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

Abstract

nase inhibition slows the progression of renal failure in rats with renal ablation. Am J Physiol Renal Physiol 284: F680-F687, 2003. First published December 10, 2002 10.1152/ajprenal.00270.2002. 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 2ϩ -free diet to inhibit arginase (MNF). Normal rats (NOR) were used as controls. Liver arginase activity was depressed in MNF rats (Ϫ35% vs. REM, P Ͻ 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 Ͻ 0.001). The glomerular filtration rate (GFR) was greatly depressed in REM rats (Ϫ47% vs. NOR, P Ͻ 0.03) but was higher in ARG and MNF rats (ϩ40 and ϩ43% vs. REM, respectively, P Ͻ 0.05), with comparable changes in renal hemodynamics. Despite the better GFR, proteinuria was decreased in both ARG and MNF rats (Ϫ42%, P Ͻ 0.05, and Ϫ57%, P Ͻ 0.01, respectively, vs. REM rats). Arginine plasma levels, significantly reduced in REM rats (Ϫ41% vs. NOR, P Ͻ 0.01), were partially restored in MNF rats (ϩ38% vs. REM), and urinary nitrite excretion, greatly depressed in REM rats (Ϫ76% vs. NOR, P Ͻ 0.01), was significantly increased in MNF rats (ϩ209% vs. REM, P Ͻ 0.05). At the renal level, arginase activity was only slightly depressed in MNF rats (Ϫ18% vs. REM), but intrarenal concentrations of arginine were lower in this latter group (P Ͻ 0.05 vs. other groups). Beyond the hemodynamic modifications, MNF rats showed a lower glomerular sclerosis index (P Ͻ 0.05 vs. REM and ARG). Inhibition of arginase slows the progression of CRF in remnant rats similarly to argininetreated rats; the better histological protection in MNF rats, however, suggests that additional factors are involved in these modifications. remnant rat; arginine; nitric oxide; chronic renal failure THE METABOLISM OF ARGININE is particularly complex: this semiessential amino acid, in fact, is endogenously synthesized in renal proximal tubules from L-citrulline (Citr) and is then degraded, through distinct enzymatic routes, to several metabolites that may affect both renal function and morphology (25,38). The first important pathway is represented by arginase, mostly present in the liver and to a much lesser extent in the kidney, which leads to formation of urea and ornithine (Orn), the precursor of polyamines and proline involved in cell-replication turnover and collagen synthesis (25). The second metabolic route is constituted by the arginine decarboxilase (ADC

Arginine, arginine analogs and nitric oxide production in chronic kidney disease

“…55 Vascular arginase activity is increased in experimental hypertension and inhibition of arginase restores endothelial NO synthesis. [56][57][58][59] Arginase I and arginase II are upregulated in the vasculature of Dahl salt-sensitive rats maintained on a high-salt diet; 58 similar findings have been reported for spontaneously hypertensive rats. 59 Particularly relevant is that inhibition of arginase protects the kidney from structural damage in the 5/6 renal mass ablation/infarction model of CKD, 56 indicating that arginase inhibition might be a novel therapeutic approach to slowing progressive renal damage.…”

“…23 The kidney contains arginase II, and endothelial cells contain both isoforms. 23,55,56 Arginases compete with NOS for L-arginine and can thereby limit NO production; indeed, NO production is attenuated in endothelial cells overexpressing arginase I and arginase II. 55 Vascular arginase activity is increased in experimental hypertension and inhibition of arginase restores endothelial NO synthesis.…”

Long-Term, High-Dosage Candesartan Suppresses Inflammation and Injury in Chronic Kidney Disease

“…For general histology, sections were processed for hematoxylin/eosin, periodic acid-Schiff, and Masson-Trichrome staining. A semiquantitative morphometric score index (SI) was used to evaluate the degree of glomerulosclerosis (22,25). Sclerosis was defined as collapse and/or obliteration of glomerular capillary tuft accompanied by hyaline material and/or increase of matrix.…”

Potential Therapeutic Role of Phosphodiesterase Type 5 Inhibition in Hypertension and Chronic Kidney Disease

“…It also decreased proteinuria in a 5/6 ablation model of CKD. 37 In contrast, Moradi et al 38 found that there was no difference in arginase I and II protein abundance among CKD and control groups in a rat 5/6 nephrectomy model. Here, high urea concentrations in CKD may inhibit arginase activity, may attenuate l-arginine catabolism, and may mitigate the fall in l-arginine levels.…”