Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats.
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.
Feldman
David L
DL
Novartis Institutes for Biomedical Research, Bldg 437, Rm 3317, One Health Plaza, E Hanover, NJ 07936, USA. david.feldman@novartis.com
Jin
Liang
L
Xuan
Hong
H
Contrepas
Aurelie
A
Zhou
Yinong
Y
Webb
Randy L
RL
Mueller
Dominik N
DN
Feldt
Sandra
S
Cumin
Frederick
F
Maniara
Wieslawa
W
Persohn
Elke
E
Schuetz
Helmut
H
Jan Danser
A H
AH
Nguyen
Genevieve
G
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
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