The journey from erythropoietin to 2019 Nobel Prize: Focus on hypoxia-inducible factors in the kidney

Pan, Szu-Yu; Chiang, Wen‐Chih; Chen, Ming-Fong

doi:10.1016/j.jfma.2020.06.006

Cited by 13 publications

(13 citation statements)

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“…HIF is the most important known cellular oxygen-sensing machinery. 6,7 The functional HIF consists of a and b subunits. HIF-a is an oxygen labile subunit that is rapidly degraded at a normoxic condition in the presence of cofactors.…”

Section: Translational Statementmentioning

confidence: 99%

Kidney pericyte hypoxia-inducible factor regulates erythropoiesis but not kidney fibrosis

Pan

Tsai

Chou

et al. 2021

Kidney International

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Prolyl hydroxylase domain enzyme (PHD) inhibitors are effective in the treatment of chronic kidney disease (CKD)associated anemia by stabilizing hypoxia inducible factor (HIF), thereby increasing erythropoietin and consequently erythropoiesis. However, concern for CKD progression needs to be addressed in clinical trials. Although preclinical studies showed an anti-inflammatory effect in kidney disease models, the effect of PHD inhibitors on kidney fibrosis was inconsistent probably because the effects of HIF are cell type and context dependent. The major kidney erythropoietin-producing cells are pericytes that produce erythropoietin through HIF-2a-dependent gene transcription. The concern for the impact of HIF in pericytes on kidney fibrosis arises from the fact that pericytes are the major precursor cells of myofibroblasts in CKD. Since cells expressing Gli1 fulfill the morphologic and anatomic criteria for pericytes, we induced Gli1 þ cellspecific HIF stabilization or knockout to study the impact of HIF in pericytes on kidney pathology of mice with or without fibrotic injury induced by unilateral ureteral obstruction. Compared with the littermate controls, mice with pericyte-specific HIF stabilization due to von Hippel-Lindau protein or PHD2 knockout showed increased serum erythropoietin and polycythemia rather than a discernible difference in kidney fibrosis. Compared with Gli1 þ pericytes sorted from littermate controls, Gli1 þ pericytes sorted from PHD2 knockout mice showed increased erythropoietin gene expression rather than discernible changes in Col1a1 or Acta2 expression. Furthermore, pericyte-specific knockout of HIF-1a or HIF-2a did not affect kidney fibrosis. Thus, our study supports the absence of negative effects of PHD inhibitors on kidney fibrosis of mice despite HIF stabilization in pericytes.

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Section: Translational Statementmentioning

confidence: 99%

Kidney pericyte hypoxia-inducible factor regulates erythropoiesis but not kidney fibrosis

Pan

Tsai

Chou

et al. 2021

Kidney International

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“…In order to further assess whether knockdown of PHD2 stimulated HIF-1α-mediated gene activation, the level of GLUT1, a target gene of HIF-1α (Makanji et al, 2014;Pan et al, 2021) and abundantly expressed in proximal tubules (Thorens et al, 1990;Dominguez et al, 1992), was measured by RT-PCR. The results showed that the GLUT1 level was significantly higher in IR+PHD2 siRNA G5-FA group compared with other groups, indicating the activation of HIF-1αmediated gene regulation by G5-FA-mediated delivery of PHD2 siRNA in kidney (Fig.…”

Section: Phd2 Mrna and Protein Were Knocked Down In Kidney But Not In Heart And Livermentioning

confidence: 99%

Kidney-Targeted Delivery of Prolyl Hydroxylase Domain Protein 2 Small Interfering RNA with Nanoparticles Alleviated Renal Ischemia/Reperfusion Injury

Xie

Wang

et al. 2021

J Pharmacol Exp Ther

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Background: Inhibition of HIF-prolyl hydroxylase (PHD) has been shown to protect against various kidney diseases. However, there are controversial reports on the effect of PHD inhibition in renoprotection. The present study determined whether delivery of PHD2 siRNA using a siRNA carrier, folic acid (FA)-decorated polyamidoamine dendrimer generation 5 (G5-FA), would mainly target kidneys and protect against renal ischemia/reperfusion injury (I/R). Methods:The renal I/R was generated by clipping the renal pedicle for 30 minutes in uninephrectomized mice. Mice were sacrificed 48 hours after I/R. Normal saline or G5-FA complexed with control or PHD2 siRNA was injected via tail vein 24 h before ischemia.Results: After the injection of near-infrared fluorescent dye-labeled G5-FA, the fluorescence was mainly detected in kidneys, but not in other organs. The reduction of PHD2 mRNA and protein was only observed in kidneys but not in other organs after injection of PHD2-siRNA-G5-FA complex. The injection of PHD2-siRNA-G5-FA significantly alleviated renal I/R injury, as shown by the inhibition of increases in serum creatinine and BUN, the blockade of increases in KIM-1 and NGAL and the improvement of histological damage compared with mice treated with control siRNA. Conclusion: PHD2 siRNA can be delivered specifically into kidneys using G5-FA and that local knockdown of PHD2 gene expression within the kidney alleviates renal I/R injury. Therefore, G5-FA is an efficient siRNA carrier to deliver siRNA into the kidney, and that local inhibition of PHD2 within the kidney may be a potential strategy for the management of acute I/R injury.

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“…Hence it is reasonable to use hepatic cell lines in the study of Epo gene regulation [ 16 , 18 , 24 – 26 ]. Decreased tissue oxygen tension appears to be the major factor triggering EPO production through hypoxia-inducible factor (HIF)-activated transcription [ 27 , 28 ]. While the hypoxia response element (HRE) + 3′-enhancer of Epo gene is liver specific [ 26 , 29 ], Storti et al report a functional HIF2α-dependent HRE in the distal 5′-enhancer located at kidney-inducible element (KIE) [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

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

Shih

Pan

et al. 2021

J Biomed Sci

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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.

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The journey from erythropoietin to 2019 Nobel Prize: Focus on hypoxia-inducible factors in the kidney

Cited by 13 publications

References 95 publications

Kidney pericyte hypoxia-inducible factor regulates erythropoiesis but not kidney fibrosis

Kidney pericyte hypoxia-inducible factor regulates erythropoiesis but not kidney fibrosis

Kidney-Targeted Delivery of Prolyl Hydroxylase Domain Protein 2 Small Interfering RNA with Nanoparticles Alleviated Renal Ischemia/Reperfusion Injury

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

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