Renal Tubular Epithelial Cell–Macrophage Crosstalk in Diabetic Kidney Disease: Mechanistic Insights and Therapeutic Potential

Diabetic kidney disease (DKD) is a major cause of chronic kidney disease and kidney failure worldwide. Although glomerular lesions have traditionally received primary attention, tubulointerstitial injury and renal tubular epithelial cell (TEC) dysfunction are closely associated with renal functional decline. Increasing evidence suggests that TECs and macrophages participate in bidirectional communication through chemokines, cytokines, damage-associated molecular patterns, metabolites, and extracellular vesicles (EVs). These signals may link tubular metabolic stress, lipotoxicity, mitochondrial dysfunction, regulated cell death, macrophage activation, maladaptive epithelial repair, and renal fibrosis. In this narrative review, we summarize current evidence regarding TEC–macrophage interactions in DKD, with emphasis on chemokine and cytokine signaling, ATP-P2X7-NLRP3 signaling, metabolite-mediated communication, and EV-associated cargo transfer. Furthermore, we briefly discuss the application of emerging technologies to the study of TEC–macrophage interactions and to the identification of promising novel mediators of intercellular communication in DKD. In summary, this review provides a comprehensive and up-to-date overview of tubular–macrophage crosstalk in DKD and highlights its importance for the development of novel therapeutic interventions.