CHRONIC NITRIC-OXIDE SYNTHASE INHIBITION AGGRAVATES GLOMERULAR INJURYIN RATS WITH SUBTOTAL NEPHRECTOMY

Besides its glomerular hemodynamic effects, nitric oxide (NO) inhibits platelet aggregation and mesangial cell proliferation, two mechanisms possibly involved in the pathogenesis of glomerulosclerosis (GS). Chr onic NO synthase inhibition in the rat leads to marked arterial hypert ension and promotes glomerular and interstitial injury, but only mild GS. In this study, NO synthase blockade by nitro-L-arginine methyl est er (L-NAME) was associated with 5/6 nephrectomy, a well-known model of GS. Sixty-eight adult male Munich-Wistar rats were distributed among four groups: SHAM (no renal ablation or drug treatment), NX (5/6 nephr ectomy), NX+NAME (5/6 nephrectomy and chronic treatment with L-NAME, 5 mg/dL in drinking water) and NX+NAME+L (as in group NX+NAME but also receiving the angiotensin II receptor inhibitor Losartan potassium (L) , 25 mg/dL in drinking water), One week after ablation, rats of Group NX showed moderate glomerular hypertension and hypertrophy. Although g lomerular enlargement was also modest in Group NX+NAME, glomerular hyp ertension was particularly severe in this group. Both alterations were absent in Group NX+NAME+L. Only incipient glomerular and interstitial injury occurred at this phase. Three weeks after ablation, renal stru ctural injury was still modest in Group NX. By contrast, Group NX+NAME exhibited marked GS, glomerular ischemic injury, interstitial expansi on, and creatinine retention. Renal injury was largely prevented in Gr oup NX+NAME+L, Tuft enlargement occurred in all groups but was most pr ominent in Group NX. NO synthase inhibition aggravates parenchymal inj ury and functional impairment in the remnant kidney by mechanisms that may involve glomerular hypertension and renin-angiotensin activation but that appear to be unrelated to glomerular enlargement.