Apelin-12 ameliorates diabetic nephropathy via p53/JAM-A axis-mediated preservation of glomerular endothelial integrity.

Diabetic nephropathy (DN) is characterized by significant endothelial barrier impairment, which leads to increased vascular permeability, albuminuria, and progressive renal dysfunction. Apelin-12, an endogenous bioactive peptide, has attracted attention for its potential protective roles in various cardiovascular and metabolic diseases, owing to its antioxidative and anti-inflammatory properties. This research investigated the renoprotective capacity of Apelin-12 against diabetic nephropathy (DN) by modulating oxidative stress and endothelial barrier dysfunction in both db/db mice and human renal glomerular endothelial cells (HRGECs). In diabetic mice, Apelin-12 treatment significantly ameliorated glomerular oxidative stress, restored JAM-A expression, and improved renal function, as evidenced by reduced albuminuria and serum creatinine levels. Histopathological analysis confirmed reduced glomerular damage. Apelin-12 also preserved endothelial marker expression and reduced inflammation without affecting blood pressure or glucose tolerance. In HRGECs, Apelin-12 attenuated high glucose-induced endothelial barrier disruption, restored JAM-A expression, activated the Nrf2/HO-1 antioxidant pathway, and suppressed p53 upregulation. Notably, p53 overexpression abolished Apelin-12's protective effects on JAM-A expression and endothelial integrity, suggesting that p53 is a critical mediator in this pathway. These findings indicate that Apelin-12 alleviates DN progression through counteracting oxidative stress and p53-dependent endothelial dysfunction, supporting its candidacy as a therapeutic agent. The study further establishes the mechanistic link between JAM-A and p53 in diabetic renal injury, providing new insights into DN pathogenesis.