First Affiliated Hospital of Zhengzhou University, Department of Nephrology. 1 Jianshe Eastern Road, Erqi District, Zhengzhou 450052, Henan, China.
First Affiliated Hospital of Zhengzhou University, Department of Nephrology. 1 Jianshe Eastern Road, Erqi District, Zhengzhou 450052, Henan, China.
Cell Signal. 2022 Oct;98:110407. doi: 10.1016/j.cellsig.2022.110407. Epub 2022 Jul 14.
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.
在糖尿病肾病（DN）中，肾小管损伤很早就会发生，并且可能在肾脏疾病的进展中起关键作用。E1A 结合蛋白 P300（EP300）基因多态性与 DN 的发生和进展相关。我们将探讨 EP300 和缺氧诱导因子 2α（HIF2α）的表达及其在 DN 进展中的关系及可能的机制。我们研究了 DN 患者肾小管中 EP300 和 HIF2α 的表达。在细胞水平上，鉴定了 EP300 和 HIF2α 之间的相互作用，并验证了它们与细胞纤维化的关系。此外，我们还研究了改变 EP300 表达对体内和体外 HIF2α 和肾小管纤维化的影响。EP300 和 HIF2α 在 DN 患者和 HK-2 细胞的肾小管中强烈表达，并且 EP300 蛋白与核内的 HIF2α 基因结合。腺病毒介导的 EP300 抑制或过表达分别下调或上调 HK-2 细胞中 HIF2α 的表达。当 HK-2 细胞中过表达 EP300 时，抑制 HIF2α 不会改变 EP300 水平，但纤维化标志物下调。在 DN 小鼠中，沉默 EP300 抑制 HIF2α 表达水平和肾小管纤维化进展。总之，本研究表明，在 DN 中，EP300 可以通过增加 HIF2α 的表达来促进肾小管上皮细胞的纤维化过程。
