Short-term nitric oxide inhibition induces progressive nephropathy after regression of initial renal injury

Chronic nitric oxide ( NO) inhibition and salt overload (HS) promote severe hypertension and renal injury, which regress quickly, although not completely, on treatment withdrawal. We investigated whether renal function and structure remain stable 6 mo after cessation of these treatments. Adult male Munich-Wistar rats were distributed among three groups: HS, receiving 3.1% Na diet; HS + N, receiving HS and the NO inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME; 30 mg (.) kg(-1) (.) day(-1) orally); and HS + N + L, receiving HS + N and the ANG II blocker losartan ( L; 50 mg (.) kg(-1) (.) day(-1) orally). In studies performed after 20 days of treatment ( protocol 1), HS + N rats exhibited severe glomerular and systemic hypertension, massive albuminuria, glomerular and interstitial injury, and infiltration by macrophages and cells expressing ANG II. These abnormalities were largely prevented in the HS + N + L group. A second cohort ( protocol 2) received HS + N for 20 days, followed by a conventional (0.5% Na) diet and no L-NAME treatment during the subsequent 30 days. At this time, systemic and glomerular pressure, along with parameters of renal injury and inflammation, were still higher than in HS or HS + N + L rats, although differences were much smaller than in protocol 1. Six months after 20-day L-NAME/salt overload treatment was ceased ( protocol 3), severe albuminuria, hypertension, and renal injury developed in HS + N rats. Again, losartan prevented most of these changes. We conclude 1) short-term HS + N treatment triggers the autonomous development of progressive glomerulosclerosis; 2) this process may involve activation of the AT(1) receptor; and 3) temporary HS + N treatment may represent a new model of slowly progressive chronic nephropathy.