Investigation of the intrinsic rénal circadian clocks Characterization of the rénal function of XPR1 and ARG2


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PhD thesis: a PhD thesis.
Investigation of the intrinsic rénal circadian clocks Characterization of the rénal function of XPR1 and ARG2
Firsov Dmitri
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Université de Lausanne, Faculté de biologie et médecine
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Investigation of the iritrinsic rénal circadian clocks.
Many rénal functions, as glomerular filtration rate, rénal blood flow as well as urine production and electrolytes excretion show circadian oscillations. Physiological circadian rhythms are generated by circadian clocks, feedback loops-interacting molecular networks allowing the organisms to coordinate their physiology and behavior with daily environmental variations. The aims of the projects we conducted are to investigate the rôle of the intrinsic rénal circadian clocks in rénal circadian rhythmicity and in the pathogenesis of diabetic nephropathy. We observed that tubular circadian clocks disruption induces profound altérations in kidney transcriptome and in intrarenal and systemic metabolic processes. Moreover, circadian clock in rénal tubular cells is involved in drug disposition. We also investigated physiological relevance of circadian clocks located in podocytes of the glomerulus and demonstrated that deletion abolishes circadian rhythmicity of glomerular filtration rate and urine production, as well as urinary sodium and potassium excretion. Furthermore, podocyte circadian clock controls expression of various genes having a critical rôle in podocyte function and known to be involved in the pathogenesis of diverse glomerular diseases. Finally, we demonstrated that disruption of tubular, but not podocyte, circadian clocks aggravates général metabolic status and rénal function of type I diabetic mice. Underlying mechanisms remain to be clarified.
Characterization of the rénal function of XPR1 and ARG2.
Recently published in vitro experiments have demonstrated a rôle for XPR1 in phosphate transport. Initially identified as the receptor used by xenotropic and polytropic murine leukemia retroviruses for cell infection, in vivo physiological rôle of XPR1 remains unknown. Using a mice model carrying an inducible Xpr1 deletion in the entire rénal tubule, we highlighted a relevant function for XPR1 in rénal phosphate homeostasis as demonstrated by the disturbed rénal phosphate handling and the strong bone phenotype exhibited by mice devoid of XPR1. Rénal ARG2 expression is strongly upregulated in many stress-induced kidney injury conditions. Whether this increase is bénéficiai or detrimental is still debated. We studied the rôle of ARG2 in mice carrying kidney-specific Arg2 deletion and subjected to unilatéral rénal ischemia followed either by 24 hours or 2 weeks of reperfusion. Although we have established the protective rôle of ARG2 in short-term ischemia-induced rénal injury, its effect on the long-term recovery is still unclear and remains to be further investigated.

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21/03/2019 11:54
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20/08/2019 16:31
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