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.