Arginase inhibition slows the progression of renal failure in rats with renal ablation

Abstract

Exogenous arginine slows the progression of chronic renal failure (CRF) in remnant rats through a nitric oxide (NO)-dependent mechanism. We tested whether the inhibition of arginase could induce similar results through the increased availability of endogenous arginine. Three groups of remnant rats were studied for 8 wk: 1) untreated rats (REM); 2) remnant rats treated with 1% l-arginine (ARG); and 3) remnant rats administered a Mn(2+)-free diet to inhibit arginase (MNF). Normal rats (NOR) were used as controls. Liver arginase activity was depressed in MNF rats (-35% vs. REM, P < 0.01). No difference in metabolic data was detected among the groups throughout the study; blood pressure was significantly lower in MNF vs. ARG and REM rats after 6 wk (P < 0.001). The glomerular filtration rate (GFR) was greatly depressed in REM rats (-47% vs. NOR, P < 0.03) but was higher in ARG and MNF rats (+40 and +43% vs. REM, respectively, P < 0.05), with comparable changes in renal hemodynamics. Despite the better GFR, proteinuria was decreased in both ARG and MNF rats (-42%, P < 0.05, and -57%, P < 0.01, respectively, vs. REM rats). Arginine plasma levels, significantly reduced in REM rats (-41% vs. NOR, P < 0.01), were partially restored in MNF rats (+38% vs. REM), and urinary nitrite excretion, greatly depressed in REM rats (-76% vs. NOR, P < 0.01), was significantly increased in MNF rats (+209% vs. REM, P < 0.05). At the renal level, arginase activity was only slightly depressed in MNF rats (-18% vs. REM), but intrarenal concentrations of arginine were lower in this latter group (P < 0.05 vs. other groups). Beyond the hemodynamic modifications, MNF rats showed a lower glomerular sclerosis index (P < 0.05 vs. REM and ARG). Inhibition of arginase slows the progression of CRF in remnant rats similarly to arginine-treated rats; the better histological protection in MNF rats, however, suggests that additional factors are involved in these modifications.