Scholar, 17Heeg M.H. Koziolek M.J. Vasko R. et al.The anti-fibrotic effects of relaxin in human renal fibroblasts are mediated in part by inhibition of the Smad2 pathway.Kidney Int. 2005; 68: 96-109Abstract Full Text Full Text PDF PubMed Scopus (136) Google ScholarVasodilatory/renal hyperfiltration1Sherwood O.D. Relaxin's physiological roles and other diverse actions.Endocr Rev. 2004; 25: 205-234Crossref PubMed Scopus (422) Google Scholar, 2Bathgate R.A.D. Hsueh A.J. Sherwood O.D. Physiology and molecular biology of the relaxin peptide family.in: Neill J.D. The Physiology of Reproduction. 3rd edn. Raven Press, New York2006: 701-790Crossref Scopus (68) Google Scholar, 4Samuel C.S. Mookerjee I. Lekgabe E.D. Actions of relaxin in non-reproductive tissues.Curr Med Chem-Immunol Endocr Metab Agents. 2005; 5: 391-402Crossref Scopus (4) Google Scholar, 19Conrad K.P. Mechanisms of renal vasodilation and hyperfiltration during pregnancy.J Soc Gynecol Invest. 2004; 11: 438-448Crossref PubMed Scopus (81) Google Scholar, 20Novak J. Danielson L.A. Kerchner L.J. et al.Relaxin is essential for renal vasodilation during pregnancy in conscious rats.J Clin Invest. 2001; 107: 1469-1475Crossref PubMed Scopus (174) Google Scholar, 21Danielson L.A. Conrad K.P. Time course and dose response of relaxin-mediated renal vasodilation, hyperfiltration, and changes in plasma osmolality in conscious rats.J Appl Physiol. 2003; 95: 1509-1514Crossref PubMed Scopus (86) Google Scholar, 23Kerchner L.J. Novak J. Hanley-Yanez K. et al.Evidence against the hypothesis that endothelial endothelin B receptor expression is regulated by relaxin and pregnancy.Endocrinology. 2005; 146: 2791-2797Crossref PubMed Scopus (35) Google Scholar Open table in a new tab The disproportionate accumulation of extracellular matrix (ECM), known as scarring or fibrosis is disfiguring and, in the case of internal organs, life threatening. Renal scarring is the final common pathway to all progressive renal disease, manifesting itself in various forms affecting both the renal parenchyma (tubulointerstitial fibrosis) and vascular structures (glomerulosclerosis and vascular sclerosis). The etiology of cardiac fibrosis is similarly diverse, a consequence of not only acute inflammation (postmyocardial infarct) but also aging, increased hemodynamic load, neurohumoral activation, and metabolic disorders. Cardiac fibrosis is in particular the hallmark of hypertensive and ischemic heart diseases. Accumulation of ECM, mainly fibrillar collagens, increases tissue stiffness and impedes both contraction and relaxation of the heart, leading to organ dysfunction. In both cardiac and renal disease, damage depends not only on the quantity of matrix produced (fibrogenesis), but also the degree of its crosslinking and its reorganization, or density. Fibrogenesis itself is dependent to a large extent on the recruitment of myofibroblasts, cells with the phenotypic features of both fibroblasts and vascular smooth muscle. Recognized by their de novo expression of α smooth muscle actin, myofibroblasts are prodigious producers of the ECM and are influenced by several mediators, including cytokines, chemokines and growth factors.5Eddy A.A. Molecular basis of renal fibrosis.Pediatr Nephrol. 2000; 15: 290-301Crossref PubMed Scopus (532) Google Scholar Furthermore, the newly synthesized matrix is remodelled by various proteases, of which the matrix metalloproteinase (MMP) family is one of the most important,5Eddy A.A. Molecular basis of renal fibrosis.Pediatr Nephrol. 2000; 15: 290-301Crossref PubMed Scopus (532) Google Scholar with the balance between fibrotic and antifibrotic signals determining the extent of scarring. While the kidney and heart have certain capacity to regenerate from acute injury, so-called healing, chronic renal, and myocardial disease results in irreversible scarring. The biology of healing and scarring are similar, with the transition between the two poorly understood. Increasingly, we recognize that there are a number of naturally occurring antifibrotic factors that are required to maintain homeostasis. Relaxin may be one such molecule. In the same way that hepatocyte growth factor and bone morphogenic protein-7 downregulate transforming growth factor-beta1 (TGF-β1) signalling by interfering with Smad signal transduction, relaxin also moderates fibrogenesis at several levels, by inhibiting the influence of several profibrotic factors, inhibiting fibroblast proliferation and/or differentiation, and stimulating MMP-induced matrix degradation (reviewed in Sherwood,1Sherwood O.D. Relaxin's physiological roles and other diverse actions.Endocr Rev. 2004; 25: 205-234Crossref PubMed Scopus (422) Google Scholar Bathgate et al.,2Bathgate R.A.D. Hsueh A.J. Sherwood O.D. Physiology and molecular biology of the relaxin peptide family.in: Neill J.D. The Physiology of Reproduction. 