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

Cisplatin (Cis) is a common chemotherapeutic agent that has been used since the 1970s [1]. Although Cis is effective, it is largely limited by its nephrotoxicity [2]. Cis is mainly excreted by the genitourinary system through glomerular filtration and tubular secretion [3]; as a result, Cis easily accumulates in proximal tubular cells (PTCs) and causes PTC injury [4]. Recent studies have mainly focused on Cis-induced Cisplatin (Cis) can cause chronic kidney disease (CKD) and promote renal fibrosis, but the underlying mechanism is not fully understood. Hypoxia inducible factor-1 alpha (HIF-1 alpha) 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-1 alpha and Notch-1 are closely related to each other. In the present study, mice with HIF-1 alpha gene knockout in proximal tubular cells (PTCs) (PT-HIF-1 alpha-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-1 alpha 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-1 alpha-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-1 alpha and N1ICD. Further inhibiting Notch-1 significantly reduced cellular fibrogenesis but did not affect HIF-1 alpha expression. The data suggested that HIF-1 alpha could promote renal fibrosis in Cis-induced CKD by activating Notch-1 both transcriptionally and post-transcriptionally and that HIF-1 alpha may serve as a potential therapeutic target for Cis-induced CKD.