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Targeting C3a/C5a receptors inhibits human mesangial cell proliferation and
alleviates immunoglobulin A nephropathy in mice
#MMPMID28295247
Zhang Y
; Yan X
; Zhao T
; Xu Q
; Peng Q
; Hu R
; Quan S
; Zhou Y
; Xing G
Clin Exp Immunol
2017[Jul]; 189
(1
): 60-70
PMID28295247
show ga
Complement activation has a deep pathogenic influence in immunoglobulin (Ig)A
nephropathy (IgAN). C3a and C5a, small cleavage fragments generated by complement
activation, are key mediators of inflammation. The fragments exert broad
proinflammatory effects by binding to specific receptors (C3aR and C5aR,
respectively). However, no studies thus far have investigated the effects of C3a,
C5a and their receptors on IgAN. We observed that C3aR and C5aR antagonists
repressed IgA-induced cell proliferation and interleukin (IL)-6 and monocyte
chemotactic protein 1 (MCP-1) production in cultured human mesangial cells
(HMCs). Furthermore, an IgAN mouse model induced by Sendai virus infection was
employed to investigate the effects of C3aR and C5aR on IgAN in vivo for the
first time. Wild-type (WT) and several knock-out mouse strains (C3aR(-/-) or
C5aR(-/-) ) were immunized intranasally with increasing doses of inactivated
virus for 14 weeks and were subjected to two intravenous viral challenges during
the time-period indicated. In the Sendai virus-induced IgAN model,
C3aR/C5aR-deficient mice had significantly reduced proteinuria, lower renal IgA
and C3 deposition, less histological damage and reduced mesangial proliferation
compared with WT mice. Both C3aR deficiency and C5aR deficiency, especially C3aR
deficiency, inhibited renal tumour necrosis factor (TNF)-?, transforming growth
factor (TGF)-?, IL-1?, IL-6 and MCP-1 expression significantly. However,
C3aR/C5aR-deficient and WT mice with IgAN did not differ with respect to their
blood urea nitrogen (BUN) and serum creatinine levels. Our findings provide
further support for the idea that C3aR and C5aR are crucially important in IgAN,
and suggest that pharmaceutically targeting C3aR/C5aR may hold promise for the
treatment of IgAN.
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