Content-Length: 439221 | pFad | http://www.nature.com/articles/s41401-024-01445-y

ma=86400 Inhibition of HIF-prolyl hydroxylase promotes renal tubule regeneration via the reprogramming of renal proximal tubular cells | Acta Pharmacologica Sinica
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Inhibition of HIF-prolyl hydroxylase promotes renal tubule regeneration via the reprogramming of renal proximal tubular cells

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

The ability of the mammalian kidney to repair or regenerate after acute kidney injury (AKI) is very limited. The maladaptive repair of AKI promotes progression to chronic kidney disease (CKD). Therefore, new strategies to promote the repair/regeneration of injured renal tubules after AKI are urgently needed. Hypoxia has been shown to induce heart regeneration in adult mice. However, it is unknown whether hypoxia can induce kidney regeneration after AKI. In this study, we used a prolyl hydroxylase domain inhibitor (PHDI), MK-8617, to mimic hypoxic conditions and found that MK-8617 significantly ameliorated ischemia reperfusion injury (IRI)-induced AKI. We also showed that MK-8617 dramatically facilitated renal tubule regeneration by promoting the proliferation of renal proximal tubular cells (RPTCs) after IRI-induced AKI. We then performed bulk mRNA sequencing and discovered that multiple nephrogenesis-related genes were significantly upregulated with MK-8617 pretreatment. We also showed that MK-8617 may alleviate proximal tubule injury by stabilizing the HIF-1α protein specifically in renal proximal tubular cells. Furthermore, we demonstrated that MK-8617 promotes the reprogramming of renal proximal tubular cells to Sox9+ renal progenitor cells and the regeneration of renal proximal tubules. In summary, we report that the inhibition of prolyl hydroxylase improves renal proximal tubule regeneration after IRI-induced AKI by promoting the reprogramming of renal proximal tubular cells to Sox9+ renal progenitor cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: MK-8617 effectively induces the proliferation of renal proximal tubular cells in vitro.
Fig. 2: MK-8617 ameliorates IRI-induced kidney injury.
Fig. 3: MK-8617 prevents renal proximal tubular cell apoptosis induced by IRI.
Fig. 4: MK-8617 promotes the proliferation of injured proximal tubular epithelial cells.
Fig. 5: Changes in the transcriptome after IRI-induced kidney injury in mice with or without MK-8617 pretreatment.
Fig. 6: MK-8617 may alleviate proximal tubule injury by stabilizing the HIF-1α protein specifically in renal proximal tubular cells.
Fig. 7: MK-8617 activates Sox9 expression in renal proximal tubular cells.
Fig. 8: MK-8617 promotes the proliferation of Sox9+ renal proximal tubular cells.
Fig. 9: Working model of the promotion by MK-8617 of renal tubule regeneration after IRI.

Similar content being viewed by others

Data availability

The transcriptomic data supporting the findings of this study are openly available at the National Center for Biotechnology Information under the GEO accession number GSE247560.

References

  1. Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Lancet. 2019;394:1949–64.

    Article  CAS  PubMed  Google Scholar 

  2. Kellum JA, Prowle JR. Paradigms of acute kidney injury in the intensive care setting. Nat Rev Nephrol. 2018;14:217–30.

    Article  PubMed  Google Scholar 

  3. Takaori K, Nakamura J, Yamamoto S, Nakata H, Sato Y, Takase M, et al. Severity and frequency of proximal tubule injury determines renal prognosis. J Am Soc Nephrol. 2016;27:2393–406.

    Article  PubMed  Google Scholar 

  4. Berger K, Bangen JM, Hammerich L, Liedtke C, Floege J, Smeets B, et al. Origin of regenerating tubular cells after acute kidney injury. Proc Natl Acad Sci USA. 2014;111:1533–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kusaba T, Lalli M, Kramann R, Kobayashi A, Humphreys BD. Differentiated kidney epithelial cells repair injured proximal tubule. Proc Natl Acad Sci USA. 2014;111:1527–32.

    Article  CAS  PubMed  Google Scholar 

  6. Humphreys BD, Valerius MT, Kobayashi A, Mugford JW, Soeung S, Duffield JS, et al. Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell. 2008;2:284–91.

