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

Author(s): Su Ee Wong, Chrishan S. Samuel, Darren J. Kelly, Yuan Zhang, Gavin J. Becker, Tim D. Hewitson.

Journal Name: Protein & Peptide Letters

Volume 20 , Issue 9 , 2013

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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.

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Article Details

VOLUME: 20
ISSUE: 9
Year: 2013
Page: [1029 - 1038]
Pages: 10
DOI: 10.2174/0929866511320090009

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