PMID- 28295247
OWN - NLM
STAT- MEDLINE
DCOM- 20170802
LR  - 20220129
IS  - 1365-2249 (Electronic)
IS  - 0009-9104 (Print)
IS  - 0009-9104 (Linking)
VI  - 189
IP  - 1
DP  - 2017 Jul
TI  - Targeting C3a/C5a receptors inhibits human mesangial cell proliferation and 
      alleviates immunoglobulin A nephropathy in mice.
PG  - 60-70
LID - 10.1111/cei.12961 [doi]
AB  - 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)-alpha, transforming growth 
      factor (TGF)-beta, IL-1beta, 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.
CI  - (c) 2017 British Society for Immunology.
FAU - Zhang, Y
AU  - Zhang Y
AD  - Department of Nephrology, First Affiliated Hospital of Zhengzhou University, 
      Zhengzhou, China.
FAU - Yan, X
AU  - Yan X
AD  - Department of Nephrology, First Affiliated Hospital of Zhengzhou University, 
      Zhengzhou, China.
FAU - Zhao, T
AU  - Zhao T
AD  - Department of Nephrology, First Affiliated Hospital of Zhengzhou University, 
      Zhengzhou, China.
FAU - Xu, Q
AU  - Xu Q
AD  - Medical Research Council Centre for Transplantation, King's College London, 
      London, UK.
FAU - Peng, Q
AU  - Peng Q
AD  - Medical Research Council Centre for Transplantation, King's College London, 
      London, UK.
FAU - Hu, R
AU  - Hu R
AD  - Department of Nephrology, First Affiliated Hospital of Zhengzhou University, 
      Zhengzhou, China.
FAU - Quan, S
AU  - Quan S
AD  - Department of Nephrology, First Affiliated Hospital of Zhengzhou University, 
      Zhengzhou, China.
FAU - Zhou, Y
AU  - Zhou Y
AD  - Department of Nephrology, First Affiliated Hospital of Zhengzhou University, 
      Zhengzhou, China.
FAU - Xing, G
AU  - Xing G
AUID- ORCID: 0000-0001-6865-7517
AD  - Department of Nephrology, First Affiliated Hospital of Zhengzhou University, 
      Zhengzhou, China.
LA  - eng
GR  - MR/J006742/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170410
PL  - England
TA  - Clin Exp Immunol
JT  - Clinical and experimental immunology
JID - 0057202
RN  - 0 (Cytokines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptor, Anaphylatoxin C5a)
RN  - 0 (Receptors, Complement)
RN  - 0 (complement C3a receptor)
RN  - 80295-42-7 (Complement C3a)
RN  - 80295-54-1 (Complement C5a)
SB  - IM
MH  - Animals
MH  - Cell Proliferation
MH  - Cells, Cultured
MH  - Complement Activation
MH  - Complement C3a/metabolism
MH  - Complement C5a/metabolism
MH  - Cytokines/immunology
MH  - Disease Models, Animal
MH  - Female
MH  - Glomerulonephritis, IGA/*metabolism/pathology/virology
MH  - Humans
MH  - Kidney/*pathology
MH  - Mesangial Cells/cytology/metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Knockout
MH  - RNA, Messenger/metabolism
MH  - Receptor, Anaphylatoxin C5a/genetics/*metabolism
MH  - Receptors, Complement/genetics/*metabolism
MH  - Sendai virus
MH  - Signal Transduction
PMC - PMC5461107
OTO - NOTNLM
OT  - C3a receptor
OT  - C5a receptor
OT  - IgA nephropathy
OT  - complement
EDAT- 2017/03/16 06:00
MHDA- 2017/08/03 06:00
PMCR- 2018/07/01
CRDT- 2017/03/16 06:00
PHST- 2017/02/28 00:00 [accepted]
PHST- 2017/03/16 06:00 [pubmed]
PHST- 2017/08/03 06:00 [medline]
PHST- 2017/03/16 06:00 [entrez]
PHST- 2018/07/01 00:00 [pmc-release]
AID - CEI12961 [pii]
AID - 10.1111/cei.12961 [doi]
PST - ppublish
SO  - Clin Exp Immunol. 2017 Jul;189(1):60-70. doi: 10.1111/cei.12961. Epub 2017 Apr 
      10.