Institut for Biomedicin

Lars Bolund

Single-Cell RNA Sequencing Reveals Renal Endothelium Heterogeneity and Metabolic Adaptation to Water Deprivation

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

DOI

  • Sébastien J Dumas, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Elda Meta, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Mila Borri, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Jermaine Goveia, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Katerina Rohlenova, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Nadine V Conchinha, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Kim Falkenberg, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Laure-Anne Teuwen, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Laura de Rooij, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Joanna Kalucka
  • Rongyuan Chen, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, P.R. China.
  • ,
  • Shawez Khan, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Federico Taverna, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Weisi Lu, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, P.R. China.
  • ,
  • Magdalena Parys, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Carla De Legher, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Stefan Vinckier, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Tobias K Karakach, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Luc Schoonjans, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, P.R. China.
  • ,
  • Lin Lin
  • Lars Bolund
  • Mieke Dewerchin, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Guy Eelen, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
  • ,
  • Ton J Rabelink, Division of Nephrology, Department of Internal Medicine, The Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands.
  • ,
  • Xuri Li, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong, China; peter.carmeliet@kuleuven.vib.be alun@biomed.au.dk.
  • ,
  • Yonglun Luo
  • Peter Carmeliet

BACKGROUND: Renal endothelial cells from glomerular, cortical, and medullary kidney compartments are exposed to different microenvironmental conditions and support specific kidney processes. However, the heterogeneous phenotypes of these cells remain incompletely inventoried. Osmotic homeostasis is vitally important for regulating cell volume and function, and in mammals, osmotic equilibrium is regulated through the countercurrent system in the renal medulla, where water exchange through endothelium occurs against an osmotic pressure gradient. Dehydration exposes medullary renal endothelial cells to extreme hyperosmolarity, and how these cells adapt to and survive in this hypertonic milieu is unknown.

METHODS: We inventoried renal endothelial cell heterogeneity by single-cell RNA sequencing >40,000 mouse renal endothelial cells, and studied transcriptome changes during osmotic adaptation upon water deprivation. We validated our findings by immunostaining and functionally by targeting oxidative phosphorylation in a hyperosmolarity model in vitro and in dehydrated mice in vivo.

RESULTS: We identified 24 renal endothelial cell phenotypes (of which eight were novel), highlighting extensive heterogeneity of these cells between and within the cortex, glomeruli, and medulla. In response to dehydration and hypertonicity, medullary renal endothelial cells upregulated the expression of genes involved in the hypoxia response, glycolysis, and-surprisingly-oxidative phosphorylation. Endothelial cells increased oxygen consumption when exposed to hyperosmolarity, whereas blocking oxidative phosphorylation compromised endothelial cell viability during hyperosmotic stress and impaired urine concentration during dehydration.

CONCLUSIONS: This study provides a high-resolution atlas of the renal endothelium and highlights extensive renal endothelial cell phenotypic heterogeneity, as well as a previously unrecognized role of oxidative phosphorylation in the metabolic adaptation of medullary renal endothelial cells to water deprivation.

OriginalsprogEngelsk
TidsskriftJournal of the American Society of Nephrology : JASN
Vol/bind31
Nummer1
Sider (fra-til)118-138
Antal sider21
ISSN1046-6673
DOI
StatusUdgivet - jan. 2020

Se relationer på Aarhus Universitet Citationsformater

ID: 173788204