Molecular Pathways and Emerging Therapeutic Targets in the Pathogenesis of Diabetic Kidney Disease

Sima Al-Masri^1*Jennifer N. Coelho²Linto Thomas^1*

• ¹University of South Florida, Tampa, United States
• ²Universidade de Sao Paulo, São Paulo, Brazil

Diabetic kidney disease (DKD) arises from intersecting metabolic, hemodynamic, inflammatory, and epigenetic programs that progressively remodel the glomerulus and tubulointerstitium on a molecular level. Hyperglycemia-driven AGE-RAGE signaling, PKC activation, and RAAS dysregulation converge on oxidative stress, endothelial dysfunction, and profibrotic transcription (e.g., TGF-beta/Smad), while mitochondrial and endoplasmic-reticulum stress amplify lipotoxicity and cell death. Innate immune activation (macrophage recruitment and inflammasome signaling) and maladaptive repair promote extracellular-matrix accumulation and nephron loss. Multi-omics studies further implicate durable chromatin and non-coding RNA changes that sustain metabolic memory despite improved glycemia. In this review, we synthesize landmark and recent mechanistic data spanning glomerular filtration barrier injury, tubular stress pathways, and immune-metabolic crosstalk, and we highlight therapeutic strategies that move upstream of symptom control. We discuss established disease-modifying agents (RAAS blockade, SGLT2 inhibitors, and non-steroidal MR antagonists) alongside investigational approaches including epigenetic modulators, AMPK/NAD+ axis targeting, and gene/RNA-based interventions. Together, these advances frame DKD as a disorder of rewired signaling and gene-regulatory circuitry, where convergent molecular nodes across podocytes, endothelium, and tubules offer the actionable considerations for durable renal protection.