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(Circulation Research. 2005;97:716.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Complement Activation in Angiotensin II–Induced Organ Damage

Erdenechimeg Shagdarsuren^*, Maren Wellner^*, Jan-Hinrich Braesen, Joon-Keun Park, Anette Fiebeler, Norbert Henke, Ralf Dechend, Petra Gratze, Friedrich C. Luft, Dominik N. Muller

From the Medical Faculty of the Charité (E.S., J.-H.B., A.F., N.H., R.D., F.C.L., D.N.M.), Franz Volhard Clinic, and HELIOS Klinikum-Berlin; Max Delbrück Center for Molecular Medicine (M.W., P.G., F.C.L., D.N.M.), Berlin-Buch, Germany; and Medical School of Hannover (J.-K.P.), Hannover, Germany.

Correspondence to Dominik N. Muller, Max Delbrück Center and Franz Volhard Clinic, Wiltberg Strasse 50, 13125 Berlin, Germany. E-mail mueller{at}fvk-berlin.de

We tested whether or not complement activation participates in angiotensin (Ang) II–induced vasculopathy. We used double transgenic rats harboring human renin and angiotensinogen genes (dTGR) with or without losartan or the human renin inhibitor aliskiren. Sprague–Dawley (SD) rats were controls. DTGR had increased blood pressure at week 5 that increased further by week 7. Albuminuria was absent at week 5 but increased markedly in weeks 6 and 7. C-reactive protein (CRP) elevation, macrophages, T cells, tumor necrosis factor (TNF)-, C1q, C3, C3c, and C5b-9 expression preceded albuminuria. C1q, C3, C3c, and C5b-9 were observed in the dTGR vessel media. C5b-9 colocalized with interleukin (IL)-6. Losartan and aliskiren reduced albuminuria and complement expression. We also studied vascular smooth muscle cells (VSMC) from dTGR compared VSMC from SD. C3 and IL-6 mRNA were analyzed after Ang II, TNF-, and CRP stimulation. VSMC from dTGR showed increased proliferation and C3 expression compared with SD. Ang II did not induce C3 mRNA in either VSMC type. However, TNF- and CRP induced C3 mRNA slightly in SD VSMC but markedly in dTGR VSMC, whereas IL-6 induction was similar in both. Thus, complement activation and cell infiltration occurred before the onset of albuminuria in Ang II–mediated renal damage. TNF- and CRP played a major role in C3 activation. VSMC from dTGR are more sensitive for C3 activation. Our data show that, in this Ang II–induced model, complement activation is a major participant and suggest that TNF- and CRP may play a role in its induction.

Key Words: angiotensin II • complement • immune system • albuminuria and renal damage

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