Therapeutic Regulation of Macrophage Polarization for Diabetic Kidney Disease by Targeted Metabolic Reprogramming

Abstract Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes. It can be identified by thickening of the glomerular basement membrane, reduced glomerular filtration rate, and persistent proteinuria. Macrophages play a key role in the pathogenesis of DKD, and their phenotype (M1 and M2) is finely regulated by metabolic reprogramming. M1 macrophages exacerbate inflammatory damage and fibrosis in renal tissue by secreting pro-inflammatory mediators and reactive oxygen species (ROS). M2 macrophages (further subdivided into M2a, M2b, M2c and M2d subtypes) primarily exert anti-inflammatory and tissue-repairing effects. Of these, the M2a and M2c subtypes are particularly crucial for anti-inflammatory repair. This study aimed to systematically review the mechanisms by which glucose, lipid, amino acid, and mitochondrial function-related metabolism influence macrophage polarization. It further explored therapeutic strategies to mitigate renal inflammation and fibrosis by regulating macrophage polarization through targeted metabolic pathways, including inhibiting glycolysis, promoting fatty acid oxidation, modulating amino acid metabolism, and enhancing mitochondrial biogenesis and oxidative phosphorylation (OXPHOS). Several natural compounds and synthetic drugs exhibit the potential to induce M2 polarization and suppress M1 polarization through metabolic reprogramming, thereby offering new directions for optimizing therapeutic strategies for DKD.