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 PDGFRb D 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-b D cells promote questions about their special characteristics and general functional response to hypoxia. To address these issues, we characterized kidney PDGFR-b D 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 D , Gli1 D , tenascin C D and interstitial SMMHC D cells were identified as zonally distributed subpopulations of PDGFR-b D cells. EPO expression could be induced by Vhl deletion in all PDGFRb D subpopulations. Under hypoxemic conditions, recruited EPO D cells were mostly part of the CD73 D subpopulation. Besides EPO production, expression of adrenomedullin and regulator of G-protein signaling 4 was upregulated in PDGFR-b D subpopulations in response to the different hypoxic stimuli. Thus, different kidney interstitial PDGFRb D 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.

Inhibition of transforming growth factor β1 signaling in resident interstitial cells attenuates profibrotic gene expression and preserves erythropoietin production during experimental kidney fibrosis in mice

“…4,10,29,[33][34][35] Resident fibroblasts and pericytes express the platelet derived growth factor receptor β (PDGFR-β) and are one of the most numerous cell types in the kidney. 4,9,31,36 A recent study also confirmed PDGFR-β + cells as the main precursors for myofibroblasts in human kidneys. 35 These PDGFR-β + cells also include all kidney cells able to produce EPO.…”

“…Localization of mRNA expression was studied with the RNAscope® Multiplex Fluorescent v2 kit (Advanced Cell Diagnostics ACD, Hayward, CA, USA), according to the manufacturer´s instructions. 9,43 Kidneys were perfusion-fixed with 10% neutral buffered formalin solution, dehydrated in an ethanol series and embedded in paraffin. Hybridization signals were detected on 5µm tissue sections using the TSA® Plus fluorophores Cy3 and Cy5 (PerkinElmer, Waltham, Massachusetts…”

“…[1][2][3][4] Ongoing renal fibrosis leads to a progressive decline of glomerular and tubular function and also restricts the endocrine functions of the kidneys resulting in insufficient production of erythropoietin (EPO) leading to anemia. [5][6][7][8][9] Among the cytokines and signaling factors that are involved in kidney disease and fibrosis progression, transforming growth factor beta1 (TGFβ1) has been studied in various models. 2,6,[10][11][12][13][14] TGFβ1 binds to TGFβ receptor 2 (TGFβ-R2).…”

“…6,[36][37][38][39] Renal fibrosis is associated with a reduced capability of the kidneys to produce erythropoietin. [5][6][7][8][9]34,40 Although the reasons for this have not yet been clearly resolved, it is thought that transformation of interstitial PDGFR-β + cells into myofibroblasts goes hand in hand with the loss of their capability to produce EPO. 5,6,34,41 In view of the major role of interstitial PDGFR-β + cells as native EPO producers and as precursors of myofibroblasts, we were interested to define the role of TGFβ1 signaling in this cell population.…”

CD73 maintains hepatocyte metabolic integrity and mouse liver homeostasis in a sex-dependent manner

“…Although CD73 has ubiquitous expression (12), recent single cell profiling experiments show that its mRNA is zonally distributed in epithelial tissues, including the liver (16), intestine (17), and kidney (18). CD73 is transcriptionally induced by hypoxia (19) and CD73-generated adenosine directly protects multiple epithelial tissues, including the liver, against hypoxic injury (20)(21)(22).…”