Diabetic kidney disease: exploring mechanistic depths and the future of pharmacological intervention

Diabetic kidney disease (DKD) is the primary driver of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally and poses a major and escalating public health concern in the context of the diabetes epidemic. Despite current therapeutic interventions, a substantial residual risk of disease progression persists, emphasizing the necessity for improved treatment strategies. A comprehensive elucidation of the molecular mechanisms underlying DKD is crucial for developing novel therapies aimed at slowing disease progression and reducing associated complications. This review provides an in-depth overview of the evolution and present knowledge on DKD, established and emerging molecular mechanisms, and evolving therapeutic approaches. Recent advances have revealed a more complex pathophysiological landscape involving mitochondrial dysfunction and endoplasmic reticulum stress. By synthesizing recent developments in the field, this review highlights the significance of these interconnected mechanisms in DKD pathogenesis and proposes innovative, underexplored therapeutic options, including a novel SIRT1 activator, NLRP3 inhibitor, PLK2 inhibitor, ET1A antagonist, and curcumin derivative that hold potential in combating DKD. Ultimately, it underscores the critical need for continued research to address unresolved questions and to develop more effective, multitargeted interventions to improve outcomes for individuals with DKD.