title: C-reactive protein promotes acute kidney injury by impairing G1/S-dependent tubular epithelium cell regeneration.
abstract: CRP (C-reactive protein) is regarded as an inflammatory biomarker in AKI (acute kidney injury), but its exact role in AKI remains unclear. Thus we sought to investigate the role of CRP in AKI. Clinically, elevated serum CRP levels were found to associate closely with increased serum creatinine and urea levels (P<0.01) in patients with AKI, which then fell after recovery from AKI. To determine the role of CRP in AKI, an ischaemia/reperfusion mouse model of AKI was developed using Tg (transgenic) mice that express human CRP. Compared with the WT (wild-type) mice, CRP Tg mice developed more severe renal injury at 24 h after ischaemia as determined by significantly increased serum creatinine and tubular necrosis. This was associated with an impaired TEC (tubular epithelium cell) regeneration as shown by an over 60% reduction in PCNA+ (proliferating-cell nuclear antigen) and BrdU+ (bromodeoxyuridine) TECs in CRP Tg mice with AKI. In vitro, the addition of CRP to a human TEC line (HK-2) also largely suppressed the proliferation of TECs. The functional role of CRP in AKI was demonstrated further by the blocking of CRP binding to the FcγRII (Fcγ receptor II) with a neutralizing anti-CD32 antibody, which restored TEC proliferation and prevented AKI in CRP Tg mice. Moreover, we found that impaired G1/S transition by suppression of the phosphorylation of CDK2 (cyclin-dependent kinase 2) and expression of cyclin E may be a key mechanism by which CRP inhibits TEC regeneration during the AKI repair process. In conclusion, CRP plays a pathogenic role in AKI by inhibiting G1/S-dependent TEC regeneration. The results of the present study suggest that targeting CRP signalling may offer a new therapeutic potential for AKI.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tang
authors.forename: Xiao Ru
authors.initials: XR
authors.lastname: Huang
authors.affiliation: *Department of Nephrology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lv
authors.forename: Arthur Chi-Kong
authors.initials: AC
authors.lastname: Chung
authors.affiliation: †Li Ka Shing Institute of Health Sciences and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: *Department of Nephrology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Jun-Zhe
authors.initials: JZ
authors.lastname: Chen
authors.affiliation: §Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, Birmingham, AL, U.S.A.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Szalai
authors.affiliation: *Department of Nephrology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Anping
authors.initials: A
authors.lastname: Xu
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Lan
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D010766:Phosphorylation; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D015427:Reperfusion Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D015415:Biomarkers; D019927:Cyclin E; C499173:FCGR2B protein, human; D017452:Receptors, IgG; D002097:C-Reactive Protein; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2