PMID- 24700863 OWN - NLM STAT- MEDLINE DCOM- 20141209 LR - 20211021 IS - 1533-3450 (Electronic) IS - 1046-6673 (Print) IS - 1046-6673 (Linking) VI - 25 IP - 10 DP - 2014 Oct TI - Hypertonicity compromises renal mineralocorticoid receptor signaling through Tis11b-mediated post-transcriptional control. PG - 2213-21 LID - 10.1681/ASN.2013091023 [doi] AB - The mineralocorticoid receptor (MR) mediates the Na(+)-retaining action of aldosterone. MR is highly expressed in the distal nephron, which is submitted to intense variations in extracellular fluid tonicity generated by the corticopapillary gradient. We previously showed that post-transcriptional events control renal MR abundance. Here, we report that hypertonicity increases expression of the mRNA-destabilizing protein Tis11b, a member of the tristetraprolin/ZFP36 family, and thereby, decreases MR expression in renal KC3AC1 cells. The 3'-untranslated regions (3'-UTRs) of human and mouse MR mRNA, containing several highly conserved adenylate/uridylate-rich elements (AREs), were cloned downstream of a reporter gene. Luciferase activities of full-length or truncated MR Luc-3'-UTR mutants decreased drastically when cotransfected with Tis11b plasmid, correlating with an approximately 50% shorter half-life of ARE-containing transcripts. Using site-directed mutagenesis and RNA immunoprecipitation, we identified a crucial ARE motif within the MR 3'-UTR, to which Tis11b must bind for destabilizing activity. Coimmunoprecipitation experiments suggested that endogenous Tis11b physically interacts with MR mRNA in KC3AC1 cells, and Tis11b knockdown prevented hypertonicity-elicited repression of MR. Moreover, hypertonicity blunted aldosterone-stimulated expression of glucocorticoid-induced leucine-zipper protein and the alpha-subunit of the epithelial Na(+) channel, supporting impaired MR signaling. Challenging the renal osmotic gradient by submitting mice to water deprivation, diuretic administration, or high-Na(+) diet increased renal Tis11b and decreased MR expression, particularly in the cortex, thus establishing a mechanistic pathway for osmotic regulation of MR expression in vivo. Altogether, we uncovered a mechanism by which renal MR expression is regulated through mRNA turnover, a post-transcriptional control that seems physiologically relevant. CI - Copyright (c) 2014 by the American Society of Nephrology. FAU - Viengchareun, Say AU - Viengchareun S AD - Institut National de la Sante et de la Recherche Medicale, U693, Le Kremlin-Bicetre, France; University of Paris-Sud, Faculte de Medecine Paris-Sud, Unite Mixte de Recherche-S693, Le Kremlin-Bicetre, France; FAU - Lema, Ingrid AU - Lema I AD - Institut National de la Sante et de la Recherche Medicale, U693, Le Kremlin-Bicetre, France; University of Paris-Sud, Faculte de Medecine Paris-Sud, Unite Mixte de Recherche-S693, Le Kremlin-Bicetre, France; FAU - Lamribet, Khadija AU - Lamribet K AD - Institut National de la Sante et de la Recherche Medicale, U1036, Grenoble, France; Commissariat a l'Energie Atomique, Institute of Life Sciences Research and Technologies, Biology of Cancer and Infection, Grenoble, France; University of Grenoble Alpes, Unite Mixte de Recherche-S1036, Grenoble, France; FAU - Keo, Vixra AU - Keo V AD - Institut National de la Sante et de la Recherche Medicale, U693, Le Kremlin-Bicetre, France; University of Paris-Sud, Faculte de Medecine Paris-Sud, Unite Mixte de Recherche-S693, Le Kremlin-Bicetre, France; FAU - Blanchard, Anne AU - Blanchard A AD - Institut National de la Sante et de la Recherche Medicale, Centre d'Investigations Cliniques 9201, Paris, France; and. FAU - Cherradi, Nadia AU - Cherradi N AD - Institut National de la Sante et de la Recherche Medicale, U1036, Grenoble, France; Commissariat a l'Energie Atomique, Institute of Life Sciences Research and Technologies, Biology of Cancer and Infection, Grenoble, France; University of Grenoble Alpes, Unite Mixte de Recherche-S1036, Grenoble, France; nadia.cherradi@cea.fr marc.lombes@u-psud.fr. FAU - Lombes, Marc AU - Lombes M AD - Institut National de la Sante et de la Recherche Medicale, U693, Le Kremlin-Bicetre, France; University of Paris-Sud, Faculte de Medecine Paris-Sud, Unite Mixte de Recherche-S693, Le Kremlin-Bicetre, France; Assistance Publique-Hopitaux de Paris, Hopital de Bicetre, Service d'Endocrinologie et des Maladies de la Reproduction, Le Kremlin-Bicetre, France nadia.cherradi@cea.fr marc.lombes@u-psud.fr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140403 PL - United States TA - J Am Soc Nephrol JT - Journal of the American Society of Nephrology : JASN JID - 9013836 RN - 0 (3' Untranslated Regions) RN - 0 (Butyrate Response Factor 1) RN - 0 (Nuclear Proteins) RN - 0 (RNA-Binding Proteins) RN - 0 (Receptors, Mineralocorticoid) RN - 0 (ZFP36L1 protein, human) RN - 0 (Zfp36l1 protein, mouse) RN - 9NEZ333N27 (Sodium) SB - IM MH - 3' Untranslated Regions MH - Animals MH - Butyrate Response Factor 1/*metabolism MH - HEK293 Cells MH - Humans MH - Kidney/*metabolism MH - Mice MH - Nuclear Proteins/*metabolism MH - RNA Processing, Post-Transcriptional MH - RNA-Binding Proteins/*metabolism MH - Receptors, Mineralocorticoid/*metabolism MH - Sodium/metabolism MH - Water Deprivation MH - Water-Electrolyte Imbalance/*metabolism PMC - PMC4178442 EDAT- 2014/04/05 06:00 MHDA- 2014/12/15 06:00 PMCR- 2015/10/01 CRDT- 2014/04/05 06:00 PHST- 2014/04/05 06:00 [entrez] PHST- 2014/04/05 06:00 [pubmed] PHST- 2014/12/15 06:00 [medline] PHST- 2015/10/01 00:00 [pmc-release] AID - ASN.2013091023 [pii] AID - 2013091023 [pii] AID - 10.1681/ASN.2013091023 [doi] PST - ppublish SO - J Am Soc Nephrol. 2014 Oct;25(10):2213-21. doi: 10.1681/ASN.2013091023. Epub 2014 Apr 3.