Thesis defense Nathan Chaté

Equipe

Team III - Vascular & Pulmonary Diseases

Directeur de thèse

Laurent Beck

Co-directrice 

Rapporteurs

Jean-Luc Battini, PhD, Directeur de recherche, Institut de Recherche en Infectiologie de Montpellier
Julie Klein, PhD, Chargée de Recherche, Institut des Maladies Métaboliques et Cardiovaculaires de Toulouse

Examinateurs

Lucie Hénaut, PhD, Ingénieure de recherche, Université de Picardie Jules Verne
David Magnen, PhD, Professeur des universités, Université Claude Bernard Lyon 1, Inserm 1033

Abstract

Inorganic phosphate (Pi) plays a central role in mineral metabolism and numerous cellular processes. However, chronic excess Pi, particularly in chronic kidney disease (CKD), promotes the development of medial vascular calcifications (MAC), major complications contributing to cardiovascular morbidity and mortality. The molecular mechanisms by which Pi induces these calcifications remain poorly understood, particularly the contribution of Pi transporters expressed in vascular smooth muscle cells (VSMC). In this context, the aim of this thesis was to characterise the role of the Pi transporter PiT2/SLC20A2 in the pathophysiology of MRC-associated MAC, according to two complementary axes: (1) to determine whether PiT2 expression in VSMCs is necessary for the development of hyperphosphataemia-induced MAC; (2) to evaluate the contribution of PiT2 as a Pi sensor regulating FGF23 secretion to phosphocalcic and cardiovascular disorders associated with CKD. For the first axis, we generated a mouse model of conditional deletion of PiT2 in VSMC (sm22Cre;PiT2lox/lox) and induced CKD by 5/6 nephrectomy combined with a Pi-enriched diet. Histological and biochemical analyses, supplemented by ex vivo models of aortic ring calcification, revealed no significant differences between mutant and control mice, suggesting that PiT2 is not required in VSMC for the development of Pi-induced MAC. For the second axis, aimed at dissecting the respective contributions of Pi and FGF23 in CKD, a mouse model of PiT2-specific deletion in osteoblasts (Col1a1Cre;PiT2lox/lox) was established to generate CKD without concomitant elevation of FGF23. However, the results showed insufficient recombination in bone tissue, highlighting the need to use a more efficient Cre line to confirm this hypothesis. Overall, our work shows that PiT2 does not play a decisive role in VSMC for the formation of MAC linked to hyperphosphataemia, but opens up new perspectives for understanding the relationship between phosphate homeostasis, FGF23 and cardiovascular damage during CKD.