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INFLAMMATION AND IMMUNOPHARMACOLOGY

Angiotensin Inhibition Reduces Glomerular Damage and Renal Chemokine Expression in MRL/lpr Mice

Medizinische Poliklinik der Ludwig-Maximilians-Universität, München, Germany (G.P.d.L., C.D.C., B.L., A.B.V., D.S.); Physiologisches Institut der Ludwig-Maximilians-Universität, München, Germany (C.d.W.); Hospital Universitario "Ramón y Cajal", Universidad de Alcalá, Madrid, Spain (E.N., A.M., F.M.); and Klinik und Poliklinik für Innere Medizin II, Klinikum der Universität Regensburg, Germany (B.B.).

Beneficial effects of angiotensin II inhibition during inflammatory renal disease may involve both hemodynamic and nonhemodynamic mechanisms. To analyze whether angiotensin II inhibition has protective effects on lupus-like, autoimmune-mediated renal damage in MRL/lpr mice, four groups of mice were treated orally for 6 weeks with: 1) vehicle, 2) enalapril (3.0 mg/kg per day), 3) candesartan cilexetil (5.0 mg/kg), or 4) amlodipine (10 mg/kg) as a blood pressure control (n = 9–12/group). All antihypertensive treatments lowered blood pressure to a similar level compared with vehicle group (enalapril: 99.8 ± 8.3 mm Hg; candesartan: 101 ± 9 mm Hg; amlodipine: 103.8 ± 6.7 mm Hg; vehicle: 113.5 ± 4.6 mm Hg). Vehicle-treated mice developed a moderate glomerular injury with albuminuria (35.1 ± 39.0 µg/mg of creatinine). Glomerular lesions consisted of immune complex deposition and mesangial expansion with increased mesangial cell proliferation. Amlodipine treatment had no significant protective effects. In contrast to vehicle- and amlodipine-treated mice, those subjected to angiotensin II blockade with enalapril or candesartan had reduced albuminuria, glomerular expansion, and mesangial proliferation. This was associated with significantly reduced renal chemokine mRNA expression compared with vehicle treatment. Our results show that inhibition of angiotensin II has protective effects on the glomerular damage of MRL/lpr mice that extend beyond hemodynamics and involve down-modulation of glomerular inflammation, reduction of mesangial cell proliferation, and decrease in chemokine expression.

Address correspondence to: Prof. Dr. Detlef Schlöndorff, Medizinische Poliklinik der LMU, Pettenkoferstraße 8a, D-80336 München, Germany. E-mail: sdorff{at}pk-i.med.uni-muenchen.de

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