Immune-metabolic interactions shape the fibrotic landscape of diabetic kidney disease: emerging mechanisms and therapeutic prospects

作者：Yachan Gao, Xinxin Pang, Huichao Zhang, Dongdong Li, Jiarui Han, Zhenyi Chen, Xiaoyong Chen, Dongyang Li · 发表于：Frontiers in Physiology · 年份：2026 · DOI：10.3389/fphys.2025.1736472 · 被引用次数：4 · 研究领域：Chronic Kidney Disease and Diabetes、Dialysis and Renal Disease Management、Acute Kidney Injury Research

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), yet its progressive fibrosis cannot be solely attributed to hyperglycemia-induced oxidative stress or glomerular hypertension. Increasing evidence highlights that the bidirectional interaction between metabolic disturbances and immune activation-termed immunometabolic interactions-plays a pivotal role in driving DKD progression. Chronic metabolic stress, encompassing hyperglycemia, lipotoxicity, mitochondrial dysfunction, and gut-derived metabolites, reprograms innate and adaptive immune cells into pro-inflammatory and pro-fibrotic states. In turn, these activated immune cells exacerbate metabolic damage by promoting reactive oxygen species (ROS) overproduction, disrupting mitochondrial homeostasis, and facilitating extracellular matrix accumulation, thereby creating a self-amplifying loop that accelerates renal fibrosis. Key immunometabolic regulators, including HIF-1α, AMPK, mTOR, and SIRT1, coordinate metabolic signals with immune responses, providing novel mechanistic insights into DKD beyond traditional models. Recent therapeutic advances-such as Sodium-Glucose Cotransporter 2(SGLT2) inhibitors, GLP-1 receptor agonists, mineralocorticoid receptor antagonists, and multi-target natural compounds-offer renoprotective effects, partly by modulating these immunometabolic pathways. Fibrotic remodeling represents a core pathological tissue restructuring event in the kidney, typified by excessiv...