The Nuclear Receptor ESRRA Protects from Kidney Disease by Coupling Metabolism and Differentiation.

Animals Cell Differentiation Cells, Cultured Kidney Diseases / metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Receptors, Estrogen / deficiency ERRalpha Estrogen-Related Receptor
ESRRA PPARA chronic kidney disease fatty-acid oxidation fibrosis kidney organoids proximal tubule cells single-cell ATAC sequencing single-cell RNA sequencing

Journal

Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170

Informations de publication

Date de publication:
02 02 2021
Historique:
received: 25 02 2020
revised: 28 08 2020
accepted: 12 11 2020
pubmed: 11 12 2020
medline: 30 11 2021
entrez: 10 12 2020
Statut: ppublish

Résumé

Kidney disease is poorly understood because of the organ's cellular diversity. We used single-cell RNA sequencing not only in resolving differences in injured kidney tissue cellular composition but also in cell-type-specific gene expression in mouse models of kidney disease. This analysis highlighted major changes in cellular diversity in kidney disease, which markedly impacted whole-kidney transcriptomics outputs. Cell-type-specific differential expression analysis identified proximal tubule (PT) cells as the key vulnerable cell type. Through unbiased cell trajectory analyses, we show that PT cell differentiation is altered in kidney disease. Metabolism (fatty acid oxidation and oxidative phosphorylation) in PT cells showed the strongest and most reproducible association with PT cell differentiation and disease. Coupling of cell differentiation and the metabolism was established by nuclear receptors (estrogen-related receptor alpha [ESRRA] and peroxisomal proliferation-activated receptor alpha [PPARA]) that directly control metabolic and PT-cell-specific gene expression in mice and patient samples while protecting from kidney disease in the mouse model.

Identifiants

DOI: 10.1016/j.cmet.2020.11.011 PMID: 33301705 PMC: PMC9259369
pubmed: 33301705
pii: S1550-4131(20)30606-9
doi: 10.1016/j.cmet.2020.11.011
pmc: PMC9259369
mid: NIHMS1817578
pii:
doi:

Substances chimiques

Receptors, Estrogen 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

379-394.e8

Subventions

Organisme : NIDDK NIH HHS
ID : R01 DK111495
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK087635
Pays : United States
Organisme : NIDDK NIH HHS
ID : DP3 DK108220
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK076077
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK105821
Pays : United States

Informations de copyright

Copyright © 2020 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests The Susztak lab is supported by Boehringer Ingelheim, Lilly, Regeneron, GSK, Merck, Bayer, and Gilead for work that is not related to the current manuscript.

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Auteurs

Poonam Dhillon (P)

Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.

Jihwan Park (J)

Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; School of Life Sciences, Gwangju Institute of Science and Technology (GIST), 123 Cheomdangwagi-ro, Buk-gu, Gwangju, Republic of Korea. Electronic address: jihwan.park@gist.ac.kr.

Carmen Hurtado Del Pozo (C)

Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Technology (BIST), Barcelona, Spain.

Lingzhi Li (L)

Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.

Tomohito Doke (T)

Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.

Shizheng Huang (S)

Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.

Juanjuan Zhao (J)

Center for Mitochondrial and Epigenomic Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Hyun Mi Kang (HM)

Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Laboratory of Disease Modeling and Therapeutics, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.

Rojesh Shrestra (R)

Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.

Michael S Balzer (MS)

Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.

Shatakshee Chatterjee (S)

Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.

Patricia Prado (P)

Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Technology (BIST), Barcelona, Spain.

Seung Yub Han (SY)

Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.

Hongbo Liu (H)

Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.

Xin Sheng (X)

Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.

Pieterjan Dierickx (P)

Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.

Kirill Batmanov (K)

Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.

Juan P Romero (JP)

Cell Therapy Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Oncohematology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Hematology and Area of Cell Therapy, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain.

Felipe Prósper (F)

Cell Therapy Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Oncohematology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Hematology and Area of Cell Therapy, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain.

Mingyao Li (M)

Department of Epidemiology and Biostatistics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.

Liming Pei (L)

Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Mitochondrial and Epigenomic Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Junhyong Kim (J)

Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.

Nuria Montserrat (N)

Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Technology (BIST), Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain; Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, Madrid, Spain. Electronic address: nmontserrat@ibecbarcelona.eu.

Katalin Susztak (K)

Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: ksusztak@pennmedicine.upenn.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › The Nuclear Receptor ESRRA Protects from...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Différenciation cellulaire › The Nuclear Receptor ESRRA Protects from...
questionsmedicales.fr › Cellules › Cellules cultivées › The Nuclear Receptor ESRRA Protects from...
questionsmedicales.fr › Maladies urogénitales › Maladies urologiques › Maladies du rein › The Nuclear Receptor ESRRA Protects from...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › The Nuclear Receptor ESRRA Protects from...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › The Nuclear Receptor ESRRA Protects from...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › The Nuclear Receptor ESRRA Protects from...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Récepteurs aux stéroïdes › Récepteurs des oestrogènes › The Nuclear Receptor ESRRA Protects from...