Reader TTS

ABSTRACT Aldosterone is a biological ligand for mineralocorticoid receptor (MR) that elevates blood pressure by promoting sodium reabsorption in the kidneys. However, the molecular

mechanisms of aldosterone-MR-mediated transcription and the role of this transcription in hypertension remain largely unknown. In this study, we aimed to identify novel MR coregulators and

elucidate one of the molecular mechanisms of hypertension. We purified MR-interacting factors from HEK293F cells stably expressing FLAG-MR through a biochemical approach and identified the

zinc finger protein castor homolog 1 isoform b (CASZ1b) as a candidate novel MR coregulator via liquid chromatography—tandem mass spectrometry analysis. The CASZ1 gene has been implicated in

hypertension in genome-wide single-nucleotide polymorphism studies, but its role in the development of hypertension remains unclear. We found that CASZ1b colocalized with MR in the kidneys

and interacted with MR in an aldosterone-dependent manner. In luciferase assays using HEK293F cells, overexpression of CASZ1b reduced aldosterone-dependent MR transcriptional activity by

~50%. In contrast, knockdown of CASZ1b via RNA interference increased the expression levels of the aldosterone-induced MR target genes epithelial Na+ channel-α (_ENaCα_) and

serum/glucocorticoid regulated kinase 1 (_SGK1_) by approximately twofold and 2.3-fold, respectively. Upon aldosterone-MR binding, CASZ1b interacted with MR and formed a protein complex with

nucleosome remodeling deacetylase (Mi-2/NuRD), a corepressor complex with chromatin remodeling and histone deacetylation activity, which suppressed ENaCα and SGK1. These findings reveal a

critical role of CASZ1b in regulating MR-mediated transcriptional activity and provide new insights into the pathophysiology of hypertension. Access through your institution Buy or subscribe

This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access

$259.00 per year only $21.58 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are

calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS

CASZ1: A PROMISING FACTOR MODULATING ALDOSTERONE BIOSYNTHESIS AND MINERALOCORTICOID RECEPTOR ACTIVITY Article 16 December 2022 THE MINERALOCORTICOID RECEPTOR LEADS TO INCREASED EXPRESSION OF

EGFR AND T-TYPE CALCIUM CHANNELS THAT SUPPORT HL-1 CELL HYPERTROPHY Article Open access 24 June 2021 LYSINE-SPECIFIC DEMETHYLASE 1 AS A COREPRESSOR OF MINERALOCORTICOID RECEPTOR Article 17

February 2022 REFERENCES * Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE, et al. Cloning of human mineralocorticoid receptor complementary DNA: structural and

functional kinship with the glucocorticoid receptor. Science. 1987;237:268–75. Article  CAS  Google Scholar  * Le Menuet D, Viengchareun S, Muffat-Joly M, Zennaro MC, Lombès M. Expression

and function of the human mineralocorticoid receptor: lessons from transgenic mouse models. Mol Cell Endocrinol. 2004;217:127–36. Article  Google Scholar  * Valinsky WC, Touyz RM, Shrier A.

Aldosterone, SGK1, and ion channels in the kidney. Clin Sci (Lond). 2018;132:173–83. Article  CAS  Google Scholar  * Riepe FG. Clinical and molecular features of type 1

pseudohypoaldosteronism. Horm Res. 2009;72:1–9. Article  CAS  Google Scholar  * Mubarik A, Anastasopoulou C, Riahi S, Aeddula NR Liddle Syndrome. _StatPearls_. StatPearls Publishing

Copyright © 2020, StatPearls Publishing LLC.: Treasure Island (FL); 2020. * Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and

mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17. Article  CAS  Google Scholar  * Pitt B, Remme W, Zannad

F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med.

2003;348:1309–21. Article  CAS  Google Scholar  * Yokota K, Shibata H, Kurihara I, Kobayashi S, Suda N, Murai-Takeda A, et al. Coactivation of the N-terminal transactivation of

mineralocorticoid receptor by Ubc9. J Biol Chem. 2007;282:1998–2010. Article  CAS  Google Scholar  * Zhang W, Xia X, Reisenauer MR, Rieg T, Lang F, Kuhl D, et al. Aldosterone-induced Sgk1

relieves Dot1a-Af9-mediated transcriptional repression of epithelial Na+ channel alpha. J Clin Investig. 2007;117:773–83. Article  CAS  Google Scholar  * Burrello J, Monticone S, Buffolo F,

