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

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Abstract

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.MethodsHuman podocytes were treated with 2nmol\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.ResultsThe 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.ConclusionsAliskiren 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)575-580
Number of pages6
JournalAmerican Journal of Hypertension
Volume23
Issue number5
DOIs
Publication statusPublished - 2010 May

Fingerprint

Podocytes
Angiotensins
Renin
imidaprilat
Small Interfering RNA
Renin-Angiotensin System
Glomerular Filtration Barrier
Phosphorylation
Angiotensin II Type 1 Receptor Blockers
Messenger RNA
Angiotensin Receptors
Albuminuria
Peptide Receptors
Therapeutics
aliskiren
Angiotensin-Converting Enzyme Inhibitors
Protein Kinases

Keywords

  • Angiotensin
  • Blood pressure
  • Extracellular signal-related protein kinase
  • Hypertension
  • Prorenin
  • SiRNA

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Aliskiren inhibits intracellular angiotensin ii levels without affecting (Pro)renin Receptor Signals in Human Podocytes. / Sakoda, Mariyo; Ichihara, Atsuhiro; Kurauchi-Mito, Asako; Narita, Tatsuya; Kinouchi, Kenichiro; Murohashi-Bokuda, Kanako; Saleem, Moin A.; Nishiyama, Akira; Suzuki, Fumiaki; Itoh, Hiroshi.

In: American Journal of Hypertension, Vol. 23, No. 5, 05.2010, p. 575-580.

Research output: Contribution to journalArticle

Sakoda, M, Ichihara, A, Kurauchi-Mito, A, Narita, T, Kinouchi, K, Murohashi-Bokuda, K, Saleem, MA, Nishiyama, A, Suzuki, F & Itoh, H 2010, 'Aliskiren inhibits intracellular angiotensin ii levels without affecting (Pro)renin Receptor Signals in Human Podocytes', American Journal of Hypertension, vol. 23, no. 5, pp. 575-580. https://doi.org/10.1038/ajh.2009.273
Sakoda, Mariyo ; Ichihara, Atsuhiro ; Kurauchi-Mito, Asako ; Narita, Tatsuya ; Kinouchi, Kenichiro ; Murohashi-Bokuda, Kanako ; Saleem, Moin A. ; Nishiyama, Akira ; Suzuki, Fumiaki ; Itoh, Hiroshi. / Aliskiren inhibits intracellular angiotensin ii levels without affecting (Pro)renin Receptor Signals in Human Podocytes. In: American Journal of Hypertension. 2010 ; Vol. 23, No. 5. pp. 575-580.
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abstract = "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.MethodsHuman podocytes were treated with 2nmol\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.ResultsThe 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.ConclusionsAliskiren 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.",
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AU - Narita, Tatsuya

AU - Kinouchi, Kenichiro

AU - Murohashi-Bokuda, Kanako

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