Endoplasmic reticulum stress in ischemic and nephrotoxic acute kidney injury

Abstract

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.

Keywords: Endoplasmic reticulum stress; acute kidney injury; apoptosis; autophagy; cisplatin; ischemia-reperfusion injury.

Figure 1:

Main signaling pathways in UPR/ER stress. The UPR has three main signaling branches. IRE1 pathway catalyzes the splicing of X-box-binding protein 1 (XBP1) mRNA and cleaves special mRNAs by regulated IRE1-dependent decay (RIDD). PERK phosphorylates and inactivates eukaryotic translation initiator factor 2α (eIF2α) resulting in the repression of protein translation and the transcription of apoptotic genes. ATF6 is transported to the Golgi apparatus and cleaved by the Site-1 and -2 Proteases (SiP1, S2P). Then it migrates to the nucleus and activates the transcription of chaperone genes.

Figure 2:. Adaptive and pro-apoptotic pathways activated in ER stress.

When the stress is mild, the adaptive pathway is activated to repress translation to reduce protein load, activate chaperone expression to increase the ER folding capacity, and degrade abnormal proteins via ER-associated degradation (ERAD) quality control or autophagy. When the stress is too long or too severe, the cell capacity of proteostasis is overwhelmed and apoptotic pathways are activated. The first apoptotic pathway is mediated by CHOP, which induces the expression of pro-apoptotic genes (e.g. Bax and Bak) and suppresses the transcription of anti-apoptotic Bcl2, causing apoptosis. The second pathway involves the activation of TRAF2 via IRE1, which results in sequential activation of ASK1 and JNK to trigger apoptosis. The third mechanism involves Ca2+ released from ER that accumulates in mitochondria resulting in cytochrome c release and caspase activation.