Candesartan suppresses chronic renal inflammation by a novel antioxidant action independent of AT1R blockade

Reactive oxygen species are thought to be critical inducers of renal inflammation and destruction. We examined the effects of candesartan, a highly selective angiotensin II type I receptor (AT1R) blocker, on renal inflammation and oxidative stress. Candesartan suppressed TNF-induced chemokine expression and NF kappa B activation independent of AT1R blockade in cultured renal tubular epithelial cells. This receptor blocker decreased reactive oxygen generation elicited by either TNF or the pro-oxidant hydrogen peroxide and reinstated redox homeostasis, suggesting a direct antioxidant effect. This result was unique to candesartan among several angiotensin II receptor blockers and occurred in cells lacking the AT1R. A dose 5 times the standard therapeutic dose lessened renal inflammation and suppressed tubular NF kappa B activation in spontaneously hypertensive rats. An ultrahigh dose ( 15 times standard) produced an even greater beneficial effect. Angiotensin II infusion did not cause any hemodynamic changes at either candesartan dose denoting a complete blockade of systemic and renal AT1R. There was, however, a dose-dependent improvement of renal redox homeostasis. Our study suggests that candesartan suppresses redox-sensitive NF kappa B-mediated renal inflammation by a direct antioxidant effect independent of AT1R blockade.