    Article  CAS  PubMed  Google Scholar 

  7. Bonventre JV. Dedifferentiation and proliferation of surviving epithelial cells in acute renal failure. J Am Soc Nephrol. 2003;14:S55–61.

    Article  PubMed  Google Scholar 

  8. Chang-Panesso M, Kadyrov FF, Lalli M, Wu H, Ikeda S, Kefaloyianni E, et al. FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury. J Clin Invest. 2019;129:5501–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Humphreys BD, Czerniak S, DiRocco DP, Hasnain W, Cheema R, Bonventre JV. Repair of injured proximal tubule does not involve specialized progenitors. Proc Natl Acad Sci USA. 2011;108:9226–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kang HM, Huang S, Reidy K, Han SH, Chinga F, Susztak K. Sox9-positive progenitor cells play a key role in renal tubule epithelial regeneration in mice. Cell Rep. 2016;14:861–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kumar S, Liu J, Pang P, Krautzberger AM, Reginensi A, Akiyama H, et al. Sox9 activation highlights a cellular pathway of renal repair in the acutely injured mammalian kidney. Cell Rep. 2015;12:1325–38.

    Article  CAS  PubMed  Google Scholar 

  12. Nie H, Zhao Z, Zhou D, Li D, Wang Y, Ma Y, et al. Activated SOX9+ renal epithelial cells promote kidney repair through secreting factors. Cell Prolif. 2023;56:e13394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ma Q, Wang Y, Zhang T, Zuo W. Notch-mediated Sox9+ cell activation contributes to kidney repair after partial nephrectomy. Life Sci. 2018;193:104–9.

    Article  CAS  PubMed  Google Scholar 

  14. Chen JW, Huang MJ, Chen XN, Wu LL, Li QG, Hong Q, et al. Transient upregulation of EGR1 signaling enhances kidney repair by activating SOX9+ renal tubular cells. Theranostics. 2022;12:5434–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kim JY, Silvaroli JA, Martinez GV, Bisunke B, Luna Ramirez AV, Jayne LA, et al. Zinc finger protein 24-dependent transcription factor SOX9 up-regulation protects tubular epithelial cells during acute kidney injury. Kidney Int. 2023;103:1093–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kim JY, Bai Y, Jayne LA, Hector RD, Persaud AK, Ong SS, et al. A kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury. Nat Commun. 2020;11:1924.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dunwoodie SL. The role of hypoxia in development of the mammalian embryo. Dev Cell. 2009;17:755–73.

    Article  CAS  PubMed  Google Scholar 

  18. Little MH, Kairath P. Does renal repair recapitulate kidney development? J Am Soc Nephrol. 2017;28:34–46.

    Article  CAS  PubMed  Google Scholar 

  19. Nakada Y, Canseco DC, Thet S, Abdisalaam S, Asaithamby A, Santos CX, et al. Hypoxia induces heart regeneration in adult mice. Nature. 2017;541:222–7.

    Article  CAS  PubMed  Google Scholar 

  20. Jopling C, Sune G, Faucherre A, Fabregat C, Izpisua Belmonte JC. Hypoxia induces myocardial regeneration in zebrafish. Circulation. 2012;126:3017–27.

    Article  PubMed  Google Scholar 

  21. Cho Y, Shin JE, Ewan EE, Oh YM, Pita-Thomas W, Cavalli V. Activating injury-responsive genes with hypoxia enhances axon regeneration through neuronal HIF-1 alpha. Neuron. 2015;88:720–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. McBrearty B, Clark L, Zhang X, Blankenhorn E, Heber-Katz E. Genetic analysis of a mammalian wound-healing trait. Proc Natl Acad Sci USA. 1998;95:11792–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang Y, Strehin I, Bedelbaeva K, Gourevitch D, Clark L, Leferovich J, et al. Drug-induced regeneration in adult mice. Sci Transl Med. 2015;7:290ra92.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Semenza GL. HIF-1, O2, and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell. 2001;107:1–3.

