Fig. 9. Proposed model summarizing the p21-dependent regulation of the hyperglycemic memory and possible interventions.

Hyperglycemia suppresses DNMT1 expression in the tubular compartment, inducing hypomethylation of the p21 promoter, p21 expression, and tubular senescence. The latter is associated with inflammation, impairs the endogenous tubular repair capability and induces tubulointerstitial fibrosis, promoting tubulointerstitial damage and DKD. Exploiting aPC-signaling (Parmodulin, 3K3A-aPC) reverses the epigenetically sustained p21 expression.