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 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-kappaB (NF-kappaB). The 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-Dawley (SD) rats (n=10), and (4) SD rats plus CsA (n=8). 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 850+/-15 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-kappaB transcriptional pathway. In contrast to dTGR, CsA increased blood pressure in normotensive SD rats by 10 mm Hg and had no effect on cardiac mass or 24-hour urinary albumin excretion. Perivascular monocyte/macrophage infiltration, IL-6, and iNOS expression or cell proliferation were not affected by CsA in SD rats. Our findings indicate that CsA protects against Ang II-induced end-organ damage and underscore the central role of vascular inflammatory response in the pathogenesis of myocardial and renal damage in dTGR. The beneficial effects of CsA in the kidney and heart are mediated, at least in part, by suppression of IL-6 and iNOS expression via NF-kappaB transcriptional pathway.
Mervaala
E
E
Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin, Germany.
Müller
D N
DN
Park
J K
JK
Dechend
R
R
Schmidt
F
F
Fiebeler
A
A
Bieringer
M
M
Breu
V
V
Ganten
D
D
Haller
H
H
Luft
F C
FC
D000419:Albuminuria / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D000804:Angiotensin II / Q000009:adverse effects*; D000808:Angiotensinogen / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure; D016572:Cyclosporine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D006977:Hypertension, Renal / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics; D007668:Kidney / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D008297:Male; D009000:Monocytes / Q000166:cytology; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D012083:Renin / Q000235:genetics*
D004791:Enzyme Inhibitors; D015850:Interleukin-6; D016328:NF-kappa B; D000808:Angiotensinogen; D000804:Angiotensin II; D009569:Nitric Oxide; D016572:Cyclosporine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D012083:Renin