title: Aliskiren inhibits intracellular angiotensin II levels without affecting (pro)renin receptor signals in human podocytes.
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.
authors.affiliation: Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Mariyo
authors.initials: M
authors.lastname: Sakoda
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Ichihara
authors.forename: Asako
authors.initials: A
authors.lastname: Kurauchi-Mito
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Narita
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kinouchi
authors.forename: Kanako
authors.initials: K
authors.lastname: Murohashi-Bokuda
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Suzuki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D048289:Imidazolidines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D050199:Podocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000502:physiology; D012083:Renin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D000093342:Prorenin Receptor; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D048049:Extracellular Signal-Regulated MAP Kinases; D005650:Fumarates; D048289:Imidazolidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D012083:Renin; D013777:Tetrazoles; D000093342:Prorenin Receptor; D000092502:Renin Inhibitors; C446481:aliskiren; C081643:candesartan; C078006:imidaprilat