Apocynin attenuates renal fibrosis via inhibition of NOXs-ROS-ERK-myofibroblast accumulation in UUO rats.
BACKGROUND
Oxidative stress has been identified as an important pathogenesis mechanism in the development of renal interstitial fibrosis in unilateral ureteral obstruction (UUO). Previous studies have demonstrated increased expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOXs) in response to UUO. We aimed to investigate whether NOXs activation was involved in the development of renal fibrosis in UUO by contribution to oxidative stress and the potential mechanism in the present study.


METHODS
Apocynin, a NOXs inhibitor, was initiated immediately by gavage after UUO was performed on Wistar rats and continued until 7 days after UUO. Changes of markers of oxidative stress, renal macrophage infiltration and fibrosis, TGF-β1 expression, NOXs expression and activity, and ERK activation were evaluated.


RESULTS
Apocynin significantly attenuated the activity of NOXs, accompanied with decreased expression of NOX2, NOX4, and oxidative stress markers in the obstructed kidneys of UUO. Additionally, collagen deposition and renal fibrosis induced by UUO were attenuated by apocynin treatment. Furthermore, apocynin treatment significantly attenuated the phosphorylation of ERK, accumulation of myofibroblast and infiltration of macrophage in obstructed kidneys. No significant effect of apocynin on UUO-induced increased TGF-β1 expression could be observed. And there was no significant change of anti-oxidants enzyme activities in the obstructed kidneys of apocynin-treated rats.


CONCLUSIONS
These results suggested that apocynin might exert beneficial effects on renal fibrosis by inhibition of NOXs activation and subsequent reduction of oxidative stress, ERK activation, and myofibroblast accumulation in UUO rats. Targeting NOXs may serve as a therapeutic strategy for the treatment of renal fibrosis.
a Renal Division, Department of Medicine , Peking University First Hospital , Beijing , China ;|b Institute of Nephrology, Peking University , Beijing , China ;|c Key Laboratory of Renal Disease, Ministry of Health of China , Beijing , China ;|d Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education , Beijing , China ;
Xi
X
Cheng
a Renal Division, Department of Medicine , Peking University First Hospital , Beijing , China ;|b Institute of Nephrology, Peking University , Beijing , China ;|c Key Laboratory of Renal Disease, Ministry of Health of China , Beijing , China ;|d Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education , Beijing , China ;
Xizi
X
Zheng
e Department of Urology , Peking University First Hospital , Beijing , China.
Yi
Y
Song
a Renal Division, Department of Medicine , Peking University First Hospital , Beijing , China ;|b Institute of Nephrology, Peking University , Beijing , China ;|c Key Laboratory of Renal Disease, Ministry of Health of China , Beijing , China ;|d Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education , Beijing , China ;
Lei
L
Qu
a Renal Division, Department of Medicine , Peking University First Hospital , Beijing , China ;|b Institute of Nephrology, Peking University , Beijing , China ;|c Key Laboratory of Renal Disease, Ministry of Health of China , Beijing , China ;|d Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education , Beijing , China ;
Jiawei
J
Tang
a Renal Division, Department of Medicine , Peking University First Hospital , Beijing , China ;|b Institute of Nephrology, Peking University , Beijing , China ;|c Key Laboratory of Renal Disease, Ministry of Health of China , Beijing , China ;|d Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education , Beijing , China ;
Liqiang
L
Meng
a Renal Division, Department of Medicine , Peking University First Hospital , Beijing , China ;|b Institute of Nephrology, Peking University , Beijing , China ;|c Key Laboratory of Renal Disease, Ministry of Health of China , Beijing , China ;|d Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education , Beijing , China ;
Yu
Y
Wang
D000098:Acetophenones / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use*; D005355:Fibrosis / Q000473:pathology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D015227:Lipid Peroxidation; D058628:Myofibroblasts; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D014517:Ureteral Obstruction / Q000150:complications*
D000098:Acetophenones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D017382:Reactive Oxygen Species; C056165:acetovanillone
Fibrosis; NADPH oxidase; oxidative stress; reactive oxygen species; ureteral obstruction