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Rotenone remarkably attenuates oxidative stress, inflammation, and fibrosis in chronic obstructive uropathy
Ying Sun1, Yue Zhang2, Daqiang Zhao3
1Nanjing Key Laboratory of Pediatrics, Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China ; Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China ; Institute of Pediatrics, Nanjing Medical University, Nanjing, China ; Division of Nephrology, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USA.
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.
Insights
Mitochondrial dysfunction contributes to chronic kidney disease (CKD). Rotenone, a mitochondrial complex I inhibitor, protected kidneys against obstructive injury by reducing oxidative stress, inflammation, and fibrosis.
Area of Science:
- Nephrology
- Mitochondrial Biology
- Pathophysiology
Background:
- Mitochondrial abnormalities are implicated in kidney disease pathogenesis, but their precise role in chronic kidney diseases (CKDs) remains unclear.
- Understanding the contribution of mitochondrial dysfunction is crucial for developing targeted therapies for obstructive kidney injury.
Purpose of the Study:
- To investigate the role of mitochondrial complex I inhibition using rotenone in a mouse model of obstructive kidney disease.
- To evaluate the effects of rotenone on tubular injury, fibrosis, oxidative stress, and inflammation in the context of unilateral ureteral obstruction (UUO).
Main Methods:
- Mice underwent unilateral ureteral obstruction (UUO) and were treated with rotenone for 7 days.
- Kidney injury was assessed using PAS staining, and fibrotic markers (FN, PAI-1, collagen I, III, α-SMA, TGF-β1) were quantified.
- Oxidative stress (TBARS, HO-1) and inflammatory markers (TNF-α, IL-1β, ICAM-1) were measured.
- Mitochondrial integrity was evaluated by assessing mitochondrial DNA copy number and mtND1 expression.
Main Results:
- Rotenone treatment significantly attenuated tubular injury and reduced fibrotic responses in UUO kidneys.
- Rotenone administration markedly decreased markers of oxidative stress and inflammation.
- Mice treated with rotenone showed restoration of mitochondrial DNA copy number and mtND1 expression, indicating amelioration of mitochondrial injury.
Conclusions:
- Mitochondrial complex I inhibition with rotenone confers protection against obstructive kidney injury.
- Rotenone mitigates kidney damage by inhibiting mitochondrial oxidative stress, inflammation, and fibrosis.
- These findings highlight the critical role of mitochondrial dysfunction in obstructive kidney disease pathogenesis and suggest potential therapeutic strategies.
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