Aliskiren inhibits intracellular angiotensin II levels without affecting (pro)renin receptor signals in human podocytes

Mariyo Sakoda, Atsuhiro Ichihara, Asako Kurauchi-Mito, Tatsuya Narita, Kenichiro Kinouchi, Kanako Murohashi-Bokuda, Moin A Saleem, Akira Nishiyama, Fumiaki Suzuki, Hiroshi Itoh

    Research output: Contribution to journalArticle (Academic Journal)peer-review

    56 Citations (Scopus)

    Abstract

    BACKGROUND: A direct renin inhibitor (DRI) had a benefit in decreasing albuminuria in type 2 diabetic patients having already been treated with angiotensin (Ang) II type 1 receptor blocker (ARB), suggesting that aliskiren may have another effect other than blockade of the traditional renin-angiotensin system (RAS). Recently, prorenin bound to (pro)renin receptor ((P)RR) was found and shown to evoke two pathways; the generation of Ang peptides and the receptor-dependent activation of extracellular signal-related protein kinase (ERK). Because (P)RR is present in the podocytes, a central component of the glomerular filtration barrier, we hypothesized that aliskiren influences the (P)RR-induced two pathways in human podocytes.

    METHODS: Human podocytes were treated with 2 nmol/l prorenin in the presence and absence of an angiotensin-converting enzyme inhibitor (ACEi) imidaprilat, an ARB candesartan, a DRI aliskiren, or the siRNA knocking down the (P)RR mRNA and the intracellular AngII levels and the phosphorylation of ERK were determined.

    RESULTS: The expression of (P)RR mRNA of human podocytes was unaffected by the treatment with RAS inhibitors, but decreased by 69% with the siRNA treatment. The basal levels of intracellular AngII and the prorenin-induced increase in intracellular AngII were significantly reduced by aliskiren and siRNA treatment, compared with imidaprilat and candesartan. The prorenin-induced ERK activation was reduced to control level by the siRNA treatment, but it was unaffected by imidaprilat, candesartan, or aliskiren.

    CONCLUSIONS: Aliskiren is the most potent inhibitor of intracellular AngII levels of human podocytes among RAS inhibitors, although it is incapable of inhibiting the (P)RR-dependent ERK phosphorylation.

    Original languageEnglish
    Pages (from-to)575-80
    Number of pages6
    JournalAmerican Journal of Hypertension
    Volume23
    Issue number5
    DOIs
    Publication statusPublished - May 2010

    Keywords

    • Amides
    • Angiotensin II
    • Angiotensin II Type 1 Receptor Blockers
    • Angiotensin-Converting Enzyme Inhibitors
    • Benzimidazoles
    • Cells, Cultured
    • Extracellular Signal-Regulated MAP Kinases
    • Fumarates
    • Humans
    • Imidazolidines
    • Phosphorylation
    • Podocytes
    • RNA, Messenger
    • RNA, Small Interfering
    • Receptors, Cell Surface
    • Renin
    • Signal Transduction
    • Tetrazoles

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