DNA methylation in kidney repair after ischemic AKI

Acute kidney injury (AKI) is associated with high mortality and increasing prevalence. After AKI, some patients can fully recover but AKI is a risk factor for, and may progress to, chronic kidney disease (CKD). Kidney repair is a key determinant of the outcome or prognosis of AKI survivors. Especially, maladaptive kidney repair after severe or multiple episodes of AKI often leads to chronic renal pathologies characterized by tubular degeneration, chronic inflammation, interstitial fibrosis, and progressive decline of renal function. DNA methylation, catalyzed by DNA methyltransferase (DNMT), is a major epigenetic mechanism in health and disease. However, very few studies examined DNA methylation in AKI and post-AKI kidney repair. In preliminary studies, we demonstrated the induction of DNMT1 and DNMT3a along with DNA methylation during kidney repair. We further suggested the involvement of DNA methylation in maladaptive kidney repair by showing the effect of 5-aza-2'-deoxycytidine (5-aza), a pharmacological inhibitor of DNMT. In addition, our global DNA methylation assay has identified differential DNA methylation of multiple genes in post-IRI kidneys, among which homeobox A5 (Hoxa5) and microRNA-219 (miR-219) were hypermethylated at their gene promoters and the hypermethylation was associated with down-regulation of their expression. In this application, we hypothesize that: DNA methylation by DNMTs plays a critical role in maladaptive kidney repair after ischemic AKI. Specifically, hypermethylation of Hoxa5 and miR-219 leads to down-regulation of these genes, resulting in changes in downstream gene expression for the development of renal fibrosis. We propose three specific aims to: 1, test the hypothesis that DNA methylation by DNMTs plays a critical role in maladaptive kidney repair; 2, test the hypothesis that hypermethylation leads to the down-regulation of Hoxa5 in maladaptive kidney repair resulting in pro-fibrotic cell signaling for renal fibrosis; and 3, test the hypothesis that hypermethylation represses miR-219 in maladaptive kidney repair leading to pro-fibrosis gene expression. The work will gain significant new insights into epigenetic regulation of kidney repair. Moreover, by targeting DNA methylation, we may identify novel therapeutic strategies to improve kidney repair and the prognosis of AKI survivors.