Nicotinamide mononucleotide protects against diabetic nephropathy via IL-6/Rab5-mediated crosstalk between proximal tubular epithelial cells and podocytes.

BACKGROUND: Diabetic nephropathy (DN) is a leading cause of chronic kidney disease and end-stage renal disease, and is a significant global healthcare burden. Although proximal tubular epithelial cells (PTECs) and podocytes are involved in DN progression, the specific molecular interactions between these cells are not well understood. AIM: To elucidate the role of interleukin-6 (IL-6)/Rab5 signaling in mediating crosstalk between PTECs and podocytes, and to evaluate the protective effects of nicotinamide mononucleotide (NMN) against DN progression. METHODS: We utilized in vitro and in vivo models to investigate the pathogenesis of DN. In vitro, human PTECs and murine podocytes were cultured under high-glucose conditions, and IL-6 neutralizing antibodies or NMN treatments were applied. Podocyte injury was assessed by measurements of nephrin endocytosis, Rab5 activity, cytoskeletal organization, cell adhesion, and cell-spreading assays. In vivo, DN was induced in mice using streptozotocin, and mice then received NMN, insulin, or both treatments over an 8-week period. Renal tissues were analyzed histologically, ultrastructurally, and immunochemically, and urinary albumin excretion was measured to assess renal function. Statistical analyses were conducted using one-way ANOVA and Tukey's test. RESULTS: High-glucose conditions induced the epithelial-mesenchymal transition (EMT) in PTECs, increased IL-6 secretion, and activated Rab5 signaling in podocytes, leading to increased nephrin endocytosis and podocyte injury. Blocking IL-6 significantly attenuated these effects. NMN treatment of diabetic mice markedly reduced podocyte injury, glomerular hypertrophy, foot-process effacement, and urinary albumin excretion. Mechanistically, NMN suppressed the EMT and IL-6 secretion by PTECs, inhibited Rab5 activation in podocytes, and prevented nephrin endocytosis, thereby preserving the cytoskeletal integrity and function of podocytes. CONCLUSION: Our findings reveal a novel pathogenic mechanism of DN in which IL-6 released from glucose-stressed PTECs activates Rab5 signaling in podocytes, followed by nephrin endocytosis and structural injury of podocytes. Importantly, NMN treatment effectively disrupted this pathological pathway of intercellular communication, and provided significant protection against DN progression. These results suggest that NMN supplementation and targeting the IL-6/Rab5 signaling axis has promise as a therapeutic strategy for managing DN.