Angiotensin II type I antagonist on oxidative stress and heat shock protein 70 (HSP 70) expression in obstructive nephropathy

Angiotensin II, a profibrotic cytokine, plays a main role in the initiation of renal fibrogenesis at a very early stage leading to a progressive loss of renal function in unilateral ureteral obstruction (UUO). We studied the involvement of AT(1) angiotensin II receptor in the physiopathology of tubulointerstitial fibrosis in UUO, focusing in the regulation of the oxidative stress state and in the HSP 70 expression, in renal tissue. UUO or control sham operation was perform to Wistar Kyoto rats after being treated with the AT1 angiotensin II receptor antagonist Losartan (10 mg/kg/day) in the drinking water for 15 days. Twenty four hours later, mRNA AT1 receptor expression was studied. Renal fibrosis was evaluated through TGFbeta expression and superoxide dismutase (SOD) activity, hydroxyl radicals, O-2(-) and total antioxidant activity were measured by spectrophotometric assay. Immunohistochemical and Western blot analysis of HSP 70 were performed. A non-hypotensive dose of Losartan significantly down regulated the expression of AT1 receptor. Prevention of renal fibrogenesis by Losartan treatment was demostrate by TGFbeta mRNA expression similar to control. Oxidative stress in obstructed kidney was evident since a decreased SOD activity and a two-fold increase in the concentration of hydroxyl radicals and O-2 was observed when compared to the control. Losartan produced down regulation of ROS with recovery of the SOD activity and higher expression of HSP 70 compared to obstructed kidney of rats receiving vehicle. We can conclude that after 24 hr of UUO, protection against tubulointerstitial fibrosis by Losartan, independent from changes in blood pressure, includes decreased oxidative stress linked to upregulation of HSP 70 expression.