Rotenone remarkably attenuates oxidative stress, inflammation, and fibrosis in chronic obstructive uropathy.

Ying Sun,Guixia Ding,Yue Zhang,Aihua Zhang,Daqiang Zhao,Songming Huang,Zhanjun Jia

doi:10.1155/2014/670106

Abstract

Mitochondrial abnormality has been shown in many kidney disease models. However, its role in the pathogenesis of chronic kidney diseases (CKDs) is still uncertain. In present study, a mitochondrial complex I inhibitor rotenone was applied to the mice subjected to unilateral ureteral obstruction (UUO). Following 7-days rotenone treatment, a remarkable attenuation of tubular injury was detected by PAS staining. In line with the improvement of kidney morphology, rotenone remarkably blunted fibrotic response as shown by downregulation of fibronectin (FN), plasminogen activator inhibitor-1 (PAI-1), collagen I, collagen III, and α-SMA, paralleled with a substantial decrease of TGF-β 1. Meanwhile, the oxidative stress markers thiobarbituric acid-reactive substances (TBARS) and heme oxygenase 1 (HO-1) and inflammatory markers TNF-α, IL-1β, and ICAM-1 were markedly decreased. More importantly, the reduction of mitochondrial DNA copy number and mitochondrial NADH dehydrogenase subunit 1 (mtND1) expression in obstructed kidneys was moderately but significantly restored by rotenone, suggesting an amelioration of mitochondrial injury. Collectively, mitochondrial complex I inhibitor rotenone protected kidneys against obstructive injury possibly via inhibition of mitochondrial oxidative stress, inflammation, and fibrosis, suggesting an important role of mitochondrial dysfunction in the pathogenesis of obstructive kidney disease.

Highlights

Fibrosis is a common event of various forms of chronic kidney diseases (CKDs)
Dysfunctional mitochondria serve as important source of reactive oxygen species (ROS) production
By blockade of mitochondrial complex I, upregulation of oxidative stress marker heme oxygenase 1 (HO-1) was significantly blocked in obstructed kidneys (Figures 3(a) and 3(b))

Summary

Introduction

Fibrosis is a common event of various forms of chronic kidney diseases (CKDs). The progression of renal fibrosis has been thought as a major pathological process leading to the progressive loss of renal function in CKDs [1,2,3]. The dysfunction of mitochondria causes ATP depletion, reactive oxygen species (ROS) overproduction, and release of proapoptotic factors like cytochrome C and mitochondrial DNA, which could result in the cell injury via oxidative damage of DNA and protein and apoptotic response and subsequent inflammation and fibrosis [16, 17]. In agreement with these notions, our previous study gave. To define the role of mitochondrial dysfunction in obstructive kidney injury, we treated the UUO mice with a mitochondrial complex I inhibitor rotenone to determine (1) whether inhibition of mitochondrial complex I can attenuate tubular injury and renal fibrosis in obstructive kidney disease and (2) whether mitochondrial complex I inhibition could affect the oxidative stress and inflammation in this particular model

Methods

Results

Discussion