Tetti M, Veglio F, Williams TA, et al. Is There a Role for Genomics in the Management of Hypertension? Int J Mol Sci. 2017;18:1131. Article  Google Scholar  * Levy D, Ehret GB, Rice K,

Verwoert GC, Launer LJ, Dehghan A, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet. 2009;41:677–87. Article  CAS  Google Scholar  * Takeuchi F, Isono M,

Katsuya T, Yamamoto K, Yokota M, Sugiyama T et al. Blood pressure and hypertension are associated with 7 loci in the Japanese population. Circulation. 121:2302–9. * Ho JE, Levy D, Rose L,

Johnson AD, Ridker PM, Chasman DI. Discovery and replication of novel blood pressure genetic loci in the Women’s Genome Health Study. J Hypertens. 2011;29:62–9. Article  CAS  Google Scholar

  * Kato N, Takeuchi F, Tabara Y, Kelly TN, Go MJ, Sim X, et al. Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east

Asians. Nat Genet. 2011;43:531–8. Article  CAS  Google Scholar  * Nakamura T, Kurihara I, Kobayashi S, Yokota K, Murai-Takeda A, Mitsuishi Y, et al. Intestinal mineralocorticoid receptor

contributes to epithelial sodium channel-mediated intestinal sodium absorption and blood pressure regulation. J Am Heart Assoc. 2018;7:e008259. Article  CAS  Google Scholar  * Fujita N, Jaye

DL, Kajita M, Geigerman C, Moreno CS, Wade PA. MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell. 2003;113:207–19. Article  CAS  Google Scholar

  * Metivier R, Penot G, Hubner MR, Reid G, Brand H, Kos M, et al. Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter.

Cell. 2003;115:751–63. Article  CAS  Google Scholar  * Tong JK, Hassig CA, Schnitzler GR, Kingston RE, Schreiber SL. Chromatin deacetylation by an ATP-dependent nucleosome remodelling

complex. Nature. 1998;395:917–21. Article  CAS  Google Scholar  * Xue Y, Wong J, Moreno GT, Young MK, Cote J, Wang WNURD. A novel complex with both ATP-dependent chromatin-remodeling and

histone deacetylase activities. Mol Cell. 1998;2:851–61. Article  CAS  Google Scholar  * Liu Z, Lam N, Thiele CJ. Zinc finger transcription factor CASZ1 interacts with histones, DNA repair

proteins and recruits NuRD complex to regulate gene transcription. Oncotarget. 2015;6:27628–40. Article  Google Scholar  * Liu Z, Lam N, Wang E, Virden RA, Pawel B, Attiyeh EF, et al.

Identification of CASZ1 NES reveals potential mechanisms for loss of CASZ1 tumor suppressor activity in neuroblastoma. Oncogene. 2017;36:97–109. Article  CAS  Google Scholar  * Liu Z,

Naranjo A, Thiele CJ. CASZ1b, the short isoform of CASZ1 gene, coexpresses with CASZ1a during neurogenesis and suppresses neuroblastoma cell growth. PLoS ONE. 2011;6:e18557. Article  CAS 

Google Scholar  * Liu Z, Yang X, Li Z, McMahon C, Sizer C, Barenboim-Stapleton L, et al. CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming

gene expression. Cell Death Differ. 2011;18:1174–83. Article  CAS  Google Scholar  * Wu YY, Chang CL, Chuang YJ, Wu JE, Tung CH, Chen YC, et al. CASZ1 is a novel promoter of metastasis in

ovarian cancer. Am J Cancer Res. 2016;6:1253–70. CAS  PubMed  PubMed Central  Google Scholar  * Amin NM, Gibbs D, Conlon FL. Differential regulation of CASZ1 protein expression during

cardiac and skeletal muscle development. Dev Dyn. 2014;243:948–56. Article  CAS  Google Scholar  * Dorr KM, Amin NM, Kuchenbrod LM, Labiner H, Charpentier MS, Pevny LH, et al. Casz1 is

required for cardiomyocyte G1-to-S phase progression during mammalian cardiac development. Development. 2015;142:2037–47. Article  CAS  Google Scholar  * Guo J, Li Z, Hao C, Guo R, Hu X,

Qian S, et al. A novel de novo CASZ1 heterozygous frameshift variant causes dilated cardiomyopathy and left ventricular noncompaction cardiomyopathy. Mol Genet Genom Med. 2019;7:e828. Google

Scholar  * Huang RT, Xue S, Wang J, Gu JY, Xu JH, Li YJ, et al. CASZ1 loss-of-function mutation associated with congenital heart disease. Gene. 2016;595:62–8. Article  CAS  Google Scholar 

* Liu Z, Li W, Ma X, Ding N, Spallotta F, Southon E, et al. Essential role of the zinc finger transcription factor Casz1 for mammalian cardiac morphogenesis and development. J Biol Chem.

