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J. Biol. Chem., Vol. 281, Issue 42, 31753-31761, October 20, 2006

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Renin Enhancer Is Critical for Control of Renin Gene Expression and Cardiovascular Function^*

David J. Adams¹², Geoffrey A. Head¹, M. Andrea Markus, Frank J. Lovicu, Louise van der Weyden², Frank Köntgen^¶, Mark J. Arends^||, Sathia Thiru^||, Dmitry N. Mayorov, and Brian J. Morris³

From the School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia, Baker Heart Research Institute, Melbourne, Victoria 8008, Australia, ^¶Ozgene Pty. Ltd., Perth 6102, Western Australia, and the ^||Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom

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-1^c enhancer. In renin-expressing As4.1 cells stably transfected with Ren-1^c promoter with or without enhancer, expression of linked -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.

Received for publication, June 15, 2006 , and in revised form, August 3, 2006.

^* This work was supported by Australian Research Council Grants A10009169 (to B. J. M. and David I. K. Martin) and DP0664650 (to B. J. M. and Peter J. Leedman) and National Health and Medical Research Council of Australia Grant 225118 (to G. A. H. and D. N. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These two authors contributed equally to this work.

² Present address: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambs, CB10 1SA, United Kingdom.

³ To whom correspondence should be addressed: Basic & Clinical Genomics Laboratory, School of Medical Sciences and Bosch Inst., Bldg. F13, University of Sydney, New South Wales 2006, Australia. Tel.: 61-2-93513688; Fax: 61-2-93512227; E-mail: brianm{at}medsci.usyd.edu.au.

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