The anti-fibrotic hormone relaxin is not reno-protective, despite being active, in an experimental model of type 1 diabetes.
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.
Howard Florey Institute, University of Melbourne, Victoria 3010, Australia.
Su Ee
SE
Wong
Chrishan S
CS
Samuel
Darren J
DJ
Kelly
Yuan
Y
Zhang
Gavin J
GJ
Becker
Tim D
TD
Hewitson
D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050527:Mesangial Cells / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D011994:Recombinant Proteins / Q000494:pharmacology; D012065:Relaxin / Q000494:pharmacology*; D012083:Renin / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D020011:Protective Agents; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; C562214:mRen2 protein, rat; D012065:Relaxin; D012083:Renin