Complement activation in angiotensin II-induced organ damage

Circ Res. 2005 Sep 30;97(7):716-24. doi: 10.1161/01.RES.0000182677.89816.38. Epub 2005 Aug 18.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / etiology
  • Angiotensin II / toxicity*
  • Angiotensinogen / physiology
  • Animals
  • Animals, Genetically Modified
  • Blood Pressure
  • C-Reactive Protein / analysis
  • C-Reactive Protein / physiology
  • Complement Activation*
  • Complement C3 / genetics
  • Complement Membrane Attack Complex / physiology
  • Humans
  • Interleukin-6 / biosynthesis
  • Kidney / drug effects*
  • Kidney / pathology
  • Male
  • Muscle, Smooth, Vascular / metabolism
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Renin / physiology
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Complement C3
  • Complement Membrane Attack Complex
  • Interleukin-6
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Angiotensinogen
  • Angiotensin II
  • C-Reactive Protein
  • Renin