RESUMO
Recent studies indicated that the nuclear transcription factor, NF-kappaB, activates a number of proinflammatory genes in subjects with progressive nephropathies. We investigated whether NF-kappaB inhibition limits progressive renal injury in the 5/6 renal ablation model (Nx). Adult male Munich-Wistar rats were subdivided in four groups: S (n = 16), subjected to sham operation; S+PDTC (n = 18), sham-operated rats receiving the NF-kappaB inhibitor pyrrolidine-dithiocarbamate (PDTC; 60 mg x kg(-1) x day(-1)) in drinking water; Nx (n = 16), Nx rats receiving vehicle only; and Nx+PDTC (n = 19), Nx rats given PDTC as above. Thirty days after renal ablation, Nx rats exhibited systemic and glomerular hypertension. Only the former was attenuated by PDTC treatment. Sixty days after renal ablation, Nx rats exhibited marked hypertension, albuminuria and creatinine retention, as well as glomerulosclerosis and cortical interstitial expansion/inflammation. Immunohistochemical analysis of Nx rats showed renal interstitial infiltration by macrophages and by cells staining positively for ANG II and its receptor, AT(1). Glomerular and interstitial cells expressing the p65 subunit of the NF-kappaB system were also found. PDTC treatment attenuated renal injury and inflammation, as well as the density of cells staining positively for the p65 subunit. Activation of the NF-kappaB system plays an important role in the pathogenesis of renal injury in the Nx model. Inhibition of this system may represent a new strategy to prevent the progression of chronic kidney disease.
Assuntos
Nefropatias/prevenção & controle , Rim/patologia , NF-kappa B/antagonistas & inibidores , Nefrectomia , Pirrolidinas/farmacologia , Tiocarbamatos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Imuno-Histoquímica , Inflamação/patologia , Nefropatias/patologia , Macrófagos/fisiologia , Masculino , Tamanho do Órgão/fisiologia , Ratos , Ratos Wistar , Circulação Renal/efeitos dos fármacos , Fator de Transcrição RelA/metabolismoRESUMO
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.