Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitor Roxadustat (FG-4592) Protects against Cisplatin-induced Acute Kidney Injury

Renal hypoxia occurs in acute kidney injury (AKI) of various etiologies. Activation of hypoxia-inducible transcription factor (HIF) has been identified as an important mechanism of cellular adaptation to low oxygen. Preconditional HIF activation protects against AKI, suggesting a new approach in AKI treatment. HIF is degraded under normoxic conditions mediated by oxygen-dependent hydroxylation of specific prolyl residues of the regulative α-subunits by HIF prolyl hydroxylases (PHD). FG-4592 is a novel, orally active small-molecule HIF PHD inhibitor for the treatment of anemia in patients with CKD. The current study aimed to evaluate the effect of FG-4592 (Roxadustat) on cisplatin-induced kidney injury. In mice, pretreatment with FG-4592 markedly ameliorated cisplatin-induced kidney injury as shown by the improved renal function (BUN, serum creatinine, and cystatin C) and kidney morphology (PAS staining) in line with a robust blockade of renal tubular injury markers of KIM-1 and NGAL. Meanwhile, the renal apoptosis and inflammation induced by cisplatin were also strikingly attenuated in FG-4592-treated mice. Along with the protective effects shown above, FG-4592 pretreatment strongly enhanced HIF-1α in tubular cells, as well as the expressions of HIF target genes. FG-4592 alone did not affect the renal function and morphology in mice. In vitro , FG-4592 treatment significantly upregulated HIF-1α and protected the tubular cells against cisplatin-induced apopt...

Source: Clinical Science - March 26, 2018 Category: Biomedical Science Authors: Yang, Y., Yu, X., Zhang, Y., Ding, G., Zhu, C., Huang, S., Jia, Z., Zhang, A. Tags: PublishAheadOfPrint Source Type: research