Oncotarget

Research Papers: Pathology:

Mitochondrial reactive oxygen species-mediated NLRP3 inflammasome activation contributes to aldosterone-induced renal tubular cells injury

Wei Ding, Honglei Guo, Chengyan Xu, Bin Wang, Minmin Zhang and Feng Ding _

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Oncotarget. 2016; 7:17479-17491. https://doi.org/10.18632/oncotarget.8243

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Abstract

Wei Ding1, Honglei Guo2, Chengyan Xu3, Bin Wang3, Minmin Zhang3 and Feng Ding1

1 Division of Nephrology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

2 Division of Nephrology, The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, China

3 Division of Nephrology, Huashan Hospital and Institute of Nephrology, Fudan University, Shanghai, China

Correspondence to:

Minmin Zhang, email:

Feng Ding, email:

Keywords: aldosterone, mitochondrial reactive oxygen species, NLRP3 inflammasome, renal tubular cells, chronic kidney disease, Pathology Section

Received: November 01, 2015 Accepted: March 11, 2016 Published: March 21, 2016

Abstract

Aldosterone (Aldo) is an independent risk factor for chronic kidney disease (CKD), and although Aldo directly induces renal tubular cell injury, the underlying mechanisms remain unclear. NLRP3 inflammasome and mitochondrial reactive oxygen species (ROS) have recently been implicated in various kinds of CKD. The present study hypothesized that mitochondrial ROS and NLRP3 inflammasome mediated Aldo–induced tubular cell injury. The NLRP3 inflammasome is induced by Aldo in a dose- and time-dependent manner, as evidenced by increased NLRP3, ASC, caspase-1, and downstream cytokines, such as interleukin (IL)-1β and IL-18. The activation of the NLRP3 inflammasome was significantly prevented by the selective mineralocorticoid receptor (MR) antagonist eplerenone (EPL) (P < 0.01). Mice harboring genetic knock-out of NLRP3 (NLRP3-/-) showed decreased maturation of renal IL-1β and IL-18, reduced renal tubular apoptosis, and improved renal epithelial cell phenotypic alternation, and attenuated renal function in response to Aldo-infusion. In addition, mitochondrial ROS was also increased in Aldo-stimulated HK-2 cells, as assessed by MitoSOXTM red reagent. Mito-Tempo, the mitochondria-targeted antioxidant, significantly decreased HK-2 cell apoptosis, oxidative stress, and the activation of NLRP3 inflammasome. We conclude that Aldo induces renal tubular cell injury via MR dependent, mitochondrial ROS-mediated NLRP3 inflammasome activation.


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