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

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

doi:10.18632/oncotarget.8243

Wei Ding, Bin Wang + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.8243

Copy DOI

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.

Highlights

Aldosterone (Aldo) is produced in the adrenal zona glomerulosa, and mediates salt and water homeostasis by interaction with mineralocorticoid receptors (MR), which are expressed in renal epithelial cells [1,2,3]
The increased expression of these proteins was detected as early as 12 h after treatment with Aldo (10-7 M). These results indicate that Aldo treatment triggered activation of the Nucleotide-binding domain and leucine-rich repeat containing PYD-3 (NLRP3) inflammasome in HK-2 cells
EPL inhibited HK-2 cell apoptosis (Figure 4C, 4D). These results indicate that Aldo induces renal tubular cell injury via an MR-dependent pathway which is mediated through activation of the NLRP3 inflammasome

Summary

Introduction

Aldosterone (Aldo) is produced in the adrenal zona glomerulosa, and mediates salt and water homeostasis by interaction with mineralocorticoid receptors (MR), which are expressed in renal epithelial cells [1,2,3]. A growing body of evidence indicates that the direct action of Aldo on the MR plays a key role in the progression of chronic kidney disease (CKD). Tubular cell injury has been suggested to be an important mechanism for the progression of CKD, which leads to tubulointerstitial fibrosis. Tubular cell apoptosis was demonstrated to be involved in the progression of polycystic kidney disease [8]. Patni et al showed that Aldo induced tubular epithelial cell apoptosis through the excessive production of reactive oxygen species (ROS) [2]. These data suggested a contribution of Aldo to the progression of renal tubular injury. The underlying mechanism of Aldo-induced renal tubular injury is still not fully understood

Objectives

Methods

Results

Conclusion