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.
Fujihara
Clarice K
CK
Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, Av. Dr. Arnaldo 455, 3-s/3342, 01246-903 São Paulo SP, Brazil.
Sena
Claudia R
CR
Malheiros
Denise M A C
DM
Mattar
Ana L
AL
Zatz
Roberto
R
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D012982:Sodium, Dietary / Q000633:toxicity*; D014563:Urodynamics / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D012982:Sodium, Dietary; D009569:Nitric Oxide; D019331:NG-Nitroarginine Methyl Ester