Hypertonicity compromises renal mineralocorticoid receptor signaling through Tis11b-mediated posttranscriptional control

Abstract : The Mineralocorticoid Receptor (MR) mediates Na+-retaining action of aldosterone. It is highly expressed in the distal nephron which is submitted to intense variations of the extracellular fluid tonicity generated by the corticopapillary gradient. We previously showed that posttranscriptional events control renal MR abundance. Here, we find that hypertonicity increases expression of the mRNA-destabilizing protein Tis11b, a member of tristetraprolin/ZFP36 family, and thereby decreases MR expression in renal KC3AC1 cells. The 3'-Untranslated region (3'-UTR) of human and mouse MR mRNA containing several highly conserved Adenylate/Uridylate-Rich Elements (ARE), were cloned downstream of a reporter gene. Luciferase activities of full length or truncated Luc-3'-UTR mutants were drastically reduced when cotransfected with Tis11b plasmid in HEK293T cells, consistent with a 50% shorter half-life of ARE-containing transcripts. We identified a crucial ARE motif within MR 3'-UTR, to which Tis11b binds as shown by site-directed mutagenesis and RNA Immunoprecipitation, responsible for Tis11b-mediated destabilizing activity. Importantly, endogenous Tis11b physically interacts with MR mRNA in KC3AC1 cells, leading to hypertonicity-elicited MR repression as demonstrated by Tis11b knockdown. Moreover, hypertonicity impaired MR signaling by blunting aldosterone-stimulated Gilz and αENaC expression in the Na+-transporting KC3AC1 cells. Challenging the renal osmotic gradient by submitting mice to water deprivation, diuretic administration or high Na+ diet increased renal Tis11b while decreased MR expression, notably in the cortex, thus establishing a mechanistic pathway for osmotic regulation of MR expression in vivo. Altogether, we uncover a previously undetected mechanism by which renal MR expression is regulated via mRNA turnover, a posttranscriptional control which appears physiologically relevant.
Type de document :
Pré-publication, Document de travail
2014
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http://www.hal.inserm.fr/inserm-00935846
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Say Viengchareun, Ingrid Lema, Kadhija Lamribet, Vixra Keo, Anne Blanchard, et al.. Hypertonicity compromises renal mineralocorticoid receptor signaling through Tis11b-mediated posttranscriptional control. 2014. 〈inserm-00935846〉

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