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Abstract: TH-PO929

CCN2 Module-IV Promotes Renal Fibrosis Through Activation of the FAK Pathway in the Tubular Epithelium

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms


  • Amano, Hiroaki, Saitama Medical University, Saitama, Japan
  • Inoue, Tsutomu, Saitama Medical University, Saitama, Japan
  • Okada, Hirokazu, Saitama Medical University, Saitama, Japan

CCN2 is known to mediate the profibrogenic actions of TGF-beta in the kidney. We previously demonstrated that CCN2 promotes renal fibrosis via its module-IV by using mutated-CCN2 knocked-in mice (CCN2m/m) expressing mutated CCN2 lacking module-IV. CCN2 was reported to use FAK, Smad2/3 and LRP6 to promote renal fibrosis. Among these, a significant decrease in p-FAK was found in primary skin fibroblasts derived from CCN2m/m compared with the wild-type cells. In this study, therefore, we examined possible downstream pathways through which CCN2 module-IV promotes fibrosis in the kidney.


Expression of candidate proteins involved in the early downstream pathways of CCN2 were measured by immunoblotting using kidney samples from CCN2m/m and wild-type mice with or without ureter obstruction (UUO). Additionally, the expression and localization of other downstream proteins of the FