Extracellular vesicle-cytokine communication in diabetic kidney disease: an integrated network linking renal resident cells and macrophages

Chronic inflammation contributes to the onset and progression of diabetic kidney disease (DKD), yet a model centered solely on soluble cytokines does not fully explain the cellular origin, spatially directed delivery, or sustained amplification of local signals. Extracellular vesicles (EVs) couple vesicular signaling with cytokine regulation through EV-associated cytokine or ligand signals and through RNA or protein cargo that reprograms cytokine production in recipient cells. This review examines how metabolic stress alters EV release and cargo composition, summarizes evidence for unidirectional and bidirectional communication between resident kidney cells and immune cells, and evaluates the EV specificity and evidential completeness of each donor-recipient axis. Evidence is strongest for communication between tubular epithelial cells and macrophages; findings involving podocytes, mesangial cells, and glomerular endothelial cells are largely unidirectional or inferred across studies. Under the in vitro polarization conditions used in the source studies, EVs from macrophages polarized toward a pro-inflammatory phenotype generally promote injury, whereas some EVs from macrophages polarized toward a reparative phenotype limit cell damage or improve autophagy. On this basis, we propose an EV-associated inflammatory communication network linked by shared inflammatory endpoints and inferred return signals. Within this network, we propose that injury-promoting and protective signals compete dynamically and thereby influence persistent inflammation and fibrosis-related disease progression. This hypothesis integrates existing evidence and offers a framework for understanding persistent inflammation in DKD and for testing therapies that target intercellular communication.