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

作者：Zhang H, Li K, Ma J, Ma L, Farooq MA, E J · 发表于：Frontiers in pharmacology · 年份：2026 · DOI：10.3389/fphar.2026.1875777 · 被引用次数：114

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, tubu...