Rotenone Attenuates Renal Injury in Aldosterone-Infused Rats by Inhibiting Oxidative Stress, Mitochondrial Dysfunction, and Inflammasome Activation
Wei Ding, Chengyan Xu, Bin Wang, Minmin Zhang
Division of Nephrology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China (mainland)
Med Sci Monit 2015; 21:3136-3143
Reactive oxygen species (ROS) and inflammation both contribute to the progression of aldosterone-induced renal injury. To better understand the underlying mechanisms, we examined mitochondrial dysfunction and NLRP3 inflammasome activation in aldosterone-infused rats, and explored the role of rotenone in attenuating these injuries.
MATERIAL AND METHODS: Sprague-Dawley rats were divided into 3 groups: vehicle-treated, aldosterone-infused, and aldosterone plus rotenone. Renal damage was evaluated using PAS staining and electron microscopy. Levels of ROS were measured from renal tissue and serum; immunohistochemistry analysis examined the inflammation pathway; Western blot and real-time PCR assessed NLRP3 inflammasome activity.
RESULTS: Glomerular segmental sclerosis, foot process effacement, and proteinuria were demonstrated in the aldosterone-infused rats. Specifically, the thiobarbituric acid-reactive substances (TBARS) oxidative stress marker, MDA, was significantly increased; ATP content and mtDNA copy number were markedly decreased; inflammatory mediators NF-κB p65 and CTGF were upregulated; and NLRP3 inflammasome and its related target proteins, IL-1β and IL-18, were also increased. Treatment with rotenone, an inhibitor of mitochondrial complex I, significantly attenuated oxidative stress, mitochondrial dysfunction, and inflammasome response in aldosterone-infused rats.
CONCLUSIONS: Rotenone ameliorated aldosterone-infused renal injury, possibly by inhibiting oxidative stress, mitochondrial dysfunction, and NLRP3 inflammasome activity. These results provide novel evidence for the role of rotenone in aldosterone-induced renal injury or other chronic kidney disease.
Keywords: Aldosterone - chemistry, Adenosine Triphosphate - chemistry, Animals, Carrier Proteins - metabolism, DNA, Mitochondrial - metabolism, Glomerulosclerosis, Focal Segmental - pathology, Inflammasomes - metabolism, Inflammation - metabolism, Kidney - pathology, Malondialdehyde - chemistry, Microscopy, Electron, Mitochondria - pathology, Oxidative Stress, Proteinuria - pathology, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species - metabolism, Real-Time Polymerase Chain Reaction, Rotenone - metabolism, Thiobarbituric Acid Reactive Substances - chemistry, Transcription Factor RelA - metabolism