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

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 ge nes. We tested the hypothesis that the immunosuppressive agent cyclosporine (CsA) protects against the Ang II-induced myocardial and renal damage in d TGR, Furthermore, we investigated the influence of CsA on interleukin-6 (IL -6) and inducible nitric oxide synthase (iNOS) expression and the DNA bindi ng activity of transcription factor necrosis factor-kappa B (NF-kappa B). T he 4-week-old rats were divided into 4 groups: (1) control dTGR (n=20), (2) dTGR plus CsA (5 mg/kg SC for 3 weeks, n=15), (3) normotensive Sprague-Daw ley (SD) rats (n=10), and (4) SD rats plus CsA (n=8). In dTGR, CsA complete ly prevented cardiovascular death (0 of 15 versus 9 of 20), decreased 24-ho ur albuminuria by 90% and systolic blood pressure by 35 mm Hg, and protecte d against the development of cardiac hypertrophy. Whole blood CsA concentra tions 24 hours after the last drug treatment were 850+/-15 ng/mL. Semiquant itative ED-I and Ki-67 (a nuclear cell proliferation-associated antigen) sc oring showed that CsA prevented perivascular monocyte/macrophage infiltrati on and prevented cell proliferation in the kidneys and hearts of dTGR, resp ectively. The beneficial effects of CsA were, at least in part, mediated by the suppression of IL-6 and iNOS expression. Electrophoretic mobility shif t assay revealed that CsA regulated inflammatory response in part through t he NF-kappa B transcriptional pathway. In contrast to dTGR, CsA increased b lood pressure in normotensive SD rats by 10 mm Hg and had no effect on card iac mass or 24-hour urinary albumin excretion. Perivascular monocyte/macrop hage infiltration, IL-6, and iNOS expression or cell proliferation were not affected by CsA in SD rats. Our findings indicate that CsA protects agains t Ang II-induced end-organ damage and underscore the central role of vascul ar inflammatory response in the pathogenesis of myocardial and renal damage in dTGR. The beneficial effects of CsA in the kidney and heart are mediate d, at least in part, by suppression of IL-6 and iNOS expression via NF-kapp a B transcriptional pathway.