Integration of DNA Methylome and Transcriptome Analysis to Identify Novel Epigenetic Targets in the Acute Kidney Injury–Chronic Kidney Disease Transition

(1) Background: the epigenetic mechanisms underlying the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remain poorly understood; (2) Methods: to investigate this process, we conducted genome-wide DNA methylation sequencing to map the epigenetic changes during the AKI-CKD transition in a mouse model. By integrating DNA methylome and transcriptome analyses, we identified genes and signaling pathways regulated by DNA methylation throughout this progression; (3) Results: our analysis identified four candidate genes-<i>Atp1a3</i>, <i>Ncf1</i>, <i>Lpl</i>, and <i>Slc27a2</i>-that were regulated by DNA methylation and strongly correlated with kidney disease prognosis. Additionally, we found that the <i>PPAR</i> signaling pathways, among others, were implicated in this process. Treatment with DNA methyltransferase inhibitors mitigated fibrosis and improved lipid metabolism in the kidneys during AKI-CKD progression; (4) Conclusions: this study provides the first comprehensive epigenetic map of the AKI-CKD transition. Our findings offer new insights into the epigenetic regulation of kidney disease progression and highlight potential therapeutic targets to prevent the transition from AKI to CKD.