The emerging role of relaxin as a novel therapeutic pathway in the treatment of chronic kidney disease

American Journal of Physiology - Regulatory Integrative and Comparative Physiology

Volumn 305, Issue 6, 2013, Pages

  Sasser, Jennifer M ^a  

^a UNIVERSITY OF MISSISSIPPI SCHOOL OF MEDICINE   (United States)

Author keywords

Glomerular sclerosis; Matrix metalloproteinases; Nitric oxide; Oxidative stress; Renal function; Transforming growth factor ; Tubulointersitital fibrosis

Indexed keywords

COLLAGENASE 3; GELATINASE A; GELATINASE B; INTERSTITIAL COLLAGENASE; MATRIX METALLOPROTEINASE; NITRIC OXIDE; RECOMBINANT RELAXIN; RELAXIN; SERELAXIN; TRANSFORMING GROWTH FACTOR BETA;

ACUTE HEART FAILURE; BIRTH; CHRONIC KIDNEY DISEASE; CONGESTIVE HEART FAILURE; DISEASE COURSE; EXPERIMENTAL MODEL; FIBROSING ALVEOLITIS; GLOMERULOSCLEROSIS; GLOMERULUS FILTRATION RATE; HEART VENTRICLE HYPERTROPHY; HUMAN; HYPERTENSION; IMMUNOHISTOCHEMISTRY; KIDNEY; KIDNEY FAILURE; KIDNEY FIBROSIS; KIDNEY FUNCTION; KIDNEY PLASMA FLOW; KIDNEY PROXIMAL TUBULE; NONHUMAN; POTASSIUM EXCRETION; PREGNANCY; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN STRUCTURE; REVIEW; SODIUM EXCRETION; SYSTEMIC SCLEROSIS; URINARY EXCRETION;

GLOMERULAR SCLEROSIS; MATRIX METALLOPROTEINASES; NITRIC OXIDE; OXIDATIVE STRESS; RENAL FUNCTION; TRANSFORMING GROWTH FACTOR-Β; TUBULOINTERSITITAL FIBROSIS;

HUMANS; KIDNEY; RECEPTORS, G-PROTEIN-COUPLED; RECEPTORS, PEPTIDE; RELAXIN; RENAL INSUFFICIENCY, CHRONIC; SIGNAL TRANSDUCTION; SODIUM;

EID: 84884398620     PISSN: 03636119     EISSN: 15221490     Source Type: Journal    
DOI: 10.1152/ajpregu.00528.2012     Document Type: Review

References (92)

