One of the main causes of chronic kidney disease (CKD), ischemic nephropathy, is brought on by maladaptive cellular stress responses, specifically endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signalling, in addition to vascular insufficiency. The primary goals of UPR activation via the Protein kinase R-like ER kinase (PERK), Inositol-requiring enzyme 1 (IRE1), and Activating Transcription Factor 6 (ATF6) pathways are to support renal tubular cell survival and restore proteostasis. Prolonged or severe ER stress, on the other hand, causes the UPR to shift toward pathogenic outcomes by triggering apoptotic (C/EBP homologous protein [CHOP], caspase-12), inflammatory (c-Jun N-terminal Kinase [JNK], nuclear factor kappa B [NF-κB]), and fibrotic (transforming growth factor-beta [TGF-β]/SMAD) cascades that lead to progressive renal dysfunction, tubular atrophy, and interstitial fibrosis. Furthermore, ER-mitochondria crosstalk connects acute ischemia injury to chronic fibrosis by exacerbating mitochondrial failure, oxidative stress, and cell death. Targeting therapy requires an understanding of the UPR's dual nature, which is beneficial during brief stress but harmful during prolonged ischemia. Promising approaches to maintain kidney function include interventions that alter particular UPR branches, improve autophagy, lower oxidative damage, and restore ER equilibrium. In addition to outlining the molecular bases of ER stress and UPR in ischemic nephropathy, this review suggests innovative therapeutic strategies meant to shift the equilibrium from maladaptive to adaptive stress responses, providing novel possibilities to slow or alter the course of CKD. This review aims to critically evaluate the molecular mechanisms of ER stress and the UPR in ischemic nephropathy, with a focus on identifying potential therapeutic strategies to preserve renal function and slow CKD progression.
