title: C-reactive protein promotes acute kidney injury via Smad3-dependent inhibition of CDK2/cyclin E.
abstract: Acute kidney injury (AKI) is exacerbated in C-reactive protein transgenic mice but alleviated in Smad3 knockout mice. Here we used C-reactive protein transgenic/Smad3 wild-type and C-reactive protein transgenic/Smad3 knockout mice to investigate the signaling mechanisms by which C-reactive protein promotes AKI. Serum creatinine was elevated, and the extent of tubular epithelial cell necrosis following ischemia/reperfusion-induced AKI was greater in C-reactive protein transgenics but was blunted when Smad3 was deleted. Exacerbation of AKI in C-reactive protein transgenics was associated with increased TGF-β/Smad3 signaling and expression of the cyclin kinase inhibitor p27, but decreased phosphorylated CDK2 and expression of cyclin E. Concomitantly, tubular epithelial cell proliferation was arrested at the G1 phase in C-reactive protein transgenics with fewer cells entering the S-phase cell cycle as evidenced by fewer bromodeoxyuridine-positive cells. In contrast, the protection from AKI in C-reactive protein transgenic/Smad3 knockout mice was associated with decreased expression of p27 and promotion of CDK2/cyclin E-dependent G1/S transition of tubular epithelial cells. In vitro studies using tubular epithelial cells showed that C-reactive protein activates Smad3 via both TGF-β-dependent and ERK/MAPK cross talk mechanisms, Smad3 bound directly to p27, and blockade of Smad3 or the Fc receptor CD32 prevented C-reactive protein-induced p27-dependent G1 cell cycle arrest. In vivo, treatment of C-reactive protein transgenics with a Smad3 inhibitor largely improved AKI outcomes. Thus, C-reactive protein may promote AKI by impairing tubular epithelial cell regeneration via the CD32-Smad3-p27-driven inhibition of the CDK2/cyclin E complex. Targeting Smad3 may offer a new treatment approach for AKI.
authors.affiliation: Department of Nephrology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Weiyan
authors.initials: W
authors.lastname: Lai
authors.affiliation: Department of Nephrology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Xiao R
authors.initials: XR
authors.lastname: Huang
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ming-Kuen Tang
authors.affiliation: Department of Nephrology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Anping
authors.initials: A
authors.lastname: Xu
authors.affiliation: Department of Medicine, The University of Alabama Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Szalai
authors.affiliation: Department of Nephrology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Tan-Qi
authors.initials: TQ
authors.lastname: Lou
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. Electronic address: hylan@cuhk.edu.hk.
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Lan
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000473:pathology*; D000818:Animals; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003404:Creatinine / Q000097:blood; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007684:Kidney Tubules / Q000166:cytology / Q000502:physiology*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017452:Receptors, IgG / Q000378:metabolism; D012038:Regeneration; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C508504:6,7-dimethyl-2-(2E)-3-(1-methyl-2-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl-prop-2-enoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride; C493961:Cdkn1b protein, mouse; D019927:Cyclin E; C499172:Fcgr2b protein, mouse; D007546:Isoquinolines; D011725:Pyridines; D011758:Pyrroles; D017452:Receptors, IgG; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002097:C-Reactive Protein; D003404:Creatinine; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2
keywords: C-reactive protein; Smad3; acute kidney injury; cell cycle arrest; p27