Complement activation in angiotensin II-induced organ damage.
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)-alpha, 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-alpha, 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-alpha 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-alpha 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-alpha and CRP may play a role in its induction.
Shagdarsuren
Erdenechimeg
E
Medical Faculty of the Charité, Franz Volhard Clinic, and HELIOS Klinikum-Berlin, Germany.
Wellner
Maren
M
Braesen
Jan-Hinrich
JH
Park
Joon-Keun
JK
Fiebeler
Anette
A
Henke
Norbert
N
Dechend
Ralf
R
Gratze
Petra
P
Luft
Friedrich C
FC
Muller
Dominik N
DN
D000419:Albuminuria / Q000209:etiology; D000804:Angiotensin II / Q000633:toxicity*; D000808:Angiotensinogen / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure; D002097:C-Reactive Protein / Q000032:analysis / Q000502:physiology; D003167:Complement Activation; D003176:Complement C3 / Q000235:genetics; D015938:Complement Membrane Attack Complex / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D003176:Complement C3; D015938:Complement Membrane Attack Complex; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000808:Angiotensinogen; D000804:Angiotensin II; D002097:C-Reactive Protein; D012083:Renin