Oral supplementation of L-arginine prevents chronic cyclosporine nephrotoxicity in rats

This study was performed to evaluate the effect of L-arginine (L-Arg) on the prevention of chronic cyclosporine (CsA) nephrotoxicity in rats. Rats pair-fed a low-salt diet (0.05%) were given CsA (15 mg/kg/day s.c.), CsA and L-Arg (L-Arg group, 1.25 g/l water), CsA and N-nitro-L-arginine methyl ester (L-NAME group, 70 mg/l water) or vehicle. After 28 days, the L-Arg group had a higher glomerular filtration rate compared to the CsA (0.42 ± 0.05 vs. 0.31 ± 0.06 ml/min/100 g, p < 0.05) and the L-NAME groups (vs. 0.19 ± 0.04 ml/min/100 g, p < 0.05) and a significantly lower serum creatinine level compared to the CsA (0.70 ± 0.06 vs. 0.92 ± 0.12 mg/dl, p < 0.05) and the L-NAME groups (vs. 1.21 ± 0.17 mg/dl, p < 0.05). The L-Arg group had less fibrosis, tubular injury (TI), and arteriolopathy than the CsA (fibrosis 0.39 ± 0.14 vs. 0.74 ± 0.15; TI 1.3 ± 0.3 vs. 2.0 ± 0.1; arteriolopathy 33 ± 7 vs. 48 ± 17, p < 0.05, respectively) and the L-NAME groups (fibrosis vs. 1.67 ± 0.32, TI vs. 2.6 ± 0.3, arteriolopathy vs. 63 ± 10, p < 0.05, respectively). Plasma renin activity in the L-Arg group was less than in the CsA (18 ± 2 vs. 23 ± 3 ng Ang I/ml/h, p < 0.05) and the L-NAME groups (vs. 30 ± 3 ng Ang I/ml/h, p < 0.05). Nitric oxide production in L-Arg group was higher than in the CsA (24.2 ± 1.7 vs. 11.1 ± 1.5 μmol/24 h, p < 0.05) and the L-NAME groups (vs. 8.4 ± 1.0 μmol/24 h, p < 0.05). In conclusion, the nitric oxide pathway is associated with the pathogenesis of chronic CsA nephrotoxicity, and exogenous L-Arg supplementation is effective in reducing chronic CsA nephrotoxicity in rats.