Effects of HIF-1α on renal fibrosis in cisplatin-induced chronic kidney disease

肾脏疾病 Notch信号通路 癌症研究 内科学 病态的 纤维化 生物 医学 内分泌学 病理 受体
作者
Hao Zhao,Yachun Han,Na Jiang,Chenrui Li,Ming Yang,Ying Xiao,Ling Wei,Xiaofen Xiong,Jinfei Yang,Chengyuan Tang,Li Xiao,Fuyou Liu,Lei Zhu,Lin Sun
出处
期刊:Clinical Science [Portland Press]
卷期号:135 (10): 1273-1288 被引量:26
标识
DOI:10.1042/cs20210061
摘要

Abstract Cisplatin (Cis) can cause chronic kidney disease (CKD) and promote renal fibrosis, but the underlying mechanism is not fully understood. Hypoxia inducible factor-1α (HIF-1α) can promote renal fibrosis in some kidney diseases, but its role in Cis-induced CKD is still unknown. Notch-1 is a recognized molecule that promotes renal fibrosis under pathological circumstances, and evidence shows that HIF-1α and Notch-1 are closely related to each other. In the present study, mice with HIF-1α gene knockout in proximal tubular cells (PTCs) (PT-HIF-1α-KO) were generated and treated with Cis to induce CKD. A human proximal tubular cell line (HK-2) and primary mouse PTCs were used for in vitro studies. The results showed that HIF-1α was increased in the kidneys of Cis-treated wild-type mice, accompanied by elevated Notch-1, Notch-1 intracellular domain (N1ICD), Hes-1 and renal fibrosis. However, these alterations were partially reversed in PT-HIF-1α-KO mice. Similar results were observed in HK-2 cells and primary mouse PTCs. In addition, treating the cells with Cis induced a marked interaction of HIF-1α and N1ICD. Further inhibiting Notch-1 significantly reduced cellular fibrogenesis but did not affect HIF-1α expression. The data suggested that HIF-1α could promote renal fibrosis in Cis-induced CKD by activating Notch-1 both transcriptionally and post-transcriptionally and that HIF-1α may serve as a potential therapeutic target for Cis-induced CKD.
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