2. Academic Validation
  3. Transforming growth factor-β1 decreases erythropoietin production through repressing hypoxia-inducible factor 2α in erythropoietin-producing cells

Transforming growth factor-β1 decreases erythropoietin production through repressing hypoxia-inducible factor 2α in erythropoietin-producing cells

  • J Biomed Sci. 2021 Nov 2;28(1):73. doi: 10.1186/s12929-021-00770-2.
Hong-Mou Shih 1 2,  Szu-Yu Pan 3 4 5,  Chih-Jen Wu 2 6 7,  Yu-Hsiang Chou 4 8,  Chun-Yuan Chen 9,  Fan-Chi Chang 4,  Yi-Ting Chen 3 4 8,  Wen-Chih Chiang 4,  Hsing-Chen Tsai 10 11,  Yung-Ming Chen 3,  Shuei-Liong Lin 12 13 14 15
Affiliations

Affiliations

  • 1 Graduate Institute of Physiology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road Section 1, Taipei, 100, Taiwan.
  • 2 Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan.
  • 3 Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan.
  • 4 Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
  • 5 Division of Nephrology, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
  • 6 Department of Medicine, Mackay Medical College, Taipei, Taiwan.
  • 7 Department of Pharmacology, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 8 Department of Internal Medicine, National Taiwan University Hospital Jin-Shan Branch, New Taipei City, Taiwan.
  • 9 School of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 10 Division of Chest Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
  • 11 Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 12 Graduate Institute of Physiology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road Section 1, Taipei, 100, Taiwan. [email protected].
  • 13 Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan. [email protected].
  • 14 Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. [email protected].
  • 15 Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan. [email protected].
PMID: 34724959 DOI: 10.1186/s12929-021-00770-2
Abstract

Background: Renal erythropoietin (EPO)-producing (REP) cells produce EPO through hypoxia-inducible factor (HIF) 2α-activated gene transcription. Insufficient EPO production leads to anemia in patients with chronic kidney disease. Although recombinant EPO is effective to improve anemia, no reliable REP cell lines limit further progress of research and development of novel treatment.

Methods: We screened Epo mRNA expression in mouse fibroblast cell lines. Small interfering RNA specific for HIF1α or HIF2α was transfected to study Epo expression in C3H10T1/2 cells. The effect of transforming growth factor-β1 (TGF-β1) on HIF-EPO axis was studied in C3H10T1/2 cells and mice.

Results: Similar to mouse REP pericytes, C3H10T1/2 cells differentiated to α-smooth muscle actin+ myofibroblasts after exposure to TGF-β1. Specific HIF knockdown demonstrated the role of HIF2α in hypoxia-induced Epo expression. Sustained TGF-β1 exposure increased neither DNA Methyltransferase nor methylation of Epas1 and Epo genes. However, TGF-β1 repressed HIF2α-encoding Epas1 promptly through activating activin receptor-like kinase-5 (ALK5), thereby decreasing Epo induction by hypoxia and prolyl hydroxylase domain inhibitor roxadustat. In mice with pro-fibrotic injury induced by ureteral obstruction, upregulation of Tgfb1 was accompanied with downregulation of Epas1 and Epo in injured kidneys and myofibroblasts, which were reversed by ALK5 Inhibitor SB431542.

Conclusion: C3H10T1/2 cells possessed the property of HIF2α-dependent Epo expression in REP pericytes. TGF-β1 induced not only the transition to myofibroblasts but also a repressive effect on Epas1-Epo axis in C3H10T1/2 cells. The repressive effect of TGF-β1 on Epas1-Epo axis was confirmed in REP pericytes in vivo. Inhibition of TGF-β1-ALK5 signaling might provide a novel treatment to rescue EPO expression in REP pericytes of injured kidney.

Keywords

Erythropoietin; Hypoxia-inducible factor 2α; Pericyte; Transforming growth factor-β1.

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