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FIH-1-modulated HIF-1α C-TAD promotes acute kidney injury to chronic kidney disease progression via regulating KLF5 signaling

Abstract

Incomplete recovery from episodes of acute kidney injury (AKI) can predispose patients to develop chronic kidney disease (CKD). Although hypoxia-inducible factor-1α (HIF-1α) is a master regulator of the response to hypoxia/ischemia, the role of HIF-1α in CKD progression following incomplete recovery from AKI is poorly understood. Here, we investigated this issue using moderate and severe ischemia/reperfusion injury (I/RI) mouse models. We found that the outcomes of AKI were highly associated with the time course of tubular HIF-1α expression. Sustained activation of HIF-1α, accompanied by the development of renal fibrotic lesions, was found in kidneys with severe AKI. The AKI to CKD progression was markedly ameliorated when PX-478 (a specific HIF-1α inhibitor, 5 mg· kg−1·d−1, i.p.) was administered starting on day 5 after severe I/RI for 10 consecutive days. Furthermore, we demonstrated that HIF-1α C-terminal transcriptional activation domain (C-TAD) transcriptionally stimulated KLF5, which promoted progression of CKD following severe AKI. The effect of HIF-1α C-TAD activation on promoting AKI to CKD progression was also confirmed in in vivo and in vitro studies. Moreover, we revealed that activation of HIF-1α C-TAD resulted in the loss of FIH-1, which was the key factor governing HIF-1α-driven AKI to CKD progression. Overexpression of FIH-1 inhibited HIF-1α C-TAD and prevented AKI to CKD progression. Thus, FIH-1-modulated HIF-1α C-TAD activation was the key mechanism of AKI to CKD progression by transcriptionally regulating KLF5 pathway. Our results provide new insights into the role of HIF-1α in AKI to CKD progression and also the potential therapeutic strategy for the prevention of renal diseases progression.

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Fig. 1: HIF-1α activation is associated with poor AKI outcomes.
Fig. 2: Sustained activation of HIF-1α is observed in severe AKI without recovery.
Fig. 3: Inhibition of HIF-1α by PX-478 hinders AKI to CKD progression.
Fig. 4: KLF5 promotes progression of CKD following AKI.
Fig. 5: KLF5 was transcriptionally regulated by the HIF-1α C-TAD.
Fig. 6: Activation of the HIF-1α C-TAD promotes AKI to CKD progression.
Fig. 7: Decreased tubular FIH-1 mediates the AKI to CKD transition.
Fig. 8: FIH-1 contributes to recovery of severe AKI.
Fig. 9: Schematic diagram showing the proposed mechanism of AKI in CKD progression.

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Acknowledgements

The authors thank Chen-chen Zhang (Southeast University School of Medicine) for confocal image acquisition and valuable technical support. This study was supported by the National Natural Science Foundation of China (82000648, 8203000544, 81720108007, and 81470922), the National Key Research and Development Program of China (2018YFC1314002), the Natural Science Foundation of Jiangsu Province (BK20200363), the Innovative and Entrepreneurial Talent (Doctor) of Jiangsu Province and the Special Fund for Basic Scientific Research of Central Universities (2242020K40151).

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ZLL, BW, and BCL designed the study, carried out experiments, analyzed data, and wrote and edited the paper; LLL, TTT, YW, STF, and JYC carried out experiments and analyzed the data; and XXZ and SDC made the figures and edited the paper; all authors approved the final version of the paper.

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Correspondence to Bin Wang or Bi-cheng Liu.

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The authors declare no competing interests.

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Li, Zl., Wang, B., Lv, Ll. et al. FIH-1-modulated HIF-1α C-TAD promotes acute kidney injury to chronic kidney disease progression via regulating KLF5 signaling. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00617-4

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Keywords

  • acute kidney injury
  • chronic kidney disease
  • renal fibrosis
  • HIF-1α C-terminal activation domain
  • KLF5
  • FIH-1
  • PX-478

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