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

Carole Henique 1, 2 Guillaume Bollée 1, 3 Xavier Loyer 1 Florian Grahammer 4, 5, 6 Neeraj Dhaun 1, 7 Marine Camus 1 Julien Vernerey 1 Léa Guyonnet 1 François Gaillard 1 Hélène Lazareth 1 Charlotte Meyer 6 Imane Bensaada 1 Luc Legrès 8 Takashi Satoh 9 Shizuo Akira 9 Patrick Bruneval 10, 11 Stefanie Dimmeler 12 Alain Tedgui 1 Alexandre Karras 1, 11, 13 Eric Thervet 13, 1, 11 Dominique Nochy 10, 11 Tobias Huber 4, 5, 6 Laurent Mesnard 14 Olivia Lenoir 1, * Pierre-Louis Tharaux 1, 13, *
* Corresponding author
1 PARCC - UMR-S U970 - Paris-Centre de Recherche Cardiovasculaire
2 IMRB - Institut Mondor de Recherche Biomédicale
3 CRCHUM - Centre de recherche du Chum [Montréal]
4 Faculty of Medicine - Department of Medicine III [Hamburg, Germany]
5 Faculty of Medicine - Department of Medicine IV [Freiburg, Germany]
6 BIOSS - Centre for Biological Signaling Studies [Freiburg]
7 BHF CoRE - British Heart Foundation Centre of Research Excellence [Edinburgh, UK]
8 UMR 1165 - Cancer et Transplantation : Physiopathologie et Réponse Thérapeutique
9 Laboratory of Host Defense / WPI Immunology Frontier Research Centre [Osaka, Japan]
10 Département de Pathologie [AP-HP Hôpital Européen Georges Pompidou]
11 Paris Descartes - Département Hospitalo-Universitaire Paris Ouest
12 Centre for Molecular Medicine - Institute of Cardiovascular Regeneration [Frankfurt, Germany]
13 Service de Néphrologie et Hémodialyse [CHU HEGP]
14 Remodelage et Reparation du Tissu Renal
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.
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Carole Henique, Guillaume Bollée, Xavier Loyer, Florian Grahammer, Neeraj Dhaun, et al.. Genetic and pharmacological inhibition of microRNA-92a maintains podocyte cell cycle quiescence and limits crescentic glomerulonephritis. Nature Communications, Nature Publishing Group, 2017, 8 (1), pp.1829. ⟨10.1038/s41467-017-01885-7⟩. ⟨inserm-02439029⟩

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