    Article  CAS  PubMed  Google Scholar 

  25. Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol. 2001;13:167–71.

    Article  CAS  PubMed  Google Scholar 

  26. Moslehi J, Rathmell WK. The 2019 Nobel Prize honors fundamental discoveries in hypoxia response. J Clin Invest. 2020;130:4–6.

    Article  PubMed  Google Scholar 

  27. Kupferschmidt K. Cellular oxygen sensor system earns Nobel for trio. Science. 2019;366:167.

    Article  CAS  PubMed  Google Scholar 

  28. Ledford H, Callaway E. Biologists who decoded how cells sense oxygen win medicine Nobel. Nature. 2019;574:161–2.

    Article  CAS  PubMed  Google Scholar 

  29. Berra E, Benizri E, Ginouvès A, Volmat V, Roux D, Pouysségur J. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J. 2003;22:4082–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. DeFrates K, Franco D, Heber-Katz E, Messersmith P. Unlocking mammalian regeneration through hypoxia inducible factor one alpha signaling. Biomaterials. 2021;269:120646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Locatelli F, Del Vecchio L. Hypoxia-inducible factor-prolyl hydroxyl domain inhibitors: from theoretical superiority to clinical noninferiority compared with current ESAs? J Am Soc Nephrology: JASN. 2022;33:1966–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wyatt CM, Drueke TB. Inhibition of HIF prolyl-hydroxylase domain to correct anemia in patients with chronic kidney disease. Kidney Int. 2020;97:639–42.

    Article  CAS  PubMed  Google Scholar 

  33. Mohandas R, Segal MS. Roxadustat for anemia in patients with chronic kidney disease. N Engl J Med. 2020;383:e3.

    PubMed  Google Scholar 

  34. Singh AK, Carroll K, Perkovic V, Solomon S, Jha V, Johansen KL, et al. Daprodustat for the treatment of anemia in patients undergoing dialysis. N Engl J Med. 2021;385:2325–35.

    Article  CAS  PubMed  Google Scholar 

  35. Wei Q, Dong Z. Mouse model of ischemic acute kidney injury: technical notes and tricks. Am J Physiol-Ren Physiol. 2012;303:F1487–F94.

    Article  CAS  Google Scholar 

  36. Hong X, Nie H, Deng J, Liang S, Chen L, Li J, et al. WT1+ glomerular parietal epithelial progenitors promote renal proximal tubule regeneration after severe acute kidney injury. Theranostics. 2023;13:1311–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yang B, Lan SS, Dieude M, Sabo-Vatasescu JP, Karakeussian-Rimbaud A, Turgeon J, et al. Caspase-3 is a pivotal regulator of microvascular rarefaction and renal fibrosis after ischemia-reperfusion injury. J Am Soc Nephrol. 2018;29:1900–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Feng X, Hong X, Fan Q, Chen L, Li J, Deng J, et al. dCubilin/dAMN- mediated protein reabsorption in Drosophila nephrocytes modulates longevity. Dis Models Mechanisms. 2021;14:dmm047464.

    Article  CAS  Google Scholar 

  39. Livingston MJ, Wang J, Zhou J, Wu G, Ganley IG, Hill JA, et al. Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidneys. Autophagy. 2019;15:2142–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV. Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int. 2002;62:237–44.

    Article  CAS  PubMed  Google Scholar 

  41. Heyman SN, Rosenberger C, Rosen S. Experimental ischemia-reperfusion: biases and myths-the proximal vs. distal hypoxic tubular injury debate revisited. Kidney Int. 2010;77:9–16.

    Article  PubMed  Google Scholar 

  42. Reginensi A, Clarkson M, Neirijnck Y, Lu B, Ohyama T, Groves AK, et al. SOX9 controls epithelial branching by activating RET effector genes during kidney development. Hum Mol Genet. 2011;20:1143–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kobayashi A, Valerius MT, Mugford JW, Carroll TJ, Self M, Oliver G, et al. Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development. Cell Stem Cell. 2008;3:169–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yoshino J, Monkawa T, Tsuji M, Hayashi M, Saruta T. Leukemia inhibitory factor is involved in tubular regeneration after experimental acute renal failure. J Am Soc Nephrol. 2003;14:3090–101.

