Endoplasmic reticulum stress is activated in post-ischemic kidneys to promote chronic kidney disease

Abstract

BackgroundAcute kidney injury (AKI) may lead to the development of chronic kidney disease (CKD), i.e. AKI-CKD transition, but the underlying mechanism remains largely unclear. Endoplasmic reticulum (ER) stress is characterized by the accumulation of unfolded or misfolded proteins in ER resulting in a cellular stress response. The role of ER stress in AKI-CKD transition remains unknown.MethodsIn this study, we examined ER stress in the mouse model of AKI-CKD transition after unilateral renal ischemia-reperfusion injury (uIR). To determine the role of ER stress in AKI-CKD transition, we tested the effects of two chemical chaperones: Tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA).FindingsuIR led to the induction of ER stress in kidneys, as indicated by increased expression of UPR molecules CHOP (C/EBP homologous protein) and BiP(binding immunoglobulin protein; also called GRP78–78 kDa glucose­regulated protein). Given at 3 days after uIR, both TUDCA and 4-PBA blocked ER stress in post-ischemic kidneys. Notably, both chemicals promoted renal recovery and suppressed tubulointerstitial injury as manifested by the reduction of tubular atrophy, renal fibrosis and myofibroblast activation. Inhibition of ER stress further attenuated renal tubular epithelial cell apoptosis, inflammation and autophagy in post-ischemic kidneys.InterpretationThese findings suggest that ER stress contributes critically to the development of chronic kidney pathologies and CKD following AKI, and inhibition of ER stress may represent a potential therapeutic strategy to impede AKI-CKD transition.

The deacetylase sirtuin 6 protects against kidney fibrosis by epigenetically blocking β-catenin target gene expression

“…Unilateral renal IR was operated as before. 44 Briefly, after anesthesia with pentobarbital (50 mg/kg, i.p. ), mice were kept on a Homeothermic Blanket Control Unit (Harvard Apparatus Ltd., Holliston, MA) to monitor and maintain body temperature at w36.5 C. The left renal pedicle was exposed by flank incision for unilateral clamping to induce ischemia for 30 minutes.…”

Thrombospondin 1 and Its Diverse Roles as a Regulator of Extracellular Matrix in Fibrotic Disease

“…113,[135][136][137][138][139][140][141] It is well established that ER stress pathways are activated in fibrotic renal disease, including in diabetic nephropathy and in ischemia, and that chemical chaperones such as 4-phenylbutyrate and tauroursodeoxycholic acid have been shown to reduce ER stress and result in fibrosis in animal models of renal disease. [142][143][144][145][146][147][148][149] It is unclear how TSP1 and other TSP family members might be participating in the UPR and other branches of the ER stress response and whether intracellular TSP1 functions are involved in fibrogenic processes. Studies on mutant COMP (TSP5) in models of pseudoachondroplasia showed a more severe phenotype in animals in which the mutant protein was expressed than in knockout mice.…”

Myo-inositol Oxygenase (MIOX) Overexpression Drives the Progression of Renal Tubulointerstitial Injury in Diabetes

“…Moreover, a clinical study on patients with renovascular complications reported an association of type 1 diabetes with polymorphism of MIOX gene, which underscores its clinical significance in the pathobiology of DN (31), although a comprehensive analysis of the events responsible for the MIOX-ROS-mediated tubulointerstitial injury in DN needs to be included in experimental animal models. Besides ROS, endoplasmic reticulum (ER) stress has also been implicated in the pathogenesis of diabetes, obesity, AKI, and chronic kidney disease (7,9,(32)(33)(34)(35). Whether MIOX worsens ER stress in DN remains to be explored.…”