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(Hypertension. 2008;52:130.)
© 2008 American Heart Association, Inc.

Original Articles

Effects of Aliskiren on Blood Pressure, Albuminuria, and (Pro)Renin Receptor Expression in Diabetic TG(mRen-2)27 Rats

David L. Feldman; Liang Jin; Hong Xuan; Aurelie Contrepas; Yinong Zhou; Randy L. Webb; Dominik N. Mueller; Sandra Feldt; Frederick Cumin; Wieslawa Maniara; Elke Persohn; Helmut Schuetz; A.H. Jan Danser; Genevieve Nguyen

From Novartis Institutes for Biomedical Research (D.L.F., L.J., H.X., Y.Z., R.L.W., F.C., W.M.), E. Hanover, NJ and Cambridge, Mass; Inserm Unit 833 (A.C., G.N.), Paris, France; Chaire de Médecine Expérimentale (A.C., G.N.), Collège de France, Paris, France; Max-Delbruck-Center (D.N.M., S.F.), Berlin-Buch, Germany; Novartis Pharma AG (E.P., H.S.), Basel, Switzerland; and the Department of Pharmacology (A.H.J.D.), Erasmus MC, Rotterdam, The Netherlands.

Correspondence to David L. Feldman, PhD, Novartis Institutes for Biomedical Research, Bldg 437, Rm 3317, One Health Plaza, E Hanover, NJ 07936. E-mail david.feldman{at}novartis.com

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-β 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 µmol/L to 10 µmol/L) did not inhibit binding of ¹²⁵I-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.

Key Words: aliskiren • renin inhibitor • TG(mRen-2)rat • diabetic nephropathy • (pro)renin receptor

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