Diabetes mellitus is a prevalent chronic condition with substantial public health implications. The global diabetes prevalence among 20-79-year-olds in 2021 was estimated to be 10.5% (536.6 million people), and it is projected to rise to 12.2% (783.2 million) in 2045. Notably, type 2 diabetes mellitus (T2DM) accounts for approximately 90% of all diabetes cases.[1,2] Diabetic kidney disease (DKD) is one of the most severe microvascular complications of diabetes, affecting approximately 30-40% of individuals with diabetes worldwide.[3,4] In patients with type 1 diabetes mellitus (T1DM), DKD occurs more frequently in those with a disease duration exceeding five years. In contrast, due to the insidious onset and low awareness rate of T2DM, the exact disease course is often difficult to ascertain, and some patients already have DKD at the time of T2DM diagnosis.[3,5] This disease is clinically characterized by persistent albuminuria and a progressive decline in renal function, and is pathologically defined by distinct histopathological features, including thickening of the glomerular basement membrane (GBM), expansion of the mesangial matrix, nodular glomerulosclerosis, and arteriolar hyalinosis. It has become the leading cause of end-stage renal disease (ESRD) that requires long-term dialysis or kidney transplantation, accounting for approximately 40% of newly diagnosed ESRD cases.[6] In addition to adverse renal outcomes, patients with DKD are also at a significantly increased risk of cardiovascular disease (CVD) and mortality.[7] Currently, the prevention and management of DKD remain a major challenge for public health worldwide.

Both clinical and preclinical studies have demonstrated that early intervention can slow the progression of DKD, whereas delayed treatment rarely alters the trajectory of renal functional decline.[6] However, conventional clinical indicators such as proteinuria and serum creatinine often become apparent only after significant structural damage.[8,9] The pathogenesis of DKD is multifactorial, involving genetic, environmental, and behavioral determinants. Hyperglycemia and hypertension represent two major modifiable risk factors.[10,11] Blood glucose control and management of comorbid hypertension are well-established strategies for slowing DKD progression.[12] For instance, intensive glycemic control targeting an HbA1c of 7% in newly diagnosed T2DM patients has been shown to delay the onset of moderate albuminuria and reduce the risk of nonfatal myocardial infarction. Nonetheless, such regimens have only reduced the incidence of microvascular complications, including DKD, by 24%.[13] Moreover, stringent glycemic control increases the risk of hypoglycemia, particularly among elderly or frail patients, and its long-term benefits must be weighed against potential hazards. Encouragingly, recent advances have revealed that sodium-glucose cotransporter 2 (SGLT2) inhibitors, mineralocorticoid receptor antagonists (MRAs), and endothelin receptor antagonists (ERAs) confer substantial renal protective benefits in DKD patients, and these agents are now increasingly integrated into clinical practice.[14,15,16]

Revealing the key molecular mechanisms underlying the progression of DKD is crucial for the discovery of novel targeted therapies. Hyperglycemia is a core initiating factor that triggers injury to intrinsic renal cells such as podocytes, renal tubular epithelial cells, and endothelial cells.[17] The underlying mechanism includes overactivation of the renin-angiotensin-aldosterone system (RAAS), metabolic disturbances, autophagy, inflammatory responses, and oxidative stress.