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A single nucleotide mutation in the mouse renin promoter disrupts blood pressure regulation
Keiji Tanimoto, … , Kazuyuki Yanai, Akiyoshi Fukamizu
Keiji Tanimoto, … , Kazuyuki Yanai, Akiyoshi Fukamizu
Published February 7, 2008
Citation Information: J Clin Invest. 2008;118(3):1006-1016. https://doi.org/10.1172/JCI33824.
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Research Article Nephrology

A single nucleotide mutation in the mouse renin promoter disrupts blood pressure regulation

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Abstract

Renin, a major regulatory component of the renin-angiotensin system, plays a pivotal role in regulating blood pressure and electrolyte homeostasis and is predominantly expressed in the kidney. Several cAMP-responsive elements have been identified within renin gene promoters. Here, we study how 2 such elements, renin proximal promoter element-2 (RP-2) and overlapping cAMP and negative regulatory elements (CNRE), affect the transcriptional regulation of renin. We generated Tg mice (TgM) bearing BACs containing either WT or mutant RP-2 or CNRE, integrated at single chromosomal loci. Analysis of the TgM revealed that RP-2 was essential to basal promoter activity in the kidney, while renin mRNA levels did not significantly change in any tissues tested in the CNRE mutant TgM. To evaluate the physiological significance of these mutations, we used the BAC Tg to rescue hypotensive Renin-null mutant mice. As predicted, no renin expression was observed in the kidneys of RP-2 mutant/Renin-null compound mice, whereas renin expression in CNRE mutant compound mice was indistinguishable from that in control mice. Consistent with this, RP-2 mutant animals were hypotensive, while CNRE mutants had normal blood pressure. Thus, transcriptional regulation of renin expression via RP-2 but not CNRE is critical for blood pressure regulation by this gene.

Authors

Keiji Tanimoto, Akiko Sugiura, Sumiyo Kanafusa, Tomoko Saito, Naoto Masui, Kazuyuki Yanai, Akiyoshi Fukamizu

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Figure 4

Effects of physiologic stimuli on renin gene expression in WT and TgM.

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Effects of physiologic stimuli on renin gene expression in WT and TgM.
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(A) Renin mRNA expression in the WT CNRE and mut CNRE TgM treated with high-sodium diet (HS) or dehydration (DH). Two groups of male TgM (8-week-old) were fed high-sodium (8%) or normal-sodium (0.6%; C for control) diets for 5 days. In another group, access to drinking water was restricted for 1 day (DH). RNA was isolated from the kidney and analyzed by semiquantitative RT-PCR using 2 sets of primer pairs, one coamplifying Tg Ren-1C (Tg) and endogenous Ren-2 and Ren-1D (endo.) genes and another specific for the Gapdh gene (top). Relative amount of renin mRNA after normalization to that of Gapdh was determined by 3 independent RT-PCR for 3 individuals in each group (bottom). Expression value of untreated control animals in each group was arbitrarily set at 100. (B and C) Renin mRNA expression in the TgM treated with or without captopril. Six pairs each of WT and mut TgM (8-week-old) were used in the study. One group was treated for 7 days with captopril dissolved in drinking water (0.5 mg/ml). Kidneys were isolated, and RNA was analyzed as described in A. Lines in B and C indicate that lanes were run on the same gel but were noncontiguous. *P < 0.05; **P < 0.01.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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