Regulation of mouse-renin gene by apurinic/apyrimidinic-endonuclease 1 (APE1/Ref-1) via recruitment of histone deacetylase 1 corepressor complex

Shiladitya Sengupta, Ranajoy Chattopadhyay, Anil K. Mantha, Sankar Mitra, Kishor K. Bhakat

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Objectives: Apurinic/apyrimidinic-endonuclease 1 (APE1) heterozygous mice have chronically elevated blood pressure. Renin of the renin-angiotensin (ANG) system for blood pressure maintenance regulates production of ANG II, a vasoactive hormone. Renin expression and secretion from kidney juxtaglomerular cells are regulated by intracellular calcium. Our objective in this study is to investigate APE1's regulatory role in renin expression. Methods: Effect of APE1 on calcium-mediated modulation of renin expression was examined by real-time reverse transcriptase-PCR, Western analysis and renin promoter-dependent luciferase activity in APE1-knockdown, APE1-overexpressing or control mouse kidney As4.1 cells. Furthermore, coimmunoprecipitation and chromatin immunoprecipitation assays were utilized to examine the association of APE1 with histone deacetylase (HDAC)1 corepressor complex and their recruitment to renin enhancer. Finally, kidney renin mRNA level and plasma-renin activity were measured in wild-type and APE1-heterozygous mice. Results: Here we show that APE1 is involved in calcium-mediated repression of renin gene. Our results further indicate that APE1 is a component of HDAC1 corepressor complex bound to renin-enhancer region. Increase in intracellular calcium ion concentration enhances the association of APE1 with HDAC1 corepressor complex and their recruitment to the enhancer region. Furthermore, APE1's N-terminal region is critical for formation and recruitment of the enhancer-bound corepressor complex. Increased renin expression in kidneys and higher plasma-renin activity in APE1 heterozygous mice further supports APE1's corepressor role in vivo. Conclusion: This study uncovers APE1's function as a novel negative regulator of renin expression, and thereby in blood pressure maintenance.

Original languageEnglish (US)
Pages (from-to)917-925
Number of pages9
JournalJournal of Hypertension
Volume30
Issue number5
DOIs
StatePublished - May 1 2012
Externally publishedYes

Fingerprint

Histone Deacetylase 1
DNA-(Apurinic or Apyrimidinic Site) Lyase
Co-Repressor Proteins
Endonucleases
Renin
Genes
Calcium
Kidney
Blood Pressure
Maintenance
Chromatin Immunoprecipitation
Renin-Angiotensin System
Luciferases
Reverse Transcriptase Polymerase Chain Reaction

Keywords

  • apurinic/apyrimidinic-endonuclease 1 (APE1/Ref-1)
  • calcium
  • hypertension
  • renin
  • transcriptional repression

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Regulation of mouse-renin gene by apurinic/apyrimidinic-endonuclease 1 (APE1/Ref-1) via recruitment of histone deacetylase 1 corepressor complex. / Sengupta, Shiladitya; Chattopadhyay, Ranajoy; Mantha, Anil K.; Mitra, Sankar; Bhakat, Kishor K.

In: Journal of Hypertension, Vol. 30, No. 5, 01.05.2012, p. 917-925.

Research output: Contribution to journalArticle

Sengupta, Shiladitya ; Chattopadhyay, Ranajoy ; Mantha, Anil K. ; Mitra, Sankar ; Bhakat, Kishor K. / Regulation of mouse-renin gene by apurinic/apyrimidinic-endonuclease 1 (APE1/Ref-1) via recruitment of histone deacetylase 1 corepressor complex. In: Journal of Hypertension. 2012 ; Vol. 30, No. 5. pp. 917-925.
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AU - Chattopadhyay, Ranajoy

AU - Mantha, Anil K.

AU - Mitra, Sankar

AU - Bhakat, Kishor K.

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AB - Objectives: Apurinic/apyrimidinic-endonuclease 1 (APE1) heterozygous mice have chronically elevated blood pressure. Renin of the renin-angiotensin (ANG) system for blood pressure maintenance regulates production of ANG II, a vasoactive hormone. Renin expression and secretion from kidney juxtaglomerular cells are regulated by intracellular calcium. Our objective in this study is to investigate APE1's regulatory role in renin expression. Methods: Effect of APE1 on calcium-mediated modulation of renin expression was examined by real-time reverse transcriptase-PCR, Western analysis and renin promoter-dependent luciferase activity in APE1-knockdown, APE1-overexpressing or control mouse kidney As4.1 cells. Furthermore, coimmunoprecipitation and chromatin immunoprecipitation assays were utilized to examine the association of APE1 with histone deacetylase (HDAC)1 corepressor complex and their recruitment to renin enhancer. Finally, kidney renin mRNA level and plasma-renin activity were measured in wild-type and APE1-heterozygous mice. Results: Here we show that APE1 is involved in calcium-mediated repression of renin gene. Our results further indicate that APE1 is a component of HDAC1 corepressor complex bound to renin-enhancer region. Increase in intracellular calcium ion concentration enhances the association of APE1 with HDAC1 corepressor complex and their recruitment to the enhancer region. Furthermore, APE1's N-terminal region is critical for formation and recruitment of the enhancer-bound corepressor complex. Increased renin expression in kidneys and higher plasma-renin activity in APE1 heterozygous mice further supports APE1's corepressor role in vivo. Conclusion: This study uncovers APE1's function as a novel negative regulator of renin expression, and thereby in blood pressure maintenance.

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