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

Carole Henique (), Guillaume Bollée, Xavier Loyer, Florian Grahammer, Neeraj Dhaun, Marine Camus, Julien Vernerey, Léa Guyonnet, François Gaillard, Hélène Lazareth, Charlotte Meyer, Imane Bensaada, Luc Legrès, Takashi Satoh, Shizuo Akira, Patrick Bruneval, Stefanie Dimmeler, Alain Tedgui, Alexandre Karras, Eric Thervet, Dominique Nochy, Tobias B. Huber, Laurent Mesnard, Olivia Lenoir and Pierre-Louis Tharaux ()
Additional contact information
Carole Henique: Institut National de la Santé et de la Recherche Médicale (INSERM)
Guillaume Bollée: Institut National de la Santé et de la Recherche Médicale (INSERM)
Xavier Loyer: Institut National de la Santé et de la Recherche Médicale (INSERM)
Florian Grahammer: Universitätsklinikum Hamburg-Eppendorf
Neeraj Dhaun: Institut National de la Santé et de la Recherche Médicale (INSERM)
Marine Camus: Institut National de la Santé et de la Recherche Médicale (INSERM)
Julien Vernerey: Institut National de la Santé et de la Recherche Médicale (INSERM)
Léa Guyonnet: Institut National de la Santé et de la Recherche Médicale (INSERM)
François Gaillard: Institut National de la Santé et de la Recherche Médicale (INSERM)
Hélène Lazareth: Institut National de la Santé et de la Recherche Médicale (INSERM)
Charlotte Meyer: Albert-Ludwigs-University
Imane Bensaada: Institut National de la Santé et de la Recherche Médicale (INSERM)
Luc Legrès: Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme MicroLaser Biotech
Takashi Satoh: Osaka University
Shizuo Akira: Osaka University
Patrick Bruneval: Sorbonne Paris Cité
Stefanie Dimmeler: Goethe University Frankfurt
Alain Tedgui: Institut National de la Santé et de la Recherche Médicale (INSERM)
Alexandre Karras: Institut National de la Santé et de la Recherche Médicale (INSERM)
Eric Thervet: Institut National de la Santé et de la Recherche Médicale (INSERM)
Dominique Nochy: Sorbonne Paris Cité
Tobias B. Huber: Universitätsklinikum Hamburg-Eppendorf
Laurent Mesnard: Institut National de la Santé et de la Recherche Médicale (INSERM)
Olivia Lenoir: Institut National de la Santé et de la Recherche Médicale (INSERM)
Pierre-Louis Tharaux: Institut National de la Santé et de la Recherche Médicale (INSERM)

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01885-7

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