p16INK4a Deletion Alleviated Obesity-Associated Kidney Fibrosis by Regulating Metabolic Reprogramming and the Inflammasome Pathway.

Recent research has revealed a close association between obesity and various metabolic disorders, including renal metabolic diseases, but the mechanism is still unknown. This study explored the role of p16INK4a in obesity-related kidney fibrosis and evaluated its potential as a therapeutic target. Using wild-type (WT) mice and p16 KO mice, we fed both groups a high-fat diet (HFD) for 6 months. Our results showed that an HFD led to significant weight gain and increased p16INK4a expression in WT mouse kidneys. Notably, p16 KO mice presented reduced fibrosis, as indicated by decreased levels of profibrotic proteins (α-SMA and collagen I) and improved histological outcomes, including reduced fibrosis in the glomeruli and renal tubules. P16 KO also suppressed the levels of several proinflammatory biomarkers (MMP1, MMP3, IL-1β, TNF-α and IL-6) and inhibited the NLRP3 inflammasome pathway. The administration of ABT263 further validated these findings by decreasing fibrosis and inflammation in HFD-fed mice, suggesting that p16INK4a contributes to both fibrotic and inflammatory processes. Metabolomic analyses revealed that p16 knockout influenced various metabolic pathways, including linoleic acid and pyrimidine metabolism, in HFD-induced kidneys. Additionally, p16INK4a over-expression was observed in the kidneys of chronic kidney disease patients with long-term hyperlipidaemia. These results highlight the critical role of p16INK4a in obesity-induced kidney damage and suggest that targeting p16INK4a may be a promising approach for treating obesity-related kidney fibrosis and inflammation.