Complement Activation in Angiotensin II–Induced Organ Damage

Abstract

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)-␣, 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 Ⅲ complement Ⅲ immune system Ⅲ albuminuria and renal damage T he innate complement system eliminates invading pathogens, stimulates opsonization, enhances phagocytosis, cytolysis, chemotaxis, and solubilizes immune complexes. Complement forms a bridge between innate and acquired immunity. 1,2 On excessive activation or inappropriate deposition, complement can cause disease. 3 The classical alternative and lectin complement pathway merge at the level of C3, resulting in the generation of C5b-9, the membrane attack complex. Complement activation has been implicated in the pathogenesis of numerous proteinuric renal diseases including glomerulonephritis, transplant rejection, and ischemiareperfusion injury. [3][4][5][6][7] Pratt et al demonstrated that the absence of local C3 production modulates renal graft survival and regulates T-cell priming of donor antigens. 4 Very recently, Lin et al reported that young spontaneous hypertensive rats (SHR) that have not yet developed hypertension showed increased C3 expression and increased vascular smooth muscle cell (VSMC) proliferation. Both were blocked by C3 downregulation. 8 Several studies showed that angiotensin (Ang) II not only is a vasoconstrictor peptide but also promotes inflammation and renal damage. We showed recently that immunosuppression improved nonimmune Ang II-mediated renal damage. 9 The evidence that Ang II affects the complement system is indirect. Abbate et al demons...

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

“…Moreover, Ang I-forming capacity of the sera from these rats was also significantly reduced. A subsequent report by this group 72 showed that treatment with aliskiren inhibited complement activation and cellular infiltration in kidneys of dTGR. These studies showed the efficacy of aliskiren in high Ang II-induced renal injury and suggested a beneficial effect of the drug in complement-dependent renal disease.…”

“…In both the above studies, 71,72 AT 1 receptor blockers were included as positive controls; they were not intended to be comparator agents. These drugs were administered at different dosages and by different routes of administration than aliskiren.…”

“…Inhibition of Ang II formation on cell surface (116) Persistent tissue RAAS blockade (91) Long renal residence time (90) • Decreased (P)RR synthesis • No activation of prorenin when it binds to (P)RR (116) • No gain in catalytic activity when renin binds to (P)RR Renal protection (71,72,75,86,87,88) Incorporates into renin granules (101) (Pro)renin secreted as inhibited enzyme (101) Efficient renin inhibition (101) No chance to cleave Aogen Inhibition of Ang II formation (71) In tissue & plasma Glomerular localization (87) Inhibition of mesangial, podocyte (25) RAAS JG cells ( * ) Figure 3 In this working model of the renoprotective actions of aliskiren, outcomes for which in vitro or in vivo evidence exists are referenced (see References); no reference indicates a logical, but still speculative outcome. Solid arrows indicate the existence of in vitro or in vivo evidence to support a causal link between the events.…”

Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

“…On the other hand, the RAAS can modulate the activation of complement system in both atherosclerosis and renal injury [53].…”

C-Reactive Protein and Asymmetric Dimethylarginine: Markers or Mediators in Cardiovascular Disorders?

“…Anti-TNFtherapy (Infliximab) has been demonstrated to lower both serum CRP and IL-6 levels in patients with a systemic inflammatory response [174]. Modification of the renin-angiotensin system may also reduce concentrations of both CRP and complement [175].…”