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

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. 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. Translational StatementTissue oxygenation is dependent on proper erythropoietin (EPO) production and local regulatory factors. We investigated different subpopulations of possible EPO-producing cells in the mouse kidney under hypoxemic stimuli and experimental kidney fibrosis. These cells comprise a heterogeneous group of interstitial cells, which share the expression of PDGFR-β. Induction of hypoxia signaling in these cells induces the expression of factors supporting tissue oxygenation. These data could provide a starting point for closer investigations of the fine regulation of tissue oxygenation. In addition, the here-defined subpopulations of PDGFR-β+ interstitial cells could present new targets for a pharmacologic approach to treat EPO deficiency. Tissue oxygenation is dependent on proper erythropoietin (EPO) production and local regulatory factors. We investigated different subpopulations of possible EPO-producing cells in the mouse kidney under hypoxemic stimuli and experimental kidney fibrosis. These cells comprise a heterogeneous group of interstitial cells, which share the expression of PDGFR-β. Induction of hypoxia signaling in these cells induces the expression of factors supporting tissue oxygenation. These data could provide a starting point for closer investigations of the fine regulation of tissue oxygenation. In addition, the here-defined subpopulations of PDGFR-β+ interstitial cells could present new targets for a pharmacologic approach to treat EPO deficiency. The kidneys are the main site of oxygen-regulated erythropoietin (EPO) production. Within the kidneys, tubulointerstitial cells produce EPO1Bachmann S. Le Hir M. Eckardt K.U. Co-localization of erythropoietin mRNA and ecto-5’-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin.J Histochem Cytochem. 1993; 41: 335-341Crossref PubMed Scopus (305) Google Scholar,2Maxwell P.H. Osmond M.K. Pugh C.W. et al.Identification of the renal erythropoietin-producing cells using transgenic mice.Kidney Int. 1993; 44: 1149-1162Abstract Full Text PDF PubMed Scopus (341) Google Scholar triggered by hypoxia inducible factor 2 (HIF-2).3Paliege A. Rosenberger C. Bondke A. et al.Hypoxia-inducible factor-2α-expressing interstitial fibroblasts are the only renal cells that express erythropoietin under hypoxia-inducible factor stabilization.Kidney Int. 2010; 77: 312-318Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar The regulation of renal EPO production occurs mainly by recruitment of EPO-producing cells that express EPO in an on/off fashion.4Eckardt K.-U. Koury S.T. Tan C.C. et al.Distribution of erythropoietin producing cells in rat kidneys during hypoxic hypoxia.Kidney Int. 1993; 43: 815-823Abstract Full Text PDF PubMed Scopus (90) Google Scholar In the normoxic kidney, few EPO-expressing cells are found at the boundary between cortex and outer medulla (OM), whereas under severe hypoxic stress, EPO-expressing cells are recruited in the whole cortex and OM.5Koury S.T. Bondurant M.C. Semenza G.L. Koury M.J. The use of in situ hybridization to study erythropoietin gene expression in murine kidney and liver.Microsc Res Tech. 1993; 25: 29-39Crossref PubMed Scopus (17) Google Scholar, 6Yamazaki S. Souma T. Hirano I. et al.A mouse model of adult-onset anaemia due to erythropoietin deficiency.Nat Commun. 2013; 4: 1950Crossref PubMed Scopus (53) Google Scholar, 7Maxwell P.H. Ferguson D.J.P. Nicholls L.G. et al.Sites of erythropoietin production.Kidney Int. 1997; 51: 393-401Abstract Full Text PDF PubMed Scopus (91) Google Scholar The identity and functional characteristics of those active and potentially EPO-producing cells are less clear. Originally, EPO-producing cells had been identified as interstitial fibroblast-like cells expressing CD73 (ecto-5′-nucleotidase).1Bachmann S. Le Hir M. Eckardt K.U. Co-localization of erythropoietin mRNA and ecto-5’-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin.J Histochem Cytochem. 