title: Renin enhancer is critical for control of renin gene expression and cardiovascular function.
abstract: The important cardiovascular regulator renin contains a strong in vitro enhancer 2.7 kb upstream of its gene. Here we tested the in vivo role of the mouse Ren-1c enhancer. In renin-expressing As4.1 cells stably transfected with Ren-1c promoter with or without enhancer, expression of linked beta-geo reporter, stable expression, and colony formation were dependent on the presence of the enhancer. We then generated mice carrying a targeted deletion of the enhancer (REKO mice) and found marked depletion of renin in renal juxtaglomerular and submandibular ductal cells, as well as hyperplasia of macula densa cells. Plasma creatinine was increased, but electrolytes were normal. Male REKO mice implanted with telemetry devices had 9 +/- 1 mm Hg lower mean arterial pressure (p < 0.001), which was partly normalized by a high NaCl diet. Locomotor activity was lower, and baroreflex sensitivity was normal. Markedly reduced mean arterial pressure variability in the midfrequency band indicated a contribution of reduced sympathetic vasomotor tone to the hypotension. In conclusion, the renin enhancer is critical for renin gene expression and physiological sequelae, including response to alteration in salt intake. The REKO mouse may be useful as a low renin expression model.
authors.affiliation: School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Head
authors.forename: M Andrea
authors.initials: MA
authors.lastname: Markus
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Lovicu
authors.forename: Louise
authors.initials: L
authors.lastname: van der Weyden
authors.forename: Frank
authors.initials: F
authors.lastname: Köntgen
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
authors.forename: Sathia
authors.initials: S
authors.lastname: Thiru
authors.forename: Dmitry N
authors.initials: DN
authors.lastname: Mayorov
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Morris
mesh_terms: D000818:Animals; D002319:Cardiovascular System; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D012083:Renin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012492:Salts / Q000494:pharmacology; D013686:Telemetry; D014162:Transfection
chemical_list: D012492:Salts; D012083:Renin