Revisiting and Expanding the Understanding of Molecular Mechanisms Underpinning Diabetic Nephropathy: An Updated and Comprehensive Review of Recent Advance

Diabetic nephropathy (DN) stands as a critical complication of diabetes mellitus, often culminating in end-stage renal disease (ESRD). The intricate molecular mechanisms underlying DN progression necessitate comprehensive exploration for effective therapeutic interventions. This review outlines key molecular insights into DN pathogenesis, including glomerular hypertrophy and hyperfiltration driven by hyperglycaemia-induced renal vasodilation. Renal fibrosis, characterized by ECM protein accumulation, is mediated by TGF-β signalling. Chronic low-grade inflammation, oxidative stress, and activation of the renin-angiotensin-aldosterone system (RAAS) contribute significantly to renal injury. Epigenetic modifications, such as DNA methylation and non-coding RNA regulation, further influence gene expression patterns in response to hyperglycaemia. Dysregulated signalling pathways including PKC, NF-κB, and mTOR play pivotal roles in cellular responses to hyperglycaemia and oxidative stress. Understanding these molecular mechanisms offers potential therapeutic targets, including agents targeting inflammation, oxidative stress, and fibrosis, alongside strategies for glycaemic and blood pressure control. Emerging therapies targeting epigenetic regulators and cellular signalling pathways hold promise for preventing and treating diabetic nephropathy.