2014;289:29801–16. Article  CAS  Google Scholar  * Qiu XB, Qu XK, Li RG, Liu H, Xu YJ, Zhang M, et al. CASZ1 loss-of-function mutation contributes to familial dilated cardiomyopathy. Clin

Chem Lab Med. 2017;55:1417–25. Article  CAS  Google Scholar  * Kim B, Jung M, Moon KC. The Prognostic Significance of Protein Expression of CASZ1 in Clear Cell Renal Cell Carcinoma. Dis

Markers. 2019;2019:1342161. PubMed  PubMed Central  Google Scholar  * Johnsson A, Durand-Dubief M, Xue-Franzen Y, Ronnerblad M, Ekwall K, Wright A. HAT-HDAC interplay modulates global

histone H3K14 acetylation in gene-coding regions during stress. EMBO Rep. 2009;10:1009–14. Article  CAS  Google Scholar  * Kurdistani SK, Robyr D, Tavazoie S, Grunstein M. Genome-wide

binding map of the histone deacetylase Rpd3 in yeast. Nat Genet. 2002;31:248–54. Article  CAS  Google Scholar  * Peserico A, Simone C. Physical and functional HAT/HDAC interplay regulates

protein acetylation balance. J Biomed Biotechnol. 2011;2011:371832. Article  Google Scholar  * Shahbazian MD, Grunstein M. Functions of site-specific histone acetylation and deacetylation.

Annu Rev Biochem. 2007;76:75–100. Article  CAS  Google Scholar  * Wang Z, Zang C, Cui K, Schones DE, Barski A, Peng W, et al. Genome-wide mapping of HATs and HDACs reveals distinct functions

in active and inactive genes. Cell. 2009;138:1019–31. Article  CAS  Google Scholar  * Shang Y, Hu X, DiRenzo J, Lazar MA, Brown M. Cofactor dynamics and sufficiency in estrogen

receptor-regulated transcription. Cell. 2000;103:843–52. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We express our deep appreciation for all the help provided by Dr S

Kato. We would like to thank Editage (www.editage.com) for English language editing. This work was supported by JSPS KAKENHI grant number 17K09734 (to KY), the Keio Gijuku Academic

Development Funds (to KY and IK), the Japan Foundation for Applied Enzymology (to KY), the Smoking Research Foundation (to KY and IK), Eli Lilly (to KY), the Takeda Science Foundation (to

IK), and the Yamaguchi Endocrine Research Foundation (to IK). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

Kenichi Yokota, Isao Kurihara, Sakiko Kobayashi, Ayano Murai-Takeda & Hiroshi Itoh * Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita

University, Oita, Japan Hirotaka Shibata Authors * Kenichi Yokota View author publications You can also search for this author inPubMed Google Scholar * Hirotaka Shibata View author

publications You can also search for this author inPubMed Google Scholar * Isao Kurihara View author publications You can also search for this author inPubMed Google Scholar * Sakiko

Kobayashi View author publications You can also search for this author inPubMed Google Scholar * Ayano Murai-Takeda View author publications You can also search for this author inPubMed 

Google Scholar * Hiroshi Itoh View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Kenichi Yokota. ETHICS DECLARATIONS

CONFLICT OF INTEREST The authors declare that they have no conflict of interest. ETHICAL APPROVAL All animal procedures were approved by the institutional review board of the Animal Care and

Use Committee and were conducted in compliance with the animal experimentation guidelines of Keio University School of Medicine. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature

remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIGURE 1 SUPPLEMENTARY FIGURE 2 RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Yokota, K., Shibata, H., Kurihara, I. _et al._ CASZ1b is a novel transcriptional corepressor of mineralocorticoid

receptor. _Hypertens Res_ 44, 407–416 (2021). https://doi.org/10.1038/s41440-020-00562-5 Download citation * Received: 22 September 2020 * Revised: 28 September 2020 * Accepted: 29 September

2020 * Published: 19 October 2020 * Issue Date: April 2021 * DOI: https://doi.org/10.1038/s41440-020-00562-5 SHARE THIS ARTICLE Anyone you share the following link with will be able to read

this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative

KEYWORDS * Aldosterone * CASZ1b * Hypertension * Mineralocorticoid receptor