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

Publication ,  Journal Article
Li, Z-L; Wang, B; Lv, L-L; Tang, T-T; Wen, Y; Cao, J-Y; Zhu, X-X; Feng, S-T; Crowley, SD; Liu, B-C
Published in: Acta Pharmacol Sin
December 2021

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.

Duke Scholars

Published In

Acta Pharmacol Sin

DOI

EISSN

1745-7254

Publication Date

December 2021

Volume

42

Issue

12

Start / End Page

2106 / 2119

Location

United States

Related Subject Headings

  • Up-Regulation
  • Signal Transduction
  • Renal Insufficiency, Chronic
  • Protein Domains
  • Phenylpropionates
  • Pharmacology & Pharmacy
  • Mustard Compounds
  • Mixed Function Oxygenases
  • Mice, Inbred C57BL
  • Male
 

Citation

APA
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ICMJE
MLA
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Li, Z.-L., Wang, B., Lv, L.-L., Tang, T.-T., Wen, Y., Cao, J.-Y., … Liu, B.-C. (2021). FIH-1-modulated HIF-1α C-TAD promotes acute kidney injury to chronic kidney disease progression via regulating KLF5 signaling. Acta Pharmacol Sin, 42(12), 2106–2119. https://doi.org/10.1038/s41401-021-00617-4
Li, Zuo-Lin, Bin Wang, Lin-Li Lv, Tao-Tao Tang, Yi Wen, Jing-Yuan Cao, Xiao-Xiao Zhu, Song-Tao Feng, Steven D. Crowley, and Bi-Cheng Liu. “FIH-1-modulated HIF-1α C-TAD promotes acute kidney injury to chronic kidney disease progression via regulating KLF5 signaling.Acta Pharmacol Sin 42, no. 12 (December 2021): 2106–19. https://doi.org/10.1038/s41401-021-00617-4.
Li Z-L, Wang B, Lv L-L, Tang T-T, Wen Y, Cao J-Y, 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 Dec;42(12):2106–19.
Li, Zuo-Lin, 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, vol. 42, no. 12, Dec. 2021, pp. 2106–19. Pubmed, doi:10.1038/s41401-021-00617-4.
Li Z-L, Wang B, Lv L-L, Tang T-T, Wen Y, Cao J-Y, Zhu X-X, Feng S-T, Crowley SD, Liu B-C. FIH-1-modulated HIF-1α C-TAD promotes acute kidney injury to chronic kidney disease progression via regulating KLF5 signaling. Acta Pharmacol Sin. 2021 Dec;42(12):2106–2119.
Journal cover image

Published In

Acta Pharmacol Sin

DOI

EISSN

1745-7254

Publication Date

December 2021

Volume

42

Issue

12

Start / End Page

2106 / 2119

Location

United States

Related Subject Headings

  • Up-Regulation
  • Signal Transduction
  • Renal Insufficiency, Chronic
  • Protein Domains
  • Phenylpropionates
  • Pharmacology & Pharmacy
  • Mustard Compounds
  • Mixed Function Oxygenases
  • Mice, Inbred C57BL
  • Male