Published online before print August 18, 2005, doi: 10.1161/01.RES.0000182677.89816.38
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Submitted on April 26, 2005
Revised on July 7, 2005
Accepted on August 10, 2005
Complement Activation in Angiotensin II-Induced Organ Damage
Erdenechimeg Shagdarsuren ;
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.
* To whom correspondence should be addressed. 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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