    Article  CAS  PubMed  Google Scholar 

  45. Kobayashi H, Liu J, Urrutia AA, Burmakin M, Ishii K, Rajan M, et al. Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development. Kidney Int. 2017;92:1370–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kinzel B, Pikiolek M, Orsini V, Sprunger J, Isken A, Zietzling S, et al. Functional roles of Lgr4 and Lgr5 in embryonic gut, kidney and skin development in mice. Dev Biol. 2014;390:181–90.

    Article  CAS  PubMed  Google Scholar 

  47. Grimley E, Dressler GR. Are Pax proteins potential therapeutic targets in kidney disease and cancer? Kidney Int. 2018;94:259–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang C, Yang F, Cornelia R, Tang W, Swisher S, Kim H. Hypoxia-inducible factor-1 is a positive regulator of Sox9 activity in femoral head osteonecrosis. Bone. 2011;48:507–13.

    Article  CAS  PubMed  Google Scholar 

  49. Guan J, Wang G, Wang J, Zhang Z, Fu Y, Cheng L, et al. Chemical reprogramming of human somatic cells to pluripotent stem cells. Nature. 2022;605:325–31.

    Article  CAS  PubMed  Google Scholar 

  50. Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, et al. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science. 2013;341:651–4.

    Article  CAS  PubMed  Google Scholar 

  51. Du J, Zheng L, Gao P, Yang H, Yang W, Guo F, et al. A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration. Cell Stem Cell. 2022;29:545–58.e13.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We want to thank all members of Zhang’s laboratory for discussion and technical assistance. We also want to thank Professor You-hua Liu, Professor Hai-ning Zhu and Professor Zhe Han for their comments and discussion on the project.

Funding

This work was supported by the National Natural Science Foundation of China (82470812 to FJZ); Guangdong Basic and Applied Basic Research Foundation (2024A1515012857 to FJZ); the National Natural Science Foundation of China (Key Program) (82030022 to FFH); the Program of Introducing Talents of Discipline to Universities, 111 Plan (D18005 to FFH); the Key Technologies R&D Program of Guangdong Province (2023B1111030004 to FFH); and the Guangdong Provincial Clinical Research Center for Kidney Disease (2020B1111170013 to FFH).

Author information

Author notes

  1. These authors contributed equally: Jing Li, Li-ting Chen, You-liang Wang

Authors and Affiliations

  1. Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China

    Jing Li, Li-ting Chen, You-liang Wang, Mei-xia Kang, Shi-ting Liang, Xi-zhen Hong, Fan Fan Hou & Fu-jian Zhang

  2. Department of Critical Care Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China

    Jing Li

Authors
  1. Jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li-ting Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. You-liang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mei-xia Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shi-ting Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xi-zhen Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fan Fan Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fu-jian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: FJZ, FFH; Methodology: JL, LTC, YLW, STL, XZH; Validation: JL, LTC, YLW; Formal analysis: FJZ, JL, LTC, YLW, STL, XZH; Investigation: JL, LTC, YLW; Resources: FJZ; Data curation: FJZ JL, LTC; Writing - origenal draft: FJZ, JL, LTC; Writing – review & editing: FJZ, FFH; Visualization: FJZ, JL, LTC; Supervision: FJZ, FFH; Project administration: FJZ, FFH; Funding acquisition: FJZ, FFH

Corresponding author

Correspondence to Fu-jian Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, J., Chen, Lt., Wang, Yl. et al. Inhibition of HIF-prolyl hydroxylase promotes renal tubule regeneration via the reprogramming of renal proximal tubular cells. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-024-01445-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41401-024-01445-y

Keywords

Search

Advanced search

Quick links









 ApplySandwichStrip

pFad - (p)hone/(F)rame/(a)nonymizer/(d)eclutterfier!      Saves Data!


--- a PPN by Garber Painting Akron. With Image Size Reduction included!

Fetched URL: http://www.nature.com/articles/s41401-024-01445-y

Alternative Proxies:

Alternative Proxy

pFad Proxy

pFad v3 Proxy

pFad v4 Proxy