Chronic Kidney Disease on Hepatic DNA Methylation in Rat (PRJCA017592)
Patients with Chronic Kidney Disease (CKD) often experience altered drug exposure and an increased risk of drug-related adverse events. CKD affects the elimination of hepatic drugs metabolism, particularly CYP enzymes. Epigenetic rugulation plays a crucial role in the expression of CYP enzymes. In this study, we aim to investigate the impact of CKD on hepatic DNA methylation, DNA methylation enzyme expression, CYP enzyme expression and activity in a rat model induced by adenine gavage. The results revealed significant alterations in DNA methylation patterns in the liver of CKD rats, particularly in the promoter regions of genes. Notably, CKD rats exhibited increased DNA methylation and transcriptional down-regulation of several CYP genes, particularly CYP2D (human CYP2D6), leading to decreased expression and metabolic activity of CYP2D. Moreover, DNMT1 expression was increased in the liver of CKD rats. Further investigation showed that the DNA methylation inhibitor zebularline or siRNA suppressed DNMT1 activity, downregulated DNA methylation, and upregulated CYP2D6  expression in HepG2 cells. These findings suggest that CKD upregulates DNMT1, increase DNA methylation of several CYP genes, especially CYP2D gene, and reduce CYP2D expression and metabolic activity. These changes may contribute to the reduced CYP2D6-mediated drug clearance observed in CKD patients.