Arginase inhibition slows the progression of renal failure in rats with renal ablation.
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.
Sabbatini
Massimo
M
Departments of Nephrology and Experimental Medicine, University Federico II, 80131 Naples, Italy. sabbatin@unina.it
Pisani
Antonio
A
Uccello
Francesco
F
Fuiano
Giorgio
G
Alfieri
Raffaele
R
Cesaro
Antonio
A
Cianciaruso
Bruno
B
Andreucci
Vittorio E
VE
D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001120:Arginine / Q000097:blood / Q000494:pharmacology; D001835:Body Weight; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D005526:Food, Formulated; D006439:Hemodynamics; D007668:Kidney / Q000201:enzymology / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000503:physiopathology; D008099:Liver / Q000378:metabolism; D008297:Male; D008345:Manganese / Q000172:deficiency; D051381:Rats; D017207:Rats, Sprague-Dawley
D008345:Manganese; D001120:Arginine; D001119:Arginase