ArticleActa physiologica (Oxford, England)2022
EPO synthesis induced by HIF-PHD inhibition is dependent on myofibroblast transdifferentiation and colocalizes with non-injured nephron segments in murine kidney fibrosis.
Article in Acta physiologica (Oxford, England), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 35 citations in OpenAlex.
- The endocrine product of renal (preglomerular) contractile pericytes depends on prolyl-4-hydroxylases 2 and 3.The Journal of physiology · 2026Article
- Navigating Anemia Therapy in CKD With Hypoxia-Inducible Factor Activators: A Review.American journal of kidney diseases : the official journal of the National Kidney Foundation · 2026Review
- Cellular microenvironment of erythropoietin-producing cells in hypoxic and injured mouse kidneys.Experimental physiology · 2026Article
- The Inflammatory Milieu Exacerbates Anemia of Chronic Kidney Disease: From the Gut-Kidney Axis to Bone Marrow Hematopoiesis Inhibition.Kidney & blood pressure research · 2026Review
- Hypoxia-inducible factor-2 stabilization is not sufficient to induce erythropoietin production in deeper medullary fibroblasts.The Journal of physiology · 2025Article
- Defective Slc7a7 transport reduces erythropoietin compromising erythropoiesis.Molecular medicine (Cambridge, Mass.) · 2025Article
- Hypoxia-inducible factor activators: a novel class of oral drugs for the treatment of anemia of chronic kidney disease.Hematology. American Society of Hematology. Education Program · 2024Review
- Insoluble HIFa protein aggregates by cadmium disrupt hypoxia-prolyl hydroxylase (PHD)-hypoxia inducible factor (HIFa) signaling in renal epithelial (NRK-52E) and interstitial (FAIK3-5) cells.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2024Article
- PHD1-3 oxygen sensors in vivo-lessons learned from gene deletions.Pflugers Archiv : European journal of physiology · 2024Review
- Alleviation of Anemia by SGLT2 Inhibitors in Patients with CKD: Mechanisms and Results of Long-Term Placebo-Controlled Trials.Clinical journal of the American Society of Nephrology : CJASN · 2024Article
- Tubular Endogenous Erythropoietin Protects Renal Function against Ischemic Reperfusion Injury.International journal of molecular sciences · 2024Article
- Long-term treatment of chronic kidney disease patients with anemia using hypoxia-inducible factor prolyl hydroxylase inhibitors: potential concerns.Pediatric nephrology (Berlin, Germany) · 2024Review
- Biophysical interplay between extracellular matrix remodeling and hypoxia signaling in regulating cancer metastasis.Frontiers in cell and developmental biology · 2024Review
- Oral administration of ethanol extract fromFrontiers in pharmacology · 2024Article
- Mechanisms of enhanced renal and hepatic erythropoietin synthesis by sodium-glucose cotransporter 2 inhibitors.European heart journal · 2023Article
- The anaemia treatment journey of CKD patients: from epoetins to hypoxia-inducible factor-prolyl hydroxylase inhibitors.Clinical kidney journal · 2023Review
- Drugs activating hypoxia-inducible factors correct erythropoiesis and hepcidin levels via renal EPO induction in mice.Blood advances · 2023Article
- Progress in the Detection of Erythropoietin in Blood, Urine, and Tissue.Molecules (Basel, Switzerland) · 2023Review
- Fount, fate, features, and function of renal erythropoietin-producing cells.Pflugers Archiv : European journal of physiology · 2022Review
- Sodium-Glucose Cotransporter 2 Inhibitors in Lupus Nephritis and ANCA-Associated Vasculitis: Unmet Needs to be Addressed.Glomerular diseasesReview
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5 authors at 2 institutions in 1 country.
Funding
Abstract
aimErythropoietin (EPO) is regulated by hypoxia-inducible factor (HIF)-2. In the kidney, it is produced by cortico-medullary perivascular interstitial cells, which transdifferentiate into collagen-producing myofibroblasts in response to injury. Inhibitors of prolyl hydroxylase domain (PHD) dioxygenases (HIF-PHIs) activate HIF-2 and stimulate kidney and liver EPO synthesis in patients with anemia of chronic kidney disease (CKD). We examined whether HIF-PHIs can reactivate EPO synthesis in interstitial cells that have undergone myofibroblast transdifferentiation in established kidney fibrosis.
methodsWe investigated Epo transcription in myofibroblasts and characterized the histological distribution of kidney Epo transcripts by RNA in situ hybridization combined with immunofluorescence in mice with adenine nephropathy (AN) treated with HIF-PHI molidustat. Lectin absorption chromatography was used to assess liver-derived EPO. In addition, we examined kidney Epo transcription in Phd2 knockout mice with obstructive nephropathy.
resultsIn AN, molidustat-induced Epo transcripts were not found in areas of fibrosis and did not colocalize with interstitial cells that expressed α-smooth muscle actin, a marker of myofibroblast transdifferentiation. Epo transcription was associated with megalin-expressing, kidney injury molecule 1-negative nephron segments and contingent on residual renal function. Liver-derived EPO did not contribute to serum EPO in molidustat-treated mice. Epo transcription was not associated with myofibroblasts in Phd2 knockout mice with obstructive nephropathy.
conclusionsOur studies suggest that HIF-PHIs do not reactivate Epo transcription in interstitial myofibroblasts and that their efficacy in inducing kidney EPO in CKD is dependent on the degree of myofibroblast formation, the preservation of renal parenchyma and the level of residual renal function.
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