Aliskiren Inhibits Intracellular Angiotensin II Levels Without Affecting (Pro)renin Receptor Signals in Human Podocytes
| Autor: | Akira Nishiyama, Asako Kurauchi-Mito, Kanako Murohashi-Bokuda, Atsuhiro Ichihara, Mariyo Sakoda, Fumiaki Suzuki, Tatsuya Narita, Hiroshi Itoh, Kenichiro Kinouchi, Moin A. Saleem |
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| Rok vydání: | 2010 |
| Předmět: |
MAPK/ERK pathway
medicine.medical_specialty Tetrazoles Angiotensin-Converting Enzyme Inhibitors Receptors Cell Surface Imidazolidines chemistry.chemical_compound Fumarates Internal medicine Renin Renin–angiotensin system Internal Medicine medicine Humans RNA Messenger Prorenin Receptor Phosphorylation RNA Small Interfering Extracellular Signal-Regulated MAP Kinases Receptor Cells Cultured biology Podocytes business.industry Angiotensin II Biphenyl Compounds Aliskiren Amides Candesartan Endocrinology chemistry Enzyme inhibitor biology.protein Benzimidazoles business Angiotensin II Type 1 Receptor Blockers Intracellular Signal Transduction medicine.drug |
| Zdroj: | American Journal of Hypertension. 23:575-580 |
| ISSN: | 1941-7225 0895-7061 |
| DOI: | 10.1038/ajh.2009.273 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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