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RNA-binding protein HuR enhances mineralocorticoid signaling in renal KC3AC1 cells under hypotonicity

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Abstract

Mineralocorticoid receptor (MR) mediates the sodium-retaining action of aldosterone in the distal nephron. Herein, we decipher mechanisms by which hypotonicity increases MR expression in renal principal cells. We identify HuR (human antigen R), an mRNA-stabilizing protein, as an important posttranscriptional regulator of MR expression. Hypotonicity triggers a rapid and reversible nuclear export of HuR in renal KC3AC1 cells, as quantified by high-throughput microscopy. We also identify a key hairpin motif in the 3′-untranslated region of MR transcript, pivotal for the interaction with HuR and its stabilizing function. Next, we show that hypotonicity increases MR recruitment onto Sgk1 promoter, a well-known MR target gene, thereby enhancing aldosterone responsiveness. Our data shed new light on the crucial role of HuR as a stabilizing factor for the MR transcript and provide evidence for a short autoregulatory loop in which expression of a nuclear receptor transcriptionally regulating water and sodium balance is controlled by osmotic tone.

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Abbreviations

MR:

Mineralocorticoid receptor

HuR:

Human antigen R

Sgk1:

Serum and glucocorticoid-regulated kinase 1

Tis11b:

Tetradecanoyl phorbol acetate inducible sequence 11b

RBP:

RNA-binding protein

3′-UTR:

3′-Untranslated region

ELAVL1:

Embryonic lethal, abnormal vision, Drosophila homolog-like 1

EGF:

Epidermal growth factor

T3:

Triiodothyronine

DCC:

Dextran charcoal-coated

RNP-IP:

Ribonucleoprotein immunoprecipitation

Luc:

Luciferase

DNA-ChiP:

DNA-chromatin immunoprecipitation

Iso:

Isotonicity

Hypo:

Hypotonicity

HTM:

High-throughput microscopy

LMB:

Leptomycin B

PKC:

Protein kinase C

miRNA:

MicroRNA

PIS:

Preimmune serum

Ucp1:

Uncoupling protein 1

MTA:

Metastasis-associate 1

PTMA:

Prothymosin

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Acknowledgements

The authors are indebted to Julie Sappa for English editing.

Author information

Author notes

  1. Marc Lombès, Nadia Cherradi, and Say Viengchareun are senior authors who equally contributed to this work.

Authors and Affiliations

  1. Inserm U1185, Faculté de Médecine Paris-Sud, Université Paris-Saclay, 63 rue Gabriel Peri, 94276, Le Kremlin-Bicêtre, France

    Ingrid Lema, Larbi Amazit, Khadija Lamribet, Jérôme Fagart, Marc Lombès & Say Viengchareun

  2. UMS 32, 94276, Le Kremlin-Bicêtre, France

    Larbi Amazit

  3. Inserm, Centre d’Investigations Cliniques 9201, 75015, Paris, France

    Anne Blanchard

  4. Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, 94275, Le Kremlin-Bicêtre, France

    Marc Lombès

  5. Institut National de la Santé et de la Recherche Médicale, Inserm U1036, 38000, Grenoble, France

    Nadia Cherradi

  6. Commissariat à l’Energie Atomique et aux Energies Alternatives, Institut de Biosciences et Biotechnologies de Grenoble, Laboratoire Biologie du Cancer et de l’Infection, 38000, Grenoble, France

    Nadia Cherradi

  7. Université Grenoble Alpes, Unité Mixte de Recherche-S1036, 38000, Grenoble, France

    Nadia Cherradi

Authors
  1. Ingrid Lema
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Contributions

IL, AB, JF, NC, ML, and SV designed the study. IL, LA, KL, SV, NC, and ML performed the study. LA, IL, KL, AB, NC, ML, and SV analyzed the data, and IL, LA, NC, ML, and SV wrote the paper.

Corresponding authors

Correspondence to Marc Lombès, Nadia Cherradi or Say Viengchareun.

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Funding

This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale, the Université Paris-Sud and Agence Nationale de la Recherche (Grant 11-BSV1-028-01). Ingrid Lema held a fellowship from the Cardiovasculaire-Obésité-Rein-Diabète-Domaine d’Intérêt Majeur (Région Ile-de-France) and HAC Pharma & SFE (Société Française d’Endocrinologie).

Conflict of interest

The authors declare that they have no competing interests.

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Lema, I., Amazit, L., Lamribet, K. et al. RNA-binding protein HuR enhances mineralocorticoid signaling in renal KC3AC1 cells under hypotonicity. Cell. Mol. Life Sci. 74, 4587–4597 (2017). https://doi.org/10.1007/s00018-017-2594-x

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