The expression of p16 was upregulated in DKD kidneys and HK2 cells cultured in high glucose media, resulting in an increase of senescence and the expression of SASPs, including TNF-α, IL-6, IL-1β, and MCP-1, to decrease the production of ATP and promote glycolysis and mitochondrial metabolic disorder. Here, CDKN2A is linked to diabetic kidney disease.