Endoplasmic Reticulum Chaperon Tauroursodeoxycholic Acid Attenuates Aldosterone-Infused Renal Injury.

Honglei Guo,Yong Gu,Hongmei Li,Wei Ding,Lilu Ling

doi:10.1155/2016/4387031

Honglei Guo, Yong Gu + Show 3 more

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https://doi.org/10.1155/2016/4387031

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Abstract

Aldosterone (Aldo) is critically involved in the development of renal injury via the production of reactive oxygen species and inflammation. Endoplasmic reticulum (ER) stress is also evoked in Aldo-induced renal injury. In the present study, we investigated the role of ER stress in inflammation-mediated renal injury in Aldo-infused mice. C57BL/6J mice were randomized to receive treatment for 4 weeks as follows: vehicle infusion, Aldo infusion, vehicle infusion plus tauroursodeoxycholic acid (TUDCA), and Aldo infusion plus TUDCA. The effect of TUDCA on the Aldo-infused inflammatory response and renal injury was investigated using periodic acid-Schiff staining, real-time PCR, Western blot, and ELISA. We demonstrate that Aldo leads to impaired renal function and inhibition of ER stress via TUDCA attenuates renal fibrosis. This was indicated by decreased collagen I, collagen IV, fibronectin, and TGF-β expression, as well as the downregulation of the expression of Nlrp3 inflammasome markers, Nlrp3, ASC, IL-1β, and IL-18. This paper presents an important role for ER stress on the renal inflammatory response to Aldo. Additionally, the inhibition of ER stress by TUDCA negatively regulates the levels of these inflammatory molecules in the context of Aldo.

Highlights

The chronic administration of aldosterone (Aldo) leads to the production of reactive oxygen species (ROS) and causes endothelial dysfunction, disruption of the glomerular filtration barrier, proteinuria, and tubular damage and regeneration, leading to the progression of chronic kidney disease [1,2,3,4,5]
The creatinine concentration was higher in Aldo-infused mice (0.30 ± 0.02) compared to Sham+V mice (0.21 ± 0.01), and treatment with tauroursodeoxycholic acid (TUDCA) decreased the level of creatinine in the Aldo-treated group (0.26 ± 0.01) (Table 2)
This study demonstrated that ROS, endoplasmic reticulum (ER) stress, and renal Nlrp3 inflammasome were increased in Aldo-infused mice

Summary

Introduction

The chronic administration of aldosterone (Aldo) leads to the production of reactive oxygen species (ROS) and causes endothelial dysfunction, disruption of the glomerular filtration barrier, proteinuria, and tubular damage and regeneration, leading to the progression of chronic kidney disease [1,2,3,4,5]. ER stress can elicit an inflammatory response through the induction of the ASC and Nlrp inflammasome [10, 11] This in turn promotes the maturation and secretion of proinflammatory cytokines, including IL-1β and IL-18, to initiate innate immune defenses and subsequently results in cellular injury [12]. The Nlrp inflammasome is a crucial event in the progression of kidney disease [13,14,15,16], including unilateral ureteral obstruction (UUO) [13], ischemia/reperfusion injury [17, 18], and proteinuric animal model [19] In those models, Nlrp3−/− mice were remarkably resistant to renal injury, possibly via the inhibition of the inflammatory response. These effects are attenuated by eplerenone, supporting the protective effect of an Aldo blockade in renal disease via inhibiting inflammatory cytokines [20]

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