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Rôles et fonctions de Vasorine, protéine osseuse, rénale et vasculaire : étude in vivo dans la formation osseuse et l'homéostasie phosphocalcique

Abstract : Vasorin (Vasn) is a type I transmembrane protein initially studied in the context of development. Vasn has also been localized in adult mice where it is highly expressed in large vessels, bones and kidneys. The main(s) role(s) of Vasn is/are actually unknown. Many bone, renal and vascular pathologies are still unexplained, and even if to date no Vasn variant has been associated with a human pathology, it is necessary to identify early markers of these pathologies as well as the molecular pathways / defective proteins. The objective of this work is to understand the main roles and functions of Vasn through several animal models; Vasn knockout (KO) mice and inducible Vasn KO mice (Cre-Lox inducible cassette). Analyzes showed that Vasn KO mice develop a non-viable phenotype, resulting in an early death around 24 days postnatal. In general, they are smaller, with severe nephrotic syndrome taking place from day 14 and have abnormal bone microarchitecture compared to Wild-Type (WT) mice. Major renal abnormalities were observed in the podocytes, with the loss of their pedicels and the absence of a slit diaphragm, which explain the accumulation of proteins found in the tubules and urine. This nephrotic syndrome progresses to severe renal failure. Vasn KO mice have an osteopenic femoral trabecular bone that is at least partly linked to increased osteoclastic activity. In addition, the media of large vessels is strongly altered, resulting in disorganization of elastic fibers and smooth muscle cells are hypertrophic or completely absent from certain areas. The inducible Vasn KO mice have a phenotype comparable to the Vasn KO mouse. An early death occurs around 24 days after deletion of the gene. Severe nephrotic syndrome is rapidly established between D15 and D17 postinduction, characterized by major proteinuria and the presence of intraperitoneal ascite. Bone microarchitecture is surprisingly abnormal compared to control mice, linked at least in part to increased osteoclastic activity. In vitro experiments of primary cell cultures taken from Vasn KO mice compared to cells taken from WT mice validated Vasn expression in podocytes, osteoclasts and smooth muscle cells. The rapid onset of osteopenia in inducible Vasn KO mice suggests a direct role for Vasn in bone remodeling. At the end of this work, the repercussions of the Vasorin loss in adult mouse models were described, and several functional tracks are explored. The involvement of Vasorin in the bone / kidney dialogue is confirmed and its analysis will be continued.
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Anne-Laure Bonnet. Rôles et fonctions de Vasorine, protéine osseuse, rénale et vasculaire : étude in vivo dans la formation osseuse et l'homéostasie phosphocalcique. Médecine humaine et pathologie. Université Sorbonne Paris Cité, 2018. Français. ⟨NNT : 2018USPCB161⟩. ⟨tel-02518248⟩

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