1. Agoulnik AI. Relaxin and Related Peptides. Springer Series: Advances in Experimental Medicine and Biology (612). New York: Landes Bioscience/ Springer Science + Business Media, 2007.
2. Agoulnik AI. Relaxin and related peptides in male reproduction. Adv Exp Med Biol 612: 49-64, 2007.
3. Baccari MC, Bani D. Relaxin and nitric oxide signaling. Curr Protein Pept Sci 9: 638-645, 2008.
4. Bani D, Masini E, Bello MG, Bigazzi M, Sacchi TB. Relaxin protects against myocardial injury caused by ischemia and reperfusion in rat heart. Am J Pathol 152: 1367-1376, 1998.
5. Bathgate RA, Ivell R, Sanborn BM, Sherwood OD, Summers RJ. International Union of Pharmacology LVII: recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacol Rev 58: 7-31, 2006.
6. Bathgate RA, Ivell R, Sanborn BM, Sherwood OD, Summers RJ. Receptors for relaxin family peptides. Ann NY Acad Sci 1041: 61-76, 2005.
7. Bathgate RA, Halls ML, van der Westhuizen ET, Callander GE, Kocan M, Summers RJ. Relaxin family peptides and their receptors. Physiol Rev 9: 405-80, 2013.
8. Bathgate RA, Samuel CS, Burazin TC, Layfield S, Claasz AA, Reytomas IG, Dawson NF, Zhao C, Bond C, Summers RJ, Parry LJ, Wade JD, Tregear GW. Human relaxin gene 3 (H3) and the equivalent mouse relaxin (M3) gene. Novel members of the relaxin peptide family. J Biol Chem 277: 1148-1157, 2002.
9. Baylis C. Nitric oxide deficiency in chronic kidney disease. Am J Physiol Renal Physiol 294: F1-F9, 2008.
10. Bogzil AH, Ashton N. Relaxin-induced changes in renal function and RXFP1 receptor expression in the female rat. Ann NY Acad Sci 1160: 313-316, 2009.
11. Bogzil AH, Eardley R, Ashton N. Relaxin-induced changes in renal sodium excretion in the anesthetized male rat. Am J Physiol Regul Integr Comp Physiol 288: R322-R328, 2005.
12. Border WA, Noble NA. TGF-β in kidney fibrosis: a target for gene therapy. Kidney Int 51: 1388-1396, 1997.
13. Brecht A, Bartsch C, Baumann G, Stangl K, Dschietzig T. Relaxin inhibits early steps in vascular inflammation. Regul Pept 166: 76-82, 2011.
14. Chow BS, Chew EG, Zhao C, Bathgate RA, Hewitson TD, Samuel CS. Relaxin signals through a RXFP1-pERK-nNOS-NO-cGMP-dependent pathway to up-regulate matrix metalloproteinases: the additional involvement of iNOS. PLos One 7: e42714, 2012.
15. Conrad KP. Unveiling the vasodilatory actions and mechanisms of relaxin. Hypertension 56: 2-9, 2010.
16. Conrad KP. Maternal vasodilation in pregnancy: the emerging role of relaxin. Am J Physiol Regul Integr Comp Physiol 301: R267-R275, 2011.
17. Conrad KP, Novak J. Emerging role of relaxin in renal and cardiovascular function. Am J Physiol Regul Integr Comp Physiol 287: R250-R261, 2004.
18. Danielson LA, Sherwood OD, Conrad KP. Relaxin is a potent renal vasodilator in conscious rats. J Clin Invest 103: 525-533, 1999.
19. Danielson LA, Welford A, Harris A. Relaxin improves renal function, and histology in aging Munich-Wistar rats. J Am Soc Nephrol 17: 1325-1333, 2006.
20. Debrah DO, Conrad KP, Jeyabalan A, Danielson LA, Shroff SG. Relaxin increases cardiac output and reduces systemic arterial load in hypertensive rats. Hypertension 46: 745-750, 2005.
21. Dschietzig T, Bartsch C, Baumann G, Stangl K. Relaxin-a pleiotropic hormone and its emerging role for experimental and clinical therapeutics. Pharmacol Ther 112: 38-56, 2006.
