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(Hypertension. 2007;49:467.)
© 2007 American Heart Association, Inc.

Original Articles

Functional Polymorphism of the Anpep Gene Increases Promoter Activity in the Dahl Salt-Resistant Rat

Kumar Kotlo; Douglas E. Hughes; Victoria L.M. Herrera; Nelson Ruiz-Opazo; Robert H. Costa; R. Brooks Robey; Robert S. Danziger

From the Departments of Medicine (K.K., R.S.D.), Biochemistry and Molecular Genetics (D.E.H., R.H.C.), Physiology and Biophysics (R.S.D.), and Pharmacology (R.S.D.), University of Illinois at Chicago; Jesse Brown Veterans Affairs Medical Center (K.K., R.S.D.), Chicago, Ill; the Department of Medicine (V.L.M.H., N.R.-O.), Boston University School of Medicine, Mass; White River Junction Veterans Affairs Medical Center (R.B.R.), White River Junction, Vt; and the Departments of Medicine and Physiology (R.B.R.), Dartmouth Medical School, Lebanon, NH.

Correspondence to Robert S. Danziger, Department of Medicine, University of Illinois at Chicago, 840 S Wood St, Chicago, IL 60612. E-mail RDanziger{at}aol.com

We have reported that aminopeptidase N/CD13, which metabolizes angiotensin III to angiotensin IV, exhibits greater renal tubular expression in the Dahl salt-resistant (SR/Jr) rat than its salt-sensitive (SS/Jr) counterpart. In this work, aminopeptidase N (Anpep) genes from SS/Jr and SR/Jr strains were compared. The coding regions contained only silent single nucleotide polymorphisms between strains. The 5' flanking regions also contained multiple single nucleotide polymorphisms, which were analyzed by electrophoretic mobility-shift assay using renal epithelial cell (HK-2) nuclear extracts and oligonucleotides corresponding with single nucleotide polymorphism–containing regions. A unique single nucleotide polymorphism 4 nucleotides upstream of a putative CCAAT/enhancer binding protein motif (nucleotides –2256 to –2267) in the 5' flanking region of the SR/Jr Anpep gene was associated with DNA-protein complex formation, whereas the corresponding sequences in SS rats were not. A chimeric reporter gene containing 4.4 Kb of Anpep 5' flank from the Dahl SR/Jr rat exhibited 2.5- to 3-fold greater expression in HK-2 cells than the corresponding construct derived from the SS strain (P<0.05). Replacing the CCAAT/enhancer binding protein cis-acting element from the SS rat with that from the SR strain increased reporter gene expression by 2.5-fold (P<0.05) and abolished this difference. CCAAT/enhancer binding protein association was confirmed by chromatin immunoprecipitation and correlated with expression, suggesting selection for a functional CCAAT/enhancer binding protein polymorphism in the 5' flank of Anpep in the Dahl SR/Jr rat. These results highlight a possible association of the Anpep gene with hypertension in Dahl rat and raise the prospect that increased Anpep may play a mechanistic role in adaptation to high salt.

Key Words: CD13 • renal salt-handling • Dahl rat • salt-sensitive hypertension • polymorphism

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