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Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mREN-2)27 rats

Authors

  • D.L. Feldman
  • L. Jin
  • H. Xuan
  • A. Contrepas
  • Y. Zhou
  • R.L. Webb
  • D.N. Mueller
  • S. Feldt
  • F. Cumin
  • W. Maniara
  • E. Persohn
  • H. Schuetz
  • A.H. Jan Danser
  • G. Nguyen

Journal

  • Hypertension

Citation

  • Hypertension 52 (1): 130-136

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 two hours exposure. In diabetic TG(mRen-2)27 rats, aliskiren (10 or 30 mg/kg/d, 10 weeks) lowered blood pressure, prevented albuminuria, and suppressed renal transforming growth factor (TGF)-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 (ERK) 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.


DOI

doi:10.1161/HYPERTENSIONAHA.107.108845