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The Anti-fibrotic Hormone Relaxin is not Reno-protective, Despite Being Active, in an Experimental Model of Type 1 Diabetes

[ Vol. 20 , Issue. 9 ]

Author(s):

Su Ee Wong, Chrishan S. Samuel, Darren J. Kelly, Yuan Zhang, Gavin J. Becker and Tim D. Hewitson   Pages 1029 - 1038 ( 10 )

Abstract:


The end-point of diabetic renal disease is the accumulation of excess collagen (fibrosis/sclerosis). A number of studies have shown that the hormone relaxin (RLX) ameliorates progression of renal and non-renal fibrosis. This study assessed the anti-fibrotic potential of RLX in streptozotocin (STZ)-treated transgenic mRen-2 rats, an accelerated model of type 1 diabetes.

Eight-week old hyperglycaemic (STZ-treated at week-6) and normoglycaemic (STZ-untreated) animals were treated with or without recombinant human gene-2 (H2) RLX for 4-weeks (by osmotic mini-pumps) and assessed for various parameters at 12-weeks of age.

Hyperglycaemic mRen-2 rats had elevated kidney weight/body weight ratio, glomerular filtration rate (GFR), albumin excretion rate (AER), interstitial collagen I and glomerulosclerosis (all p<0.05 vs non-diabetic controls). H2 RLX infusion had no effect on any of these parameters. Increased MMP-2 levels in RLX-treated rats demonstrated that the hormone was administered and active in this model. The inability of H2 RLX to slow glomerulopathy in diabetic mRen-2 rats could be in part due to the absence of its receptor, RXFP1, in rat mesangial cells, a primary mediator of diabetic glomerulosclerosis and/or the lack of any effect on TGF-β1/Smad2 signalling, a well described mediator of RLX activity.

These findings highlight the cell specific actions of RLX, the dissociation of anti-fibrogenic (collagen synthesis) and antifibrolytic (MMP mediated collagen degradation) properties, and the central involvement of TGF-β1 in its actions.

Keywords:

Relaxin, diabetic nephropathy, sclerosis, mesangial cells, matrix metalloproteinases, TGF-β1, Smad2.

Affiliation:

Department of Nephrology, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.



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