3rd edn. Raven Press, New York2006: 701-790Crossref Scopus (68) Google Scholar and Samuel et al.4Samuel C.S. Mookerjee I. Lekgabe E.D. Actions of relaxin in non-reproductive tissues.Curr Med Chem-Immunol Endocr Metab Agents. 2005; 5: 391-402Crossref Scopus (4) Google Scholar). Definitive evidence for the importance of endogenous relaxin in regulating this process has been provided by studies of the natural development of relaxin-deficient (RLX-/-) mice. Male RLX-/- mice developed an age-related progressive fibrosis in several tissues, including the kidney6Samuel C.S. Zhao C. Bond C.P. et al.Relaxin-1-deficient mice develop an age-related progression of renal fibrosis.Kidney Int. 2004; 65: 2054-2064Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar and heart.7Du X.J. Samuel C.S. Gao X.M. et al.Increased myocardial collagen and ventricular diastolic dysfunction in relaxin deficient mice: a gender-specific phenotype.Cardiovasc Res. 2003; 57: 395-404Crossref PubMed Scopus (139) Google Scholar By 12 months of age, the kidney collagen concentration of male RLX-/- mice was 25–30% greater than levels measured in wild-type (RLX+/+) animals,6Samuel C.S. Zhao C. Bond C.P. et al.Relaxin-1-deficient mice develop an age-related progression of renal fibrosis.Kidney Int. 2004; 65: 2054-2064Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar resulting in increased cortical thickening, focal increases in interstitial fibrosis, a general diffuse increase in glomerular matrix, and renal dysfunction. An age-dependent increase in left ventricular collagen content and concentration was also more pronounced in RLX-/- mice than RLX+/+ littermates.7Du X.J. Samuel C.S. Gao X.M. et al.Increased myocardial collagen and ventricular diastolic dysfunction in relaxin deficient mice: a gender-specific phenotype.Cardiovasc Res. 2003; 57: 395-404Crossref PubMed Scopus (139) Google Scholar These findings were associated with increased atrial hypertophy, left ventricular procollagen I mRNA expression, chamber stiffness, and diastolic dysfunction in RLX-/- mice from 9 months of age and onwards. These differences were however gender specific, with no such phenotype in female RLX-/- mice. Although the reason for this is unclear, current interest is focused on the potential compensatory role of other gender-specific hormones. Relaxin and/or relaxin-3 gene transcripts have been identified by RT-PCR in the rodent atria and ventricles of the heart7Du X.J. Samuel C.S. Gao X.M. et al.Increased myocardial collagen and ventricular diastolic dysfunction in relaxin deficient mice: a gender-specific phenotype.Cardiovasc Res. 2003; 57: 395-404Crossref PubMed Scopus (139) Google Scholar, 8Samuel C.S. Unemori E.N. Mookerjee I. et al.Relaxin modulates cardiac fibroblast proliferation, differentiation, and collagen production and reverses cardiac fibrosis in vivo.Endocrinology. 2004; 145: 4125-4133Crossref PubMed Scopus (234) Google Scholar, 9Kompa A.R. Samuel C.S. Summers R.J. Inotropic responses to human gene 2 (B29) relaxin in a rat model of myocardial infarction (MI): effect of pertussis toxin.Br J Pharmacol. 2002; 137: 710-718Crossref PubMed Scopus (59) Google Scholar and the medulla and cortex of the kidney,6Samuel C.S. Zhao C. Bond C.P. et al.Relaxin-1-deficient mice develop an age-related progression of renal fibrosis.Kidney Int. 2004; 65: 2054-2064Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar with immunohistochemistry confirming local renal expression (Figure 1). Furthermore, high-affinity binding sites for relaxin have been identified in the cardiac atrium of male and female rats.10Osheroff P.L. Cronin M.J. Lofgren J.A. Relaxin binding in the rat heart atrium.Proc Natl Acad Sci USA. 1992; 89: 2384-2388Crossref PubMed Scopus (82) Google Scholar These combined findings suggest that the heart and kidneys are both potential sources and/or target organs for relaxin. Despite the similarity between relaxin's actions in the heart and kidney though, potentially important differences exist. Both H1 and H2 relaxin are constitutively expressed in cardiovascular tissues and upregulated in the right atria and left ventricles of patients with congestive heart failure, with the plasma levels of relaxin increasing with severity of disease.11Dschietzig T. Richter C. Bartsch C. et al.The pregnancy hormone relaxin is a player in human heart failure.FASEB J. 2001; 15: 2187-2195Crossref PubMed Scopus (176) Google Scholar Similarly, increased relaxin-3 expression was detected in the rat heart, following myocardial infarction.9Kompa A.R. Samuel C.S. Summers R.J. Inotropic responses to human gene 2 (B29) relaxin in a rat model of myocardial infarction (MI): effect of pertussis toxin.Br J Pharmacol. 