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Different subpopulations of kidney interstitial cells produce erythropoietin and factors supporting tissue oxygenation in response to hypoxia in vivo


Broeker, Katharina A E; Fuchs, Michaela A A; Schrankl, Julia; Kurt, Birgül; Nolan, Karen A; Wenger, Roland H; Kramann, Rafael; Wagner, Charlotte; Kurtz, Armin (2020). Different subpopulations of kidney interstitial cells produce erythropoietin and factors supporting tissue oxygenation in response to hypoxia in vivo. Kidney International, 98(4):918-931.

Abstract

Genetic induction of hypoxia signaling by deletion of the von Hippel-Lindau (Vhl) protein in mesenchymal PDGFR-β+ cells leads to abundant HIF-2 dependent erythropoietin (EPO) expression in the cortex and outer medulla of the kidney. This rather unique feature of kidney PDGFR-β+ cells promote questions about their special characteristics and general functional response to hypoxia. To address these issues, we characterized kidney PDGFR-β+ EPO expressing cells based on additional cell markers and their gene expression profile in response to hypoxia signaling induced by targeted deletion of Vhl or exposure to low oxygen and carbon monoxide respectively, and after unilateral ureteral obstruction. CD73+, Gli1+, tenascin C+ and interstitial SMMHC+ cells were identified as zonally distributed subpopulations of PDGFR-β+ cells. EPO expression could be induced by Vhl deletion in all PDGFR-β+ subpopulations. Under hypoxemic conditions, recruited EPO+ cells were mostly part of the CD73+ subpopulation. Besides EPO production, expression of adrenomedullin and regulator of G-protein signaling 4 was upregulated in PDGFR-β+ subpopulations in response to the different hypoxic stimuli. Thus, different kidney interstitial PDGFR-β+ subpopulations exist, capable of producing EPO in response to different stimuli. Activation of hypoxia signaling in these cells also induces factors likely contributing to improved kidney interstitial tissue oxygenation.

Abstract

Genetic induction of hypoxia signaling by deletion of the von Hippel-Lindau (Vhl) protein in mesenchymal PDGFR-β+ cells leads to abundant HIF-2 dependent erythropoietin (EPO) expression in the cortex and outer medulla of the kidney. This rather unique feature of kidney PDGFR-β+ cells promote questions about their special characteristics and general functional response to hypoxia. To address these issues, we characterized kidney PDGFR-β+ EPO expressing cells based on additional cell markers and their gene expression profile in response to hypoxia signaling induced by targeted deletion of Vhl or exposure to low oxygen and carbon monoxide respectively, and after unilateral ureteral obstruction. CD73+, Gli1+, tenascin C+ and interstitial SMMHC+ cells were identified as zonally distributed subpopulations of PDGFR-β+ cells. EPO expression could be induced by Vhl deletion in all PDGFR-β+ subpopulations. Under hypoxemic conditions, recruited EPO+ cells were mostly part of the CD73+ subpopulation. Besides EPO production, expression of adrenomedullin and regulator of G-protein signaling 4 was upregulated in PDGFR-β+ subpopulations in response to the different hypoxic stimuli. Thus, different kidney interstitial PDGFR-β+ subpopulations exist, capable of producing EPO in response to different stimuli. Activation of hypoxia signaling in these cells also induces factors likely contributing to improved kidney interstitial tissue oxygenation.

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Contributors:Prof. Stefan Offermanns (Centre for Molecular Medicine, Medical Faculty, Goethe University, Frankfurt am Main) for providing the SMMHCCreERT2/þ mouse line, The expert technical assistance provided by Susanne Fink, Ramona Steppan, and Svende Pfundstein is gratefully acknowledged
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Nephrology
Uncontrolled Keywords:Nephrology
Language:English
Date:1 October 2020
Deposited On:11 Nov 2020 10:19
Last Modified:12 Nov 2020 21:01
Publisher:Elsevier
ISSN:0085-2538
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.kint.2020.04.040
PubMed ID:32454122
Project Information:
  • : FunderGerman Research Foundation (DFG)
  • : Grant IDKu 859/15-2
  • : Project Title
  • : FunderSFB 1350
  • : Grant ID387509280
  • : Project Title
  • : FunderSwiss National Science Foundation
  • : Grant ID
  • : Project Title
  • : Project Websitehttps://www.nccr-kidney.ch/

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