Roles of the peroxisome proliferator-activated receptors (PPARs) in the pathogenesis of diabetic kidney disease (DKD)

Diabetic kidney disease (DKD), a prevalent microvascular complication of diabetes, is a leading cause of chronic kidney disease and end-stage renal disease. Moreover, it plays a crucial role in the morbidity and mortality of diabetic patients. Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor superfamily, are key regulators of energy homeostasis, with three distinct subtypes identified: PPARα, PPARγ, and PPARβ/δ. They regulate gene transcription associated with energy metabolism, differentiation, inflammation, and cellular development. In recent years, the increasing incidence of DKD has intensified interest in elucidating the mechanisms and roles of PPARs in DKD. Unlike previous reviews-which focused primarily on individual PPAR subtypes or isolated pathological processes-this review adopts a unique "cell-type-specific perspective." It systematically elucidates the distinct roles of all three PPAR isotypes (α, γ, and β/δ) across key renal cell types (podocytes, mesangial cells, tubular cells) in DKD. We also explore the potential influence of PPAR genetic polymorphisms on DKD susceptibility. Beyond conventional review frameworks, we propose an innovative therapeutic strategy encompassing PPAR-based multi-target synergistic approaches and nanotechnology-driven cell-specific targeted therapy. This offers novel directions to overcome current therapeutic bottlenecks.