The dysregulated unfolded protein response in diabetic kidney disease: mechanisms and crosstalk with cell death pathways.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage kidney failure worldwide, yet the molecular mechanisms driving progressive renal injury remain incompletely understood. Chronic metabolic stress in diabetes disrupts endoplasmic reticulum (ER) homeostasis, leading to sustained activation of the unfolded protein response (UPR). While transient UPR signaling is adaptive and restores proteostasis, persistent ER stress in the diabetic milieu shifts UPR signaling toward maladaptive pathways that promote cellular dysfunction and death. This review summarizes the canonical UPR branches mediated by protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6), and discusses their dysregulation in the diabetic kidney. We highlight how chronic glucolipotoxicity, oxidative stress, and protein overload drive prolonged UPR activation in podocytes and tubular epithelial cells, leading to loss of proteostatic balance and progressive nephron injury. Importantly, emerging evidence indicates that UPR signaling interacts with multiple regulated cell death pathways, including apoptosis, autophagy dysfunction, ferroptosis, pyroptosis, and necroptosis, forming a pathological crosstalk network that determines renal cell fate. This maladaptive integration amplifies inflammation, oxidative stress, mitochondrial dysfunction, and fibrotic remodeling, ultimately contributing to podocyte depletion, tubular atrophy, and disease progression. Finally, we discuss therapeutic strategies to restore ER proteostasis and modulate UPR-mediated cell death signaling, highlighting their potential as disease-modifying approaches in DKD. A deeper understanding of UPR dysregulation and its interaction with cell death pathways may provide novel mechanistic insights and facilitate the development of targeted therapies for diabetic kidney disease.