title: Regulation of mouse-renin gene by apurinic/apyrimidinic-endonuclease 1 (APE1/Ref-1) via recruitment of histone deacetylase 1 corepressor complex.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  This study uncovers APE1's function as a novel negative regulator of renin expression, and thereby in blood pressure maintenance.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-1079, USA.
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Sengupta
authors.forename: Ranajoy
authors.initials: R
authors.lastname: Chattopadhyay
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mantha
authors.forename: Sankar
authors.initials: S
authors.lastname: Mitra
authors.forename: Kishor K
authors.initials: KK
authors.lastname: Bhakat
mesh_terms: D000818:Animals; D002843:Chromatin / Q000378:metabolism; D056970:Co-Repressor Proteins / Q000378:metabolism*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D005786:Gene Expression Regulation; D006579:Heterozygote; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D006973:Hypertension / Q000628:therapy; D047468:Immunoprecipitation; D007668:Kidney / Q000166:cytology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012083:Renin / Q000096:biosynthesis* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
chemical_list: D002843:Chromatin; D056970:Co-Repressor Proteins; D034741:RNA, Small Interfering; D008156:Luciferases; D012083:Renin; D056284:Histone Deacetylase 1; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase