Glomerulo–Tubular Crosstalk in Diabetic Kidney Disease: From Pathophysiology to Novel Therapeutics

Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease and kidney failure worldwide despite advances in glycemic and blood pressure control. Although DKD has traditionally been viewed as a primarily glomerular disorder, growing evidence suggests that its progression is shaped by complex communication between the glomerulus and the tubulointerstitium. Under diabetic conditions characterized by persistent hyperglycemia, oxidative stress, and metabolic imbalance, signaling networks among glomerular endothelial cells, podocytes, and mesangial cells become disrupted. Glomerular injury may generate downstream signals, including proteinuria and loss of protective mediators, that impose inflammatory and metabolic stress on proximal tubular epithelial cells and may activate profibrotic pathways. Conversely, injured tubular cells release cytokines, chemokines, and extracellular vesicles that may influence glomerular cells and further contribute to structural damage. In addition, metabolic disturbances within tubular cells, such as lipid accumulation, mitochondrial dysfunction, and cellular stress responses, may promote tubulointerstitial fibrosis. Viewing DKD as a disorder of disrupted glomerulo-tubular communication provides an integrated framework linking pathophysiological mechanisms with emerging therapeutic strategies aimed at slowing disease progression.