Hypertonicity Compromises Renal Mineralocorticoid Receptor Signaling through Tis11b-Mediated Post-Transcriptional Control

Abstract

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 39-untranslated regions (39-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-39-UTR mutants decreased drastically when cotransfected with Tis11b plasmid, correlating with an approximately 50% shorter half-life of AREcontaining transcripts. Using site-directed mutagenesis and RNA immunoprecipitation, we identified a crucial ARE motif within the MR 39-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 a-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.

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

“…Posttranscriptional modifications affecting the stability of the mRNAs encoding the MR have been reported in the kidney. Hypertonicity induces the mRNA-destabilizing protein Tis11b, which interacts with the adenylate/uridylate-rich elements present in the 39 untranslated region of the MR mRNA, increasing MR mRNA turnover and accelerating mRNA destabilization, therefore reducing MR expression (Viengchareun et al, 2014). Ubiquitylation of the MR has been demonstrated to be modulated by phosphorylation, leading to enhanced MR degradation and therefore affecting MR signaling (Faresse et al, 2010(Faresse et al, , 2012.…”

Corticosteroid receptors adopt distinct cyclical transcriptional signatures

“…Lastly, we investigated whether the activity of the 11bHSD2 enzyme was detected in HK-GFP-hMR cells by monitoring the conversion of cortisol or corticosterone into their keto derivatives, as quantified by liquid chromatographytandem mass spectrometry (27). The murine renal KC3AC1 cell line, known to express the 11bHSD2 enzyme (31,32), was used as a positive control. As illustrated in Fig.…”

Role of JAK3 in the Pathogenesis of Oxidative Stress-Induced Kidney Fibrosis

“…Regulation and/or dysregulation of numerous biological processes, including oxidative stress, remodelling of cellular function and morphology, and disturbance of metabolic pathways, are all key mechanisms. The intricate network of transcriptional, post-transcriptional and translational processes is known to act throughout biology to determine functional outcomes (20). Among these, mechanisms for the regulation of protein translation are not well understood.…”