2002; 137: 710-718Crossref PubMed Scopus (59) Google Scholar Conversely, relaxin mRNA expression is downregulated in the kidney after unilateral ureteric obstruction (unpublished observations). However, controversy surrounds the role and significance of local relaxin synthesis. A parallel, but in many ways quite distinct area of research, is the effect of exogenous relaxin. Such work has concentrated on exploring relaxin as a potential antifibrotic therapy. Relaxin has repeatedly been shown to inhibit excessive collagen accumulation in various cell culture and animal models of fibrosis (reviewed in Sherwood,1Sherwood O.D. Relaxin's physiological roles and other diverse actions.Endocr Rev. 2004; 25: 205-234Crossref PubMed Scopus (422) Google Scholar Bathgate et al.,2Bathgate R.A.D. Hsueh A.J. Sherwood O.D. Physiology and molecular biology of the relaxin peptide family.in: Neill J.D. The Physiology of Reproduction. 3rd edn. Raven Press, New York2006: 701-790Crossref Scopus (68) Google Scholar and Samuel et al.4Samuel C.S. Mookerjee I. Lekgabe E.D. Actions of relaxin in non-reproductive tissues.Curr Med Chem-Immunol Endocr Metab Agents. 2005; 5: 391-402Crossref Scopus (4) Google Scholar), ostensively a function of both its ability to decrease collagen synthesis and increase its degradation. The production of recombinant relaxin has been a major advance in relaxin biology, providing the opportunity to undertake a number of interventionist studies. Human recombinant relaxin (H2 relaxin) is biologically active in rodents, and has formed the basis of most in vitro and in vivo studies. A number of recent in vivo studies have now clearly shown that exogenous relaxin is able to moderate the progression of disease in several experimental rodent models of renal fibrosis.6Samuel C.S. Zhao C. Bond C.P. et al.Relaxin-1-deficient mice develop an age-related progression of renal fibrosis.Kidney Int. 2004; 65: 2054-2064Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 12Garber S.L. Mirochnik Y. Brecklin C.S. et al.Relaxin decreases renal interstitial fibrosis and slows progression of renal disease.Kidney Int. 2001; 59: 876-882Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, 13Garber S.L. Mirochnik Y. Brecklin C. et al.Effect of relaxin in two models of renal mass reduction.Am J Nephrol. 2003; 23: 8-12Crossref PubMed Scopus (61) Google Scholar, 14Mcdonald G.A. Sarkar P. Rennke H. et al.Relaxin increases ubiquitin-dependent degradation of fibronectin in vitro and ameliorates renal fibrosis in vivo.Am J Physiol Renal Physiol. 2003; 285: F59-F67Crossref PubMed Scopus (58) Google Scholar, 15Lekgabe E.D. Kiriazis H. Zhao C. et al.Relaxin reverses cardiac and renal fibrosis in spontaneously hypertensive rats.Hypertension. 2005; 46: 412-418Crossref PubMed Scopus (150) Google Scholar Continuous 2- to 4-week-infusion of relaxin with osmotic minipumps was shown to ameliorate fibrosis in several animal models. Morphometric studies in a rat model of bromoethylamine-induced renal papillary necrosis demonstrated that 28 days of H2 relaxin infusion decreased the fractional area of interstitial collagen staining by 75%. This was associated with a parallel reduction in immunoreactive TGFβ1, macrophage infiltration and a preservation of glomerular filtration rate.12Garber S.L. Mirochnik Y. Brecklin C.S. et al.Relaxin decreases renal interstitial fibrosis and slows progression of renal disease.Kidney Int. 2001; 59: 876-882Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar Similar effects were seen in both ablative and infarction models of 5/6 nephrectomy. There was a decrease in hypertension in the infarction model, but no change in blood pressure in the normotensive ablation model, suggesting that the preservation of glomerular filtration rate may be both blood pressure dependent and independent.13Garber S.L. Mirochnik Y. Brecklin C. et al.Effect of relaxin in two models of renal mass reduction.Am J Nephrol. 2003; 23: 8-12Crossref PubMed Scopus (61) Google Scholar Likewise, relaxin decreased focal glomerulosclerosis and interstitial fibrosis in an antiglomerular basement membrane nephritis model of disease.14Mcdonald G.A. Sarkar P. Rennke H. et al.Relaxin increases ubiquitin-dependent degradation of fibronectin in vitro and ameliorates renal fibrosis in vivo.Am J Physiol Renal Physiol. 2003; 285: F59-F67Crossref PubMed Scopus (58) Google Scholar While a means of preventing fibrogenesis is important, the ability to remove established fibrosis represents the 'holy grail.' The clinical reality is that many renal patients present with chronic disease, and therefore, established fibrosis. Again, studies of the natural history of RLX-/- mice have provided valuable insights. Treatment of established renal6Samuel C.S. Zhao C. Bond C.P. et al.Relaxin-1-defic
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