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

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

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    16 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)1006-1016
    Number of pages11
    JournalJournal of Clinical Investigation
    Volume118
    Issue number3
    DOIs
    Publication statusPublished - Mar 2008

    All Science Journal Classification (ASJC) codes

    • Medicine(all)

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