The profibrotic effects of MK‐8617 on tubulointerstitial fibrosis mediated by the KLF5 regulating pathway

The discovery of hypoxia‐inducible factor (HIF)‐prolyl hydroxylase inhibitor (PHI) has revolutionized the treatment strategy for renal anemia. However, the presence of multiple transcription targets of HIF raises safety concerns regarding HIF‐PHI. Here, we explored the dose‐dependent effect of MK‐8617 (MK), a kind of HIF‐PHI, on renal fibrosis. MK was administered by oral gavage to mice for 12 wk at doses of 1.5, 5, and 12.5 mg/kg. In vitro , the human proximal tubule epithelial cell line HK‐2 was treated with increasing doses of MK administration. Transcriptome profiling was performed, and fibrogenesis was evaluated. The dose‐dependent biphasic effects of MK on tubulointerstitial fibrosis (TIF) were observed in chronic kidney disease mice. Accordingly, high‐dose MK treatment could significantly enhance TIF. Using RNA‐sequencing, combined with in vivo and in vitro experiments, we found that Krüppel‐like factor 5 (KLF5) expression level was significantly increased in the proximal tubular cells, which could be transcriptionally regulated by HIF‐1α with high‐dose MK treatment but not low‐dose MK. Furthermore, our study clarified that HIF‐1α‐KLF5‐TGF‐β1 signaling activation is the potential mechanism of high‐dose MK‐induced TIF, as knockdown of KLF5 reduced TIF in vivo . Collectively, our study demonstrates that high‐dose MK treatment initiates TIF by activating HIF‐1α‐KLF5‐TGF‐β1 signaling. These findings provide novel insights into TIF induction by high‐dose MK (HIF‐PHI), suggesting that the safety dosage window needs to be emphasized in future clinical applications.—Li, Z.‐L., Lv, L.‐L., Wang, B., Tang, T.‐T., Feng, Y., Cao, J.‐Y., Jiang, L.‐Q., Sun, Y.‐B., Liu, H., Zhang, X.‐L., Ma, K.‐L., Tang, R.‐N., Liu, B.‐C. The profibrotic effects of MK‐8617 on tubulointerstitial fibrosis mediated by the KLF5 regulating pathway. FASEB J. 33, 12630–12643 (2019). www.fasebj.org