EP300 promotes renal tubular epithelial cell fibrosis by increasing HIF2α expression in diabetic nephropathy

Renal tubular damage occurs early in diabetic nephropathy (DN) and may play a key role in the progression of kidney disease. E1A binding protein P300 (EP300) gene polymorphism correlates with the development and advancement of DN. We will explore the expression and relationship of EP300 and hypoxia-inducible factor 2 α (HIF2α) and the possible mechanism in the progression of DN. We studied the expression of EP300 and HIF2α in the renal tubules of patients with DN. At the cellular level, the interaction between EP300 and HIF2α were identified, and their relationship with cellular fibrosis was validated. Furthermore, we examined the effect of altered EP300 expression on downstream HIF2α and renal tubular fibrosis in vivo and in vitro. EP300 and HIF2α were strongly expressed in the renal tubules of DN patients and in HK-2 cells, and EP300 protein bound to the HIF2α gene in the nucleus. Adenovirus-mediated EP300 inhibition or overexpression downregulated or upregulated HIF2α expression in HK-2 cells, respectively. When EP300 was overexpressed in HK-2 cells, inhibition of HIF2α did not change the EP300 level, but the fibrotic marker was downregulated. In DN mice, silencing EP300 inhibited HIF2α expression levels and renal tubular fibrosis progression. In conclusion, this study defined that EP300 could promote renal tubular epithelial cell fibrotic processes by increasing HIF2α expression in DN.