title: Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats.
abstract: The aim of this study was to explore the effects of the renin inhibitor aliskiren in streptozotocin-diabetic TG(mRen-2)27 rats. Furthermore, we investigated in vitro the effect of aliskiren on the interactions between renin and the (pro)renin receptor and between aliskiren and prorenin. Aliskiren distributed extensively to the kidneys of normotensive (non)diabetic rats, localizing in the glomeruli and vessel walls after 2 hours exposure. In diabetic TG(mRen-2)27 rats, aliskiren (10 or 30 mg/kg per day, 10 weeks) lowered blood pressure, prevented albuminuria, and suppressed renal transforming growth factor-beta and collagen I expression versus vehicle. Aliskiren reduced (pro)renin receptor expression in glomeruli, tubules, and cortical vessels compared to vehicle (in situ hybridization). In human mesangial cells, aliskiren (0.1 micromol/L to 10 micromol/L) did not inhibit binding of (125)I-renin to the (pro)renin receptor, nor did it alter the activation of extracellular signal-regulated kinase 1/2 by renin (20 nmol/L) preincubated with aliskiren (100 nmol/L) or affect gene expression of the (pro)renin receptor. Evidence was obtained that aliskiren binds to the active site of prorenin. The above results demonstrate the antihypertensive and renoprotective effects of aliskiren in experimental diabetic nephropathy. The evidence that aliskiren can reduce in vivo gene expression for the (pro)renin receptor and that it may block prorenin-induced angiotensin generation supports the need for additional work to reveal the mechanism of the observed renoprotection by this renin inhibitor.
authors.affiliation: Novartis Institutes for Biomedical Research, Bldg 437, Rm 3317, One Health Plaza, E Hanover, NJ 07936, USA. david.feldman@novartis.com
authors.forename: David L
authors.initials: DL
authors.lastname: Feldman
authors.forename: Liang
authors.initials: L
authors.lastname: Jin
authors.forename: Hong
authors.initials: H
authors.lastname: Xuan
authors.forename: Aurelie
authors.initials: A
authors.lastname: Contrepas
authors.forename: Yinong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Randy L
authors.initials: RL
authors.lastname: Webb
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Mueller
authors.forename: Sandra
authors.initials: S
authors.lastname: Feldt
authors.forename: Frederick
authors.initials: F
authors.lastname: Cumin
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Maniara
authors.forename: Elke
authors.initials: E
authors.lastname: Persohn
authors.forename: Helmut
authors.initials: H
authors.lastname: Schuetz
authors.forename: A H
authors.initials: AH
authors.lastname: Jan Danser
authors.forename: Genevieve
authors.initials: G
authors.lastname: Nguyen
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D000577:Amides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D005650:Fumarates / Q000493:pharmacokinetics / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012083:Renin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000093342:Prorenin Receptor; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; D024042:Collagen Type I; D024061:Collagen Type III; D024141:Collagen Type IV; D005650:Fumarates; D011956:Receptors, Cell Surface; D012083:Renin; D016212:Transforming Growth Factor beta; D000093342:Prorenin Receptor; D000092502:Renin Inhibitors; C446481:aliskiren