Renal interstitial fibroblasts coproduce erythropoietin and renin under anaemic conditions.
Aged
Anemia
/ complications
Animals
Biomarkers
Blood Pressure
Chronic Disease
Disease Models, Animal
Erythropoietin
/ biosynthesis
Female
Fibroblasts
/ metabolism
Fibrosis
Gene Expression
Humans
Hypotension
/ complications
Hypoxia
/ etiology
Kidney
/ metabolism
Kidney Diseases
/ etiology
Male
Mice
Mice, Knockout
Mice, Transgenic
Middle Aged
Renin
/ biosynthesis
Signal Transduction
Erythropoiesis
Hypoxia
Renal anaemia
Renin-angiotensin system
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Feb 2021
Feb 2021
Historique:
received:
03
04
2020
revised:
08
12
2020
accepted:
04
01
2021
pubmed:
29
1
2021
medline:
14
10
2021
entrez:
28
1
2021
Statut:
ppublish
Résumé
Erythrocyte mass contributes to maintaining systemic oxygen delivery and blood viscosity, with the latter being one of the determinants of blood pressure. However, the physiological response to blood pressure changes under anaemic conditions remain unknown. We show that anaemia decreases blood pressure in human patients and mouse models. Analyses of pathways related to blood pressure regulation demonstrate that anaemia enhances the expression of the gene encoding the vasopressor substance renin in kidneys. Although kidney juxtaglomerular cells are known to continuously produce renin, renal interstitial fibroblasts are identified in the present study as a novel site of renin induction under anaemic hypotensive conditions in mice and rats. Notably, some renal interstitial fibroblasts are found to simultaneously express renin and the erythroid growth factor erythropoietin in the anaemic mouse kidney. Antihypertensive agents but not hypoxic stimuli induced interstitial renin expression, suggesting that blood pressure reduction triggers interstitial renin induction in anaemic mice. The interstitial renin expression was also detected in injured fibrotic kidneys of the mouse and human, and the renin-expressing interstitial cells in murine fibrotic kidneys were identified as myofibroblasts originating from renal interstitial fibroblasts. Since the elevated expression levels of renin in fibrotic kidneys along with progression of renal fibrosis were well correlated to the systemic blood pressure increase, the renal interstitial renin production seemed to affect systemic blood pressure. Renal interstitial fibroblasts function as central controllers of systemic oxygen delivery by producing both renin and erythropoietin. Grants-in-Aid from Japan Society for the Promotion of Science (JSPS) KAKENHI (17K19680, 15H04691, and 26111002) and the Takeda Science Foundation.
Sections du résumé
BACKGROUND
BACKGROUND
Erythrocyte mass contributes to maintaining systemic oxygen delivery and blood viscosity, with the latter being one of the determinants of blood pressure. However, the physiological response to blood pressure changes under anaemic conditions remain unknown.
METHODS AND FINDINGS
RESULTS
We show that anaemia decreases blood pressure in human patients and mouse models. Analyses of pathways related to blood pressure regulation demonstrate that anaemia enhances the expression of the gene encoding the vasopressor substance renin in kidneys. Although kidney juxtaglomerular cells are known to continuously produce renin, renal interstitial fibroblasts are identified in the present study as a novel site of renin induction under anaemic hypotensive conditions in mice and rats. Notably, some renal interstitial fibroblasts are found to simultaneously express renin and the erythroid growth factor erythropoietin in the anaemic mouse kidney. Antihypertensive agents but not hypoxic stimuli induced interstitial renin expression, suggesting that blood pressure reduction triggers interstitial renin induction in anaemic mice. The interstitial renin expression was also detected in injured fibrotic kidneys of the mouse and human, and the renin-expressing interstitial cells in murine fibrotic kidneys were identified as myofibroblasts originating from renal interstitial fibroblasts. Since the elevated expression levels of renin in fibrotic kidneys along with progression of renal fibrosis were well correlated to the systemic blood pressure increase, the renal interstitial renin production seemed to affect systemic blood pressure.
INTERPRETATION
CONCLUSIONS
Renal interstitial fibroblasts function as central controllers of systemic oxygen delivery by producing both renin and erythropoietin.
FUNDING
BACKGROUND
Grants-in-Aid from Japan Society for the Promotion of Science (JSPS) KAKENHI (17K19680, 15H04691, and 26111002) and the Takeda Science Foundation.
Identifiants
pubmed: 33508746
pii: S2352-3964(21)00002-5
doi: 10.1016/j.ebiom.2021.103209
pmc: PMC7841315
pii:
doi:
Substances chimiques
Biomarkers
0
Erythropoietin
11096-26-7
Renin
EC 3.4.23.15
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103209Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interests The authors declare no competing interests.