Systemic administration of recombinant human relaxin (RHRLX) ameliorates the acute cyclosporine nephrotoxicity in rats

Abstract

Relaxin: a 6KD peptide hormone of pregnancy belonging to insulin family, has three major biological actions: antifibrotic, angiogenic and vasodilatory. Previous publications have shown that treatment with recombinant human relaxin (rhRlx) elicits potent renal vasodilation and hyperfiltration in conscious rats in a nitric oxide (NO)-dependent manner, thereby mimicking pregnancy. The objective of this study was to evaluate the effect of rhRlx treatment in acute cyclosporine nephrotoxicity in rats. A total of 124 rats female Sprague Dawley rats were treated with either Cyclosporine (30 mg/kg po day 0-10) or vehicle (olive oil) for 10 days. Recombinant human relaxin (rhRlx) at a dose of either 0.1 mg/kg/day or 0.5 mg/kg/day was administered to rats subcutaneously via Alzet pumps (Alza Corp., Mountain view, CA) from day 0-10. On day 5 and day 10 of treatment, the kidney function (urine flow rate [UFR] and glomeruli filtration rate [GFR]) measured by metabolic cages was recorded. On day 10, the animals were euthanized and the kidneys fixed for were subjected to histological evaluation. Consistent with previously published results, systemic administration of rhRlx (0.5 mg/kg) to normal rats enhanced both GFR and UFR by day 5 (147% & 168% compared to the baseline, respectively). CsA treatment alone significantly reduced GFR and UFR on both day 5 and day 10 compared to baseline by 30-35% (p<0.05). The GFR and UFR in animals treated with both CsA and rhRlx at either a dose of 0.1mg/kg or 0.5 mg/kg were significantly improved compare to those of animals treated with CsA alone (p<0.05). Histological evaluation of cross-sections of the kidneys from rats at day 10 revealed marked improvement on tubulopathy and arteriolopathy. The data from this study demonstrated that systemic administration of rhRlx enhanced kidney functions in normal rats and ameliorated cyclosporine induced acute nephrotoxicity in rats. The results indicate that systemic administration of rhRlx may have potential benefit in preventing cyclosporine-induced nephrotoxicity.