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Cyclosporin A protects against angiotensin II-induced end-organ damage in double transgenic rats harboring human renin and angiotensinogen genes. Hypertension 35

By Eero Mervaala, Dominik N. Müller, Joon-keun Park, Ralph Dechend, Folke Schmidt, Anette Fiebeler, Markus Bieringer, Volker Breu, Detlev Ganten, Hermann Haller and Friedrich C. Luft


Abstract—Leukocyte infiltration and adhesion molecule activation play a central role in the pathogenesis of angiotensin II (Ang II)–induced end-organ damage in double transgenic rats (dTGR) harboring human renin and angiotensinogen genes. We tested the hypothesis that the immunosuppressive agent cyclosporine (CsA) protects against the Ang II–induced myocardial and renal damage in dTGR. Furthermore, we investigated the influence of CsA on interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS) expression and the DNA binding activity of transcription factor necrosis factor-kB (NF-kB). The 4-week-old rats were divided into 4 groups: (1) control dTGR (n520), (2) dTGR plus CsA (5 mg/kg SC for 3 weeks, n515), (3) normotensive Sprague-Dawley (SD) rats (n510), and (4) SD rats plus CsA (n58). In dTGR, CsA completely prevented cardiovascular death (0 of 15 versus 9 of 20), decreased 24-hour albuminuria by 90 % and systolic blood pressure by 35 mm Hg, and protected against the development of cardiac hypertrophy. Whole blood CsA concentrations 24 hours after the last drug treatment were 850615 ng/mL. Semiquantitative ED-1 and Ki-67 (a nuclear cell proliferation–associated antigen) scoring showed that CsA prevented perivascular monocyte/macrophage infiltration and prevented cell proliferation in the kidneys and hearts of dTGR, respectively. The beneficial effects of CsA were, at least in part, mediated by the suppression of IL-6 and iNOS expression. Electrophoretic mobility shift assay revealed that CsA regulated inflammatory response in part through the NF-kB transcriptional pathway. In contrast to dTGR, CsA increased blood pressure in normotensive SD rats b

Year: 2000
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