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Endogenous Relaxin Is a Naturally Occurring Modulator of Experimental Renal Tubulointerstitial Fibrosis

Department of Nephrology (T.D.H., R.M., G.J.B.), Royal Melbourne Hospital, Parkville, Victoria 3050, Australia; and Departments of Medicine (T.D.H., R.M., G.J.B.) and Biochemistry and Molecular Biology (I.M., G.W.T., C.S.S.), Howard Florey Institute of Experimental Physiology and Medicine (I.M., C.Z., G.W.T., C.S.S.), University of Melbourne, Victoria 3010, Australia

Address all correspondence and requests for reprints to: Chrishan S. Samuel, Ph.D., Howard Florey Institute, University of Melbourne, Parkville, Victoria 3010, Australia. E-mail: c.samuel{at}hfi.unimelb.edu.au.

Relaxin is a naturally occurring regulator of collagen turnover. In this study, we determined the role of endogenous relaxin in the pathogenesis of primary tubulointerstitial fibrosis after unilateral ureteric obstruction (UUO). Four- to 6-wk-old relaxin (RLX) gene-knockout (RLX^–/–) and age-matched wild-type (RLX^+/+) mice, with equivalent baseline collagen levels, were subjected to UUO. Obstructed and contralateral kidneys were collected at d 0, 3, and 10 after surgery and analyzed for changes in inflammatory and fibrosis-related markers. UUO was associated with a progressive increase in fibrosis in all obstructed, but not contralateral kidneys. The increase in total collagen (hydroxyproline analysis) was associated with more -smooth muscle actin (-SMA) staining (myofibroblasts) and interstitial collagen sub-types (SDS-PAGE; types I, III, and V), whereas gelatin zymography demonstrated increased expression of matrix metalloproteinase-2 after surgery. By d 10 after UUO, there was a 5-fold decrease in RLX mRNA expression (quantitative RT-PCR) in RLX^+/+ animals. Total collagen and -SMA expression were significantly greater in the obstructed kidneys of RLX^–/– mice 3 d after UUO (both P < 0.05 vs. RLX^+/+ D3 after UUO), but comparable to that in RLX^+/+ animals 10 d after UUO. Administration of recombinant H2 relaxin to RLX^–/– mice 4 d before UUO ameliorated the increase in collagen and -SMA expression (both P < 0.05 vs. untreated RLX^–/– mice) by d 3 after UUO. Expression of monocyte chemoattractant protein-1 and macrophage infiltration (inflammation) in addition to that of matrix metalloproteinases was unaffected by genotype after UUO. These combined data demonstrate that endogenous RLX acts as a modulating factor in tubulointerstitial fibrosis, a hallmark of progressive renal disease. This is likely to be via direct effects on renal myofibroblast function.

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