Aliskiren Inhibits Intracellular Angiotensin II Levels Without Affecting (Pro)renin Receptor Signals in Human Podocytes

• Published in: American journal of hypertension 2010-05, Vol.23 (5), p.575-580
• Main Authors: Sakoda, Mariyo, Ichihara, Atsuhiro, Kurauchi-Mito, Asako, Narita, Tatsuya, Kinouchi, Kenichiro, Murohashi-Bokuda, Kanako, Saleem, Moin A., Nishiyama, Akira, Suzuki, Fumiaki, Itoh, Hiroshi
• Format: Article
• Language: English
• Subjects: Amides - pharmacology; angiotensin; Angiotensin II - metabolism; Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Arterial hypertension. Arterial hypotension; Benzimidazoles - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; blood pressure; Cardiology. Vascular system; Cells, Cultured; Endocrine kidney. Renin-angiotensin-aldosterone system; Extracellular Signal-Regulated MAP Kinases - metabolism; extracellular signal–related protein kinase; Fumarates - pharmacology; Fundamental and applied biological sciences. Psychology; Humans; hypertension; Imidazolidines - pharmacology; Medical sciences; Phosphorylation - drug effects; Podocytes - cytology; Podocytes - drug effects; Podocytes - metabolism; prorenin; Receptors, Cell Surface - drug effects; Receptors, Cell Surface - physiology; Renin - antagonists & inhibitors; Renin - pharmacology; RNA, Messenger - metabolism; RNA, Small Interfering - pharmacology; Signal Transduction - drug effects; Signal Transduction - physiology; siRNA; Tetrazoles - pharmacology; Vertebrates: endocrinology
• ISSN: 0895-7061; 1941-7225; 1879-1905
• DOI: 10.1038/ajh.2009.273

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 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. 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.