Classical Complement Pathway Activation in the Kidneys of Women With Preeclampsia

Abstract

A growing body of evidence suggests that complement dysregulation plays a role in the pathogenesis of preeclampsia. The kidney is one of the major organs affected in preeclampsia. Because the kidney is highly susceptible to complement activation, we hypothesized that preeclampsia is associated with renal complement activation. We performed a nationwide search for renal autopsy material in the Netherlands using a computerized database (PALGA). Renal tissue was obtained from 11 women with preeclampsia, 25 pregnant controls, and 14 non-pregnant controls with hypertension. The samples were immunostained for C4d, C1q, MBL, properdin, C3d, C5b-9, IgA, IgG, and IgM. Preeclampsia was significantly associated with renal C4d—a stable marker of complement activation—and the classical pathway marker C1q. In addition, the prevalence of IgM was significantly higher in the kidneys of the preeclamptic women. No other complement markers studied differed between the groups. Our findings in human samples were validated using a soluble fms-like tyrosine kinase 1 (sFlt-1) mouse model of preeclampsia. The kidneys in the sFlt-1–injected mice had significantly more C4 deposits than the control mice. The association between preeclampsia and renal C4d, C1q, and IgM levels suggests that the classical complement pathway is involved in the renal injury in preeclampsia. Moreover, our finding that sFlt-1–injected mice develop excess C4 deposits indicates that angiogenic dysregulation may play a role in complement activation within the kidney. We suggest that inhibiting complement activation may be beneficial for preventing the renal manifestations of preeclampsia.

VEGF regulates local inhibitory complement proteins in the eye and kidney

“…These findings link the pathogenesis of glomerular TMA associated with anti-VEGF therapy to that of complement-mediated aHUS and may explain why the renal glomerulus is susceptible to complement-mediated disease. Interestingly, preeclampsia, another glomerular disease associated with endotheliosis and caused by chronic VEGF inhibition secondary to increased soluble VEGFR1, is also associated with complement activation (58, 59), suggesting that this work may also be relevant to this disease.…”

Complement 5a‐mediated trophoblasts dysfunction is involved in the development of pre‐eclampsia

“…The complement system includes a variety of complement components and some of them have been reported to be associated with PE [22][23][24][25][26]. Upon activation of the complement cascade, the formation of C3 and C5 convertase results in the cleavage of the complement component C5 to C5a and C5b.…”

Role of IgM and angiotensin II Type I receptor autoantibodies in local complement activation in placental ischemia-induced hypertension in the rat

“…Multiple studies demonstrated significantly enhanced systemic complement system activation in preeclamptic pregnancies compared to normal pregnancies (Derzsy et al, 2010; Regal et al, 2015a). Both the placenta and kidney also showed evidence of increased local complement activation in preeclampsia, coincident with up-regulation of message for complement regulators but no evidence of changes in regulator expression using immunohistochemistry have been reported (Burwick et al, 2014; Buurma et al, 2012; Lokki et al, 2014; Penning et al, 2015). However, the event or events that initiate complement activation in preeclampsia are unknown.…”