22. Dschietzig T, Brecht A, Bartsch C, Baumann G, Stangl K, Alexiou K. Relaxin improves TNF-α-induced endothelial dysfunction: the role of glucocorticoid receptor and phosphatidylinositol 3-kinase signaling. Cardiovasc Res 95: 97-107, 2012.
23. Dschietzig TC, Richter C, Bartsch C, Laule M, Armbruster FP, Baumann G, Stangl K. The pregnancy hormone relaxin is a player in human heart failure. FASEB J 15: 2187-2195, 2001.
24. Dschietzig T, Teichman S, Unemori E, Wood S, Boehmer J, Richter C, Baumann G, Stangl K. Intravenous recombinant human relaxin in compensated heart failure: a safety, tolerability, and pharmacodynamic trial. J Card Fail 15: 182-190, 2009.
25. Du XJ, Samuel CS, Gao XM, Zhao L, Parry LJ, Tregear GW. Increased myocardial collagen and ventricular diastolic dysfunction in relaxin deficient mice: a gender-specific phenotype. Cardiovasc Res 57: 395-404, 2003.
26. Eddy AA. Molecular basis of renal fibrosis. Pediatr Nephrol 15: 290-301, 2000.
27. Ferreira VM, Gomes TS, Reis LA, Ferreira AT, Razvickas CV, Schor N, Boim MA. Receptor-induced dilatation in the systemic and intrarenal adaptation to pregnancy in rats. PLos One 4: e4845, 2009.
28. Fevold HL, Hisaw FL, Meyer RK. The relaxative hormone of the corpus luteum: its purification and concentration. J Am Chem Soc 52: 3340-3348, 1930.
29. Garber SL, Mirochnik Y, Brecklin CS, Unemori EN, Singh AK, Slobodskoy L, Grove BH, Arruda JA, Dunea G. Relaxin decreases renal interstitial fibrosis and slows progression of renal disease. Kidney Int 59: 876-882, 2001.
30. Garber SL, Mirochnik Y, Brecklin C, Slobodskoy L, Arruda JA, Dunea G. Effect of relaxin in two models of renal mass reduction. Am J Nephrol 23: 8-12, 2003.
31. Graham EF, Dracy AE. The effect of relaxin and mechanical dilatation of the bovine cervix. J Dairy Sci 36: 772-777, 1953.
32. Gunnersen JM, Crawford RJ, Tregear GW. Expression of the relaxin gene in rat tissues. Mol Cell Endocrinol 110: 55-64, 1995.
33. Hall K. The effects of pregnancy and relaxin on the histology of the pubic symphysis of the mouse. J Endocrinol 5: 174-185, 1947.
34. Heeg MH, Koziolek MJ, Vasko R, Schaefer L, Sharma K, Muller GA, Strutz F. The antifibrotic effects of relaxin in human renal fibroblasts are mediated in part by inhibition of the Smad2 pathway. Kidney Int 68: 96-109, 2005.
35. Hewitson TD, Ho WY, Samuel CS. Antifibrotic properties of relaxin: in vivo mechanism of action in experimental renal tubulointerstitial fibrosis. Endocrinology 151: 4938-4948, 2010.
36. Hewitson TD, Mookerjee I, Masterson R, Zhao C, Tregear GW, Becker GJ, Samuel CS. Endogenous relaxin is a naturally occurring modulator of experimental renal tubulointerstitial fibrosis. Endocrinology 148: 660-669, 2007.
37. Hewitson TD, Zhao C, Wigg B, Lee SW, Simpson ER, Boon WC, Samuel CS. Relaxin and castration in male mice protect from, but testosterone exacerbates, age-related cardiac and renal fibrosis, whereas estrogens are an independent determinant of organ size. Endocrinology 153: 188-199, 2012.
38. Hisaw F. Experimental relaxation of the pubic ligament of the guinea pig. Proc Soc Exp Biol Med 23: 661-663, 1926.
39. Hsu SY. New insights into the evolution of the relaxin-LGR signaling system. Trends Endocrinol Metab 14: 303-309, 2003.
40. Hsu SY, Kudo M, Chen T, Nakabayashi K, Bhalla A, van der Spek PJ, van Duin M, Hsueh AJ. The three subfamilies of leucine rich repeatcontaining G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7. Mol Endocrinol 14: 1257-1271, 2000.
41. Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, Hsueh AJ. Activation of orphan receptors by the hormone relaxin. Science 295: 671-674, 2002.
42. Jeyabalan A, Novak J, Danielson LA, Kerchner LJ, Opett SL, Conrad KP. Essential role for vascular matrix metalloproteinases-2 in relaxininduced renal vasodilation, hyperfiltration, and reduced myogenic reactivity of small arteries. Circ Res 93: 1249-1257, 2003.
43. Kapila S, Wang W, Uston K. Matrix metalloproteinase induction by relaxin causes cartilage matrix degradation in target synovial joints. Ann NY Acad Sci 1160: 322-328, 2009.
44. Kompa AR, Samuel CS, Summers RJ. Inotropic responses to human gene 2 (B29) relaxin in a rat model of myocardial infarction (MI): effect of pertussis toxin. Br J Pharmacol 137: 710-718, 2002.
45. Krajnc-Franken MA, van Disseldorp AJ, Koenders JE, Mosselman S, van Duin M, Gossen JA. Impaired nipple development and parturition in LGR7 knockout mice. Mol Cell Biol 24: 687-696, 2004.
46. Krantz JC Jr, Bryant HH, Carr CJ. The action of aqueous corpus luteum extract upon uterine activity. Surg Gynecol Obstet 90: 372-375, 1950.
47. Kubota Y, Temelcos C, Bathgate RA, Smith KJ, Scott D, Zhao C, Hutson JM. The role of insulin 3, testosterone, Mullerian inhibiting substance and relaxin in rat gubernacular growth. Mol Hum Reprod 8: 900-905, 2002.
48. Kumagai JS, Hsu SY, Matsumi H, Roh JS, Fu P, Wade JD, Bathgate RA, Hsueh AJ. INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent. J Biol Chem 277: 31283-31286, 2002.
49. Lekgabe ED, Kiriazis H, Zhao C, Xu Q, Moore XL, Su Y, Bathgate RA, Du XJ, Samuel CS. Relaxin reverses cardiac and renal fibrosis in spontaneously hypertensive rats. Hypertension 46: 412-418, 2005.
50. Lenhart JA, Ryan PL, Ohleth KM, Palmer SS, Bagnell CA. Relaxin increases secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9 during uterine and cervical growth and remodeling in the pig. Endocrinology 142: 3941-3949, 2001.
51. López-Hernández FJ, López-Novoa JM. Role of TGF-β in chronic kidney disease: an integration of tubular, glomerular and vascular effects. Cell Tissue Res 347: 141-154, 2012.
52. Masini E, Bani D, Bello MG, Bigazzi M, Mannaioni PF, Sacchi TB. Relaxin counteracts myocardial damage induced by ischemia-reperfusion in isolated guinea pig hearts: evidence for an involvement of nitric oxide. Endocrinology 138: 4713-4720, 1997.
53. Masini E, Cuzzocrea S, Mazzon E, Muia C, Vannacci A, Fabrizi F, Bani D. Protective effects of relaxin in ischemia/reperfusion-induced intestinal injury due to splanchnic artery occlusion. Br J Pharmacol 148: 1124-1132, 2006.
54. Masterson R, Hewitson TD, Kelynack K, Martic M, Parry L, Bathgate R, Darby I, Becker G. Relaxin down-regulates renal fibroblast function and promotes matrix remodelling in vitro. Nephrol Dial Transplant 19: 544-552, 2004.
55. McGuane JT, Parry LJ. Relaxin and the extracellular matrix: molecular mechanisms of action and implications for cardiovascular disease. Expert Rev Mol Med 7: 1-18, 2005.
56. McDonald GA, Sarkar P, Rennke H, Unemori E, Kalluri R, Sukhatme VP. Relaxin increases ubiquitin-dependent degradation of fibronectin in vitro and ameliorates renal fibrosis in vivo. Am J Physiol Renal Physiol 285: F59-F67, 2003.
57. Moncada S, Higgs EA. Nitric oxide and the vascular endothelium. Hand Exp Pharmacol 176: 213-254, 2006.
58. Mookerjee I, Hewitson TD, Halls ML, Summers RJ, Mathai ML, Bathgate RA, Tregear GW, Samuel CS. Relaxin inhibits renal myofibroblast differentiation via RXFP1, the nitric oxide pathway, and Smad2. FASEB J 23: 1219-1229, 2009.
59. Novak J, Parry LJ, Matthews JE, Kerchner LJ, Indovina K, Hanley-Yanez K, Doty KD, Debrah DO, Shroff SG, Conrad KP. Evidence for local relaxin ligand-receptor expression and function in arteries. FASEB J 20: 2352-2362, 2006.
60. Osheroff PL, Cronin MJ, Lofgren JA. Relaxin binding in the rat heart atrium. Proc Natl Acad Sci USA 89: 2384-2388, 1992.
61. Osheroff PL, Ho WH. Expression of relaxin mRNA and relaxin receptors in postnatal and adult rat brains and hearts. Localization and developmental patterns. J Biol Chem 268: 15193-15199, 1993.
62. Osheroff PL, Ling VT, Vandlen RL, Cronin MJ, Lofgren JA. Preparation of biologically active 32P-labeled human relaxin. Displaceable binding to rat uterus, cervix, and brain. J Biol Chem 265: 9396-9401, 1990.
63. Palejwala S, Weiss G, Goldsmith LT. Relaxin stimulates expression of matrix metalloproteinase 2 by human lower uterine segment fibroblasts. J Soc Gynecol Invest 7: 124A, 2000.
64. Park JI, Chang CL, Hsu SY. New insights into biological roles of relaxin and relaxin-related peptides. Rev Endocr Metab Disord 6: 291-296, 2005.
65. Royce SG, Miao YR, Lee M, Samuel CS, Tregear GW, Tang ML. Relaxin reverses airway remodeling and airway dysfunction in allergic airways disease. Endocrinology 150: 2692-2699, 2009.
66. Samuel CS. Relaxin: antifibrotic properties and effects in models of disease. Clin Med Res 3: 241-249, 2005.
67. Samuel CS, Hewitson TD. Relaxin in cardiovascular and renal disease. Kidney Int 69: 1498-1502, 2006.
68. Samuel CS, Hewitson TD, Unemori EN, Tang ML. Drugs of the future: the hormone relaxin. Cell Mol Life Sci 64: 1539-1557, 2007.
69. Samuel CS, Hewitson TD, Zhang Y, Kelly DJ. Relaxin ameliorates fibrosis in experimental diabetic cardiomyopathy. Endocrinology 149: 3286-3293, 2008.
70. Samuel CS, Unemori EN, Mookerjee I, Bathgate RA, Layfield SL, Mak J, Tregear GW, Du XJ. Relaxin modulates cardiac fibroblast proliferation, differentiation, and collagen production and reverses cardiac fibrosis in vivo. Endocrinology 145: 4125-4133, 2004.
71. Samuel CS, Zhao C, Bathgate RA, Bond CP, Burton MD, Parry LJ, Summers RJ, Tang ML, Amento EP, Tregear GW. Relaxin deficiency in mice is associated with an age-related progression of pulmonary fibrosis. FASEB J 17: 121-123, 2003.
72. Samuel CS, Zhao C, Bathgate RA, DU XJ, Summers RJ, Amento EP, Walker LL, McBurnie M, Zhao L, Tregear GW. The relaxin geneknockout mouse: A model of progressive fibrosis. Ann NY Acad Sci 1041: 173-181, 2005.
73. Samuel CS, Zhao C, Bond CP, Hewitson TD, Amento EP, Scott RJ, Layfield S, Riesewijk A, Morita H, Tregear GW, Bathgate RA. Identification and characterization of the mouse and rat relaxin receptors as the novel orthologues of human leucine-rich repeat-containing G-protein-coupled receptor 7. Clin Exp Pharmacol Physiol 31: 828-832, 2004.
74. Samuel CS, Zhao C, Bond CP, Hewitson TD, Amento EP, Summers RJ. Relaxin-1-deficient mice develop an age-related progression of renal fibrosis. Kidney Int 65: 2054-2064, 2004.
75. Sasser JM, Molnar M, Baylis C. Relaxin ameliorates hypertension and increases nitric oxide metabolite excretion in angiotensin II but not N(ω)-nitro-l-arginine methyl ester hypertensive rats. Hypertension 58: 197-204, 2011.
76. Scott DJ, Layfield S, Riesewijk A, Morita H, Tregear GW, Bathgate RA. Identification and characterization of the mouse and rat relaxin receptors as the novel orthologues of human leucine-rich repeat-containing G-protein-coupled receptor 7. Clin Exp Pharmacol Physiol 31: 828-832, 2004.
77. Sherwood OD. Relaxin. In: The Physiology of Reproduction, edited by Knobil E and Neill JC. New York: Raven Press, New York, 1994, p. 1861-1009.
78. Sherwood OD. Relaxin's physiological roles and other diverse actions. Endocr Rev 25: 205-234, 2004.
79. Smith MC, Danielson LA, Conrad KP, Davison JM. Influence of recombinant human relaxin on renal hemodynamics in healthy volunteers. J Am Soc Nephrol 17: 3192-3197, 2006.
80. St-Louis J, Massicotte G. Chronic decrease of blood pressure by rat relaxin in spontaneously hypertensive rats. Life Sci 37: 1351-1357, 1985.
81. Tan YY, Wade JD, Tregear GW, Summers RJ. Quantitative autoradiographic studies of relaxin binding in rat atria, uterus and cerebral cortex: characterization and effects of oestrogen treatment. Br J Pharmacol 127: 91-98, 1999.
82. Teerlink JR, Metra M, Felker GM, Ponikowski P, Voors AA, Weatherley BD, Marmor A, Katz A, Grzybowski J, Unemori E, Teichman SL, Cotter G. Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study. Lancet 373: 1429-1439, 2009.
83. Teerlink JR, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, Ponikowski P, Unemori E, Voors AA, Adams KF Jr, Dorobantu MI, Grinfeld LR, Jondeau G, Marmor A, Masip J, Pang PS, Werdan K, Teichman SL, Trapani A, Bush CA, Saini R, Schumacher C, Severin TM, Metra M. RELAXin in Acute Heart Failure (RELAX-AHF) Investigators. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 81: 29-39, 2013.
84. Teichman SL, Unemori E, Dschietzig T, Conrad K, Voors AA, Teerlink JR, Felker GM, Metra M, Cotter G. Relaxin, a pleiotropic vasodilator for the treatment of heart failure. Heart Fail Rev 14: 321-329, 2009.
85. Turner JM, Bauer C, Abramowitz MK, Melamed ML, Hostetter TH. Treatment of chronic kidney disease. Kidney Int 81: 351-62, 2012.
86. Unemori EN, Amento EP. Relaxin modulates synthesis and secretion of procollagenase and collagen by human dermal fibroblasts. J Biol Chem 265: 10681-10685, 1990.
87. Unemori EN, Pickford LB, Salles AL, Piercy CE, Grove BH, Erikson ME, Amento EP. 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.
88. Unemori E, Sibai B, Teichman SL. Scientific rationale and design of a phase I safety study of relaxin in women with severe preeclampsia. Ann NY Acad Sci 1160: 381-384, 2009.
89. Wilkinson TN, Speed TP, Tregear GW, Bathgate RA. Evolution of the relaxin-like peptide family. BMC Evol Biol 5: 14, 2005.
90. Williams EJ, Benyon RC, Trim N, Hadwin R, Grove BH, Arthur MJ, Unemori EN, Iredale JP. Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo. Gut 49: 577-583, 2001.
91. Xu Q, Chakravorty A, Bathgate RA, Dart AM, Du XJ. Relaxin therapy reverses large artery remodeling and improves arterial compliance in senescent spontaneously hypertensive rats. Hypertension 55: 1260-1266, 2010.
92. Yoshida T, Kumagai H, Suzuki A, Kobayashi N, Ohkawa S, Odamaki M, Kohsaka T, Yamamoto T, Ikegaya N. Relaxin ameliorates saltsensitive hypertension and renal fibrosis. Nephrol Dial Transplant 27: 2190-2197, 2012.