1993; 41: 335-341Crossref PubMed Scopus (305) Google Scholar More recent studies have suggested that in addition to CD73+ cells, also other cell types are able to express EPO.8Pan X. Suzuki N. Hirano I. et al.Isolation and characterization of renal erythropoietin-producing cells from genetically produced anemia mice.PLoS One. 2011; 6e25839Crossref PubMed Scopus (85) Google Scholar Such a heterogeneity of renal EPO-producing cells has also been suggested by data from mice lacking HIF prolyl-4-hydroxylases in renal stroma cell precursors9Kobayashi H. Liu Q. Binns T.C. et al.Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin..J Clin Invest. 2016; 126: 1926-1938Crossref PubMed Scopus (78) Google Scholar and has received support by the concept that EPO-producing cells could be telocytes10Imeri et of renal cell by gene HIF-2 cell and a Int. Full Text Full Text PDF PubMed Scopus Google Scholar or in and Full Text Full Text PDF PubMed Scopus Google Scholar EPO-producing cells have a as et of renal cell by gene HIF-2 cell and a Int. Full Text Full Text PDF PubMed Scopus Google T. M. et in renal is by of hypoxia 2016; PubMed Scopus Google C. et production by PDGFR-β+ 2016; PubMed Scopus Google Scholar and are to S. Le Hir M. Eckardt K.U. Co-localization of erythropoietin mRNA and ecto-5’-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin.J Histochem Cytochem. 1993; 41: 335-341Crossref PubMed Scopus (305) Google S.T. Bondurant M.C. Semenza G.L. Koury M.J. The use of in situ hybridization to study erythropoietin gene expression in murine kidney and liver.Microsc Res Tech. 1993; 25: 29-39Crossref PubMed Scopus (17) Google T. M. et in renal is by of hypoxia 2016; PubMed Scopus Google Scholar are in renal in and Full Text Full Text PDF PubMed Scopus Google Scholar EPO-producing cells are the of in the T. S. T. et of renal erythropoietin-producing cells 2013; PubMed Scopus Google Scholar and the of the kidneys to produce EPO interstitial in of kidney T. M. et in renal is by of hypoxia 2016; PubMed Scopus Google of renal Int. Full Text PDF PubMed Scopus Google Scholar, of anemia in PubMed Scopus Google Scholar, P.H. Ferguson D.J.P. Nicholls L.G. et interstitial response to renal fibroblast-like cells and have for erythropoietin gene Int. 1997; Full Text PDF PubMed Scopus Google Scholar This concept of EPO-producing cells is by the that are mainly in the and to a in the of the renal Int. Full Text PDF PubMed Scopus Google Scholar The concept is also by the that HIF in cells expressing the cell A. C. and and 2011; Full Text Full Text PDF PubMed Scopus Google Scholar induces EPO expression in the of the cortex and the C. et production by PDGFR-β+ 2016; PubMed Scopus Google Scholar whereas HIF in cells expressing the A. C. and and 2011; Full Text Full Text PDF PubMed Scopus Google Scholar only induces EPO expression in the A. et 2 and murine erythropoietin in 2016; PubMed Scopus Google Scholar renal cells inducible EPO expression to express as an of renal EPO-producing C. et production by PDGFR-β+ 2016; PubMed Scopus Google Scholar PDGFR-β+ cells in all EPO production in these cells to be to the kidneys and the C. et production by PDGFR-β+ 2016; PubMed Scopus Google A. et 2 and murine erythropoietin in 2016; PubMed Scopus Google Scholar The of EPO expression to the kidneys is likely the of of oxygen is rather due to the of renal PDGFR-β+ cells to express This is by the that of in PDGFR-β+ cells by deletion of the von Hippel-Lindau induces EPO expression only in the kidneys to a low also in C. et production by PDGFR-β+ 2016; PubMed Scopus Google Scholar This of EPO expression the about other and functional characteristics of renal EPO-producing PDGFR-β+ cells. different tubulointerstitial cell types have been cells expressing S. Le Hir M. Eckardt K.U. Co-localization of erythropoietin mRNA and ecto-5’-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin.J Histochem Cytochem. 1993; 41: 335-341Crossref PubMed Scopus (305) Google Scholar,2Maxwell P.H. Osmond M.K. Pugh C.W. et al.Identification of the renal erythropoietin-producing cells using transgenic mice.Kidney Int. 1993; 44: 1149-1162Abstract Full Text PDF PubMed Scopus (341) Google Scholar the mesenchymal cell M. et induces and PubMed Scopus (90) Google Scholar the protein tenascin Q. et of a mouse for in renal interstitial One. 2013; PubMed Scopus Google Scholar or markers for A. C. and and 2011; Full Text Full Text PDF PubMed Scopus Google S. 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Osmond M.K. Pugh C.W. et al.Identification of the renal erythropoietin-producing cells using transgenic mice.Kidney Int. 1993; 44: 1149-1162Abstract Full Text PDF PubMed Scopus (341) Google Scholar In we identified subpopulations of PDGFR-β+ cells, which and M. et induces and PubMed Scopus (90) Google Q. et of a mouse for in renal interstitial One. 2013; PubMed Scopus Google M. fibroblasts in the a of and PubMed Scopus Google Scholar were in the the between the cortex and the were found in the outer of the cells were mainly in the cells were in the and in the of the these are in M. et induces and PubMed Scopus (90) Google Q. et of a mouse for in renal interstitial One. 2013; PubMed Scopus Google Hir M. Eckardt K.U. induces in fibroblasts of of rat Google Scholar inducible deletion of Vhl from PDGFR-β+ cells, we found EPO expression in all interstitial CD73+ cells, which of all PDGFR-β+ EPO-expressing cells. This CD73+ cells as the site of EPO S. Le Hir M. Eckardt K.U. Co-localization of erythropoietin mRNA and ecto-5’-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin.J Histochem Cytochem. 1993; 41: 335-341Crossref PubMed Scopus (305) Google Scholar,2Maxwell P.H. Osmond M.K. Pugh C.W. et al.Identification of the renal erythropoietin-producing cells using transgenic mice.Kidney Int. 1993; 44: 1149-1162Abstract Full Text PDF PubMed Scopus (341) Google Scholar The of EPO-expressing PDGFR-β+ cells were mostly in the CD73+, Gli1+, and interstitial SMMHC+ cells were M. et induces and PubMed Scopus (90) Google Q. et of a mouse for in renal interstitial One. 2013; PubMed Scopus Google A. N. et in mouse PubMed Scopus Google Scholar The deletion of Vhl in cells induced EPO expression and These are by a recent study cells as possible production for T. S. et induction of erythropoietin in PubMed Scopus Google Scholar EPO-expressing cells the for EPO-expressing cells of et of renal cell by gene HIF-2 cell and a Int. Full Text Full Text PDF PubMed Scopus Google T. S. T. et of renal erythropoietin-producing cells 2013; PubMed Scopus Google Scholar or of C. et production by PDGFR-β+ 2016; PubMed Scopus Google Scholar cells are to which in of interstitial kidney et are to Full Text Full Text PDF PubMed Scopus Google et and kidney Clin Invest. PubMed Scopus Google Scholar In addition, cells expressing as EPO only interstitial SMMHC+ cells, cells in the and could express EPO after deletion of We SMMHC+ able to express EPO as for the of of the renal 1997; Google Scholar These cells are to a in the regulation of for the of of the renal 1997; Google regulation of renal PubMed Scopus Google Scholar In addition to CD73+, Gli1+, and SMMHC+ a of to have the for EPO production. To the of these subpopulations to the EPO-producing cells under hypoxemic conditions, we mice to low or of EPO cells the and the kidney as and K.-U. Koury S.T. Tan C.C. et al.Distribution of erythropoietin producing cells in rat kidneys during hypoxic hypoxia.Kidney Int. 1993; 43: 815-823Abstract Full Text PDF PubMed Scopus (90) Google P.H. Ferguson D.J.P. Nicholls L.G. et al.Sites of erythropoietin production.Kidney Int. 1997; 51: 393-401Abstract Full Text PDF PubMed Scopus (91) Google S.T. Koury M.J. Bondurant M.C. et of erythropoietin-producing cells in kidneys of mice by in situ renal erythropoietin and erythropoietin PubMed Google Scholar The of the recruited EPO cells could be to the CD73+ of PDGFR-β+ interstitial cells In the outer of the cells also to the additional EPO production, whereas the and subpopulations a under these These are in S. Le Hir M. Eckardt K.U. Co-localization of erythropoietin mRNA and ecto-5’-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin.J Histochem Cytochem. 1993; 41: 335-341Crossref PubMed Scopus (305) Google X. Suzuki N. Hirano I. et al.Isolation and characterization of renal erythropoietin-producing cells from genetically produced anemia mice.PLoS One. 2011; 6e25839Crossref PubMed Scopus (85) Google T. S. et induction of erythropoietin in PubMed Scopus Google Scholar the identified in study to a during experimental kidney fibrosis. of EPO-producing cells a expression of EPO mRNA in the whereas EPO production in the kidney cortex This is under EPO expression could be in the of The kidneys of mice a EPO mRNA expression during cells in the in the the to express EPO whereas to express T. M. et in renal is by of hypoxia 2016; PubMed Scopus Google T. S. T. et of renal erythropoietin-producing cells 2013; PubMed Scopus Google P.H. Ferguson D.J.P. 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