Hypermethylation leads to the loss of HOXA5, resulting in JAG1 expression and NOTCH signaling for renal fibrosis

DNA methylation has been implicated in renal fibrosis. In this study, we demonstrated the induction of DNA methyltransferases and global DNA methylation in fibrotic kidneys, and further proved the beneficial effects of their inhibitor 5-Aza in renal fibrosis. HOXA5 was shown to be down-regulated in fibrotic kidneys through hypermethylation, and this down-regulation led to JAG1 expression and consequent activation of NOTCH signaling for renal fibrogenesis. These findings unveil DNA methylation and related genes, such as HOXA5, as potential therapeutic targets in renal fibrotic disease. To investigate the differentially methylated genes in kidney fibrosis, C57BL/6 mice were subjected to unilateral ureter obstruction for 7 days (UUO7D with daily-saline injection), UUO 7D with daily-5'Aza injection, and sham operation. The genomic DNA from the kidney cortex and outer medulla were extracted for bisulfite sequencing.