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Nat Commun. 2017 Nov 28;8(1):1829. doi: 10.1038/s41467-017-01885-7.

Genetic and pharmacological inhibition of microRNA-92a maintains podocyte cell cycle quiescence and limits crescentic glomerulonephritis.

Henique C1,2,3,4, Bollée G5,6,7, Loyer X5,6, Grahammer F8,9,10, Dhaun N5,11, Camus M5, Vernerey J5, Guyonnet L5,6, Gaillard F5,6, Lazareth H5,6, Meyer C10, Bensaada I5,6, Legrès L12, Satoh T13, Akira S13, Bruneval P6,14,15, Dimmeler S16, Tedgui A5,6, Karras A5,6,15,17, Thervet E5,6,15,17, Nochy D6,14,15, Huber TB8,9,10, Mesnard L18,19, Lenoir O5,6, Tharaux PL20,21,22.

Author information

1
Paris Cardiovascular Research Centre-PARCC, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, 75015, France. carole.henique@inserm.fr.
2
Paris Descartes University, Sorbonne Paris Cité, Paris, 75006, France. carole.henique@inserm.fr.
3
Institut Mondor de Recherche Biomédicale, team 21, Unité Mixte de Recherche (UMR) 955, Institut National de la Santé et de la Recherche Médicale (INSERM), Créteil, 94000, France. carole.henique@inserm.fr.
4
Université Paris-Est Créteil, Créteil, 94000, France. carole.henique@inserm.fr.
5
Paris Cardiovascular Research Centre-PARCC, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, 75015, France.
6
Paris Descartes University, Sorbonne Paris Cité, Paris, 75006, France.
7
Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Montréal, H2X 0A9, QC, Canada.
8
III. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, 20246, Germany.
9
Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, P.O. Box 79085, Germany.
10
BIOSS Centre for Biological Signalling Studies and Center for Biological Systems Analysis (ZBSA), Albert-Ludwigs-University, Freiburg, 79104, Germany.
11
British Heart Foundation Centre of Research Excellence (BHF CoRE), Edinburgh, EH16 4TJ, UK.
12
Unité Mixte de Recherche (UMR_S) 1165, Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme MicroLaser Biotech, Paris, 75010, France.
13
Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, 565-0871, Japan.
14
Department of Pathology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.
15
Département Hospitalo-Universitaire, Paris Descartes University-Hôpitaux Universitaires Paris Ouest, Paris, 75015, France.
16
Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University Frankfurt, Frankfurt, 60590, Germany.
17
Renal Division, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.
18
Unité Mixte de Recherche (UMR) 702, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, 75020, France.
19
Faculty of Medicine, University Pierre and Marie Curie, Paris, 75020, France.
20
Paris Cardiovascular Research Centre-PARCC, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, 75015, France. pierre-louis.tharaux@inserm.fr.
21
Paris Descartes University, Sorbonne Paris Cité, Paris, 75006, France. pierre-louis.tharaux@inserm.fr.
22
Renal Division, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France. pierre-louis.tharaux@inserm.fr.

Abstract

Crescentic rapidly progressive glomerulonephritis (RPGN) represents the most aggressive form of acquired glomerular disease. While most therapeutic approaches involve potentially toxic immunosuppressive strategies, the pathophysiology remains incompletely understood. Podocytes are glomerular epithelial cells that are normally growth-arrested because of the expression of cyclin-dependent kinase (CDK) inhibitors. An exception is in RPGN where podocytes undergo a deregulation of their differentiated phenotype and proliferate. Here we demonstrate that microRNA-92a (miR-92a) is enriched in podocytes of patients and mice with RPGN. The CDK inhibitor p57Kip2 is a major target of miR-92a that constitutively safeguards podocyte cell cycle quiescence. Podocyte-specific deletion of miR-92a in mice de-repressed the expression of p57Kip2 and prevented glomerular injury in RPGN. Administration of an anti-miR-92a after disease initiation prevented albuminuria and kidney failure, indicating miR-92a inhibition as a potential therapeutic strategy for RPGN. We demonstrate that miRNA induction in epithelial cells can break glomerular tolerance to immune injury.

PMID:
29184126
PMCID:
PMC5705755
DOI:
10.1038/s41467-017-01885-7
[Indexed for MEDLINE]
Free PMC Article

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