Acute kidney injury (AKI) is a major kidney disease characterized by an abrupt loss of renal function. Accumulating evidence indicates that incomplete or maladaptive repair after AKI can result in kidney fibrosis and the development and progression of chronic kidney disease (CKD). Hypoxia, a condition of insufficient supply of oxygen to cells and tissues, occurs in both acute and chronic kidney diseases under a variety of clinical and experimental conditions. Hypoxia-inducible factors (HIFs) are the “master” transcription factors responsible for gene expression in hypoxia. Recent researches demonstrate that HIFs play an important role in kidney injury and repair by regulating HIF target genes, including microRNAs. However, there are controversies regarding the pathological roles of HIFs in kidney injury and repair. In this review, we describe the regulation, expression, and functions of HIFs, and their target genes and related functions. We also discuss the involvement of HIFs in AKI and kidney repair, presenting HIFs as effective therapeutic targets.

Acute kidney injury (AKI) is a medical condition characterized by kidney damage with a rapid decline of renal function, which is associated with high mortality and morbidity. Recent research has further established an intimate relationship between AKI and chronic kidney disease. Perturbations of kidney cells in AKI result in the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER), leading to unfolded protein response (UPR) or ER stress. In this review, we analyze the role and regulation of ER stress in AKI triggered by renal ischemia-reperfusion and cisplatin nephrotoxicity. The balance between the two major components of UPR, the adaptive pathway and the apoptotic pathway, plays a critical role in determining the cell fate in ER stress. The adaptive pathway is evoked to attenuate translation, induce chaperones, maintain protein homeostasis and promote cell survival. Prolonged ER stress activates the apoptotic pathway, resulting in the elimination of dysfunctional cells. Therefore, regulating ER stress in kidney cells may provide a therapeutic target in AKI. KEY MESSAGES Perturbations of kidney cells in acute kidney injury result in the accumulation of unfolded and misfolded proteins in ER, leading to unfolded protein response (UPR) or ER stress. The balance between the adaptive pathway and the apoptotic pathway of UPR plays a critical role in determining the cell fate in ER stress. Modulation of ER stress in kidney cells may provide a therapeutic strategy for acute kidney injury.

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.

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