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 NFkappaB 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 NFkappaB 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 NFkappaB-mediated renal inflammation by a direct antioxidant effect independent of AT1R blockade.
Chen
Shan
S
Division of Kidney Disease and Hypertension, Department of Medicine, Brown University School of Medicine, Providence, Rhode Island 02903, USA.
Ge
Yan
Y
Si
Jin
J
Rifai
Abdalla
A
Dworkin
Lance D
LD
Gong
Rujun
R
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D004847:Epithelial Cells; D006801:Humans; D006973:Hypertension / Q000378:metabolism; D007249:Inflammation / Q000517:prevention & control*; D007674:Kidney Diseases / Q000473:pathology / Q000517:prevention & control*; D007684:Kidney Tubules / Q000166:cytology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D000975:Antioxidants; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016328:NF-kappa B; D020011:Protective Agents; D013777:Tetrazoles; C081643:candesartan