Vasorin

A cross-talk between bone homeostasis and the kidney has been revealed by the association of chronic kidney disease (CKD) and mineral bone disorder (MBD). The abnormalities observed in CKD-MBD also contribute to vascular calcification, a major cause of mortality in patients undergoing dialysis. This underlines the need to identify sensitive markers in order to i) rapidly determine the origin of the kidney pathology and ii) select for each patient the therapeutic with the best efficacy. Vasorin (VASN), a type I membrane protein involved in TGF-beta signaling, was identified in the urine of patients with nephropathies. Initially studied in the context of the development, Vasn was shown to be strongly expressed in several adult tissues, including large arterial vessels, bone, teeth, and kidney. In this later, it was shown to be expressed both in the collecting ducts and in the glomeruli. The investigation of Vasn knock-out (KO) mice by our Consortium has provided little information regarding Vasn function(s) as mice die around 21 days. When compared to Wild type (WT) or heterozygous (HET) mice, post-natal (P) day 21 Vasn KO mice display a very severe phenotype with short stature, severe nephrotic syndrome (NS) from P15 onwards and abnormal bone and tooth mineralization. In the kidney, major abnormalities were observed in glomeruli, and podocytes were the most affected cells are characterized by loss of their foot processes and absence of slit diaphragm, which is essential for proper selective urine filtration. In addition, the media of the large vessels was strongly altered, manifested by disorganization of the elastic fibers and hypertrophic vascular smooth muscle cells (VSMCs) with some areas devoid of cells. Thus, having access to conditional Vasn KO mice, our Consortium will aim to further understand the pathophysiological functions of Vasn, specifically in 1) bone and tooth formation, and bone homeostasis, 2) large vessel organization and the development of ectopic calcifications, 3) renal tubule function and the maintenance of mineral homeostasis, 4) glomerulus and podocyte homeostasis. In that purpose, we will develop Cre-lox models including deletion of Vasn specifically in either bones and teeth, large vessels, tubules or nephrons and analyze the phenotype of these mice by sharing our expertise as a role for soluble Vasn (sVasn) that may mediate interorgan crosstalk. We will perform functional tests in conditional KO mice such as tubule perfusion, vascular hemodynamic, models of bone, tooth, or vascular injury. In parallel, in vitro experiments will also be carried out by Partners on primary cell cultures thanks to cells sampled in tamoxifen inducible Vasn KO for the different tissues (primary culture of podocytes, osteoblasts or VSMCs). In both in vivo and in vitro experiments, we will investigate the molecular pathways associated to Vasn by conducting several transcriptomic studies and determine whether the interaction with TGF-beta signaling is restricted to large vessels or common with the other organs. Finally, we will investigate human tissue collections and databases of patients with NS and CKD and/or vascular and bone diseases to analyze more in depth Vasn role(s) in these disorders. In a clinical perspective, VASN variant(s) may have a central role in rare or acquired nephrotic syndromes, bone disorders or more generally in cardiovascular diseases, and may constitute a therapeutic target.