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.

Dexmedetomidine alleviates cisplatin‑induced acute kidney injury by attenuating endoplasmic reticulum stress‑induced apoptosis via the α2AR/PI3K/AKT pathway

“…The er is an intracellular organelle that serves an important role in protein homeostasis (14). The er can restore homeostasis via the uPr.…”

“…Previous studies have focused on the development of anti-inflammatory and anti-apoptotic drugs to manage cP-induced renal injury (8,13). The endoplasmic reticulum (er) can serve a critical role in cP cellular toxicity (13,14). The er is the organelle responsible for synthesis and maturation of proteins, calcium storage and maintenance of cell homeostasis (15).…”

“…However, in cases of severe erS, accumulation of a large number of unfolded proteins results in the dissociation of the 78-kda glucose-regulated protein (GrP78) from transmembrane proteins, and activation of the downstream signaling molecules c/eBP homologous protein (cHoP) and caspase-12, eventually leading to apoptosis (17). Previous studies have experimentally shown amelioration of cP-induced nephrotoxicity mediated by attenuating erS-induced apoptosis (14,18,19). in addition, the Pi3K/aKT signaling pathway has a central role in cell growth, differentiation and apoptosis (20).…”

Fibroblast Growth Factor 2 Attenuates Renal Ischemia-Reperfusion Injury via Inhibition of Endoplasmic Reticulum Stress

“…In our previous study, we demonstrated that FGF2 could protect against renal I/R injury via attenuation of mitochondrial damage and HMGB1/TLR2-mediated inflammatory response (Tan et al, 2017). In addition, other findings revealed that ER stress is involved in AKI triggered by renal I/R injury and nephrotoxic drugs (Gallazzini and Pallet, 2018;Yan et al, 2018). Many studies have reported that ER stress could trigger inflammatory responses and regulate mitochondrial metabolic status through the UPR signaling pathway (Bronner et al, 2015;So, 2018;Gallazzini and Pallet, 2018;Inoue et al, 2019).…”

Cross organelle stress response disruption promotes gentamicin-induced proteotoxicity

“…ER stress has been implicated in causing ischemic and nephrotoxic acute kidney injury (AKI) 20 . The CORE is an attractive target for gentamicin-induced proteotoxicity because ER-mitochondrial collaboration prevents the toxic protein misfolding that accompanies normal protein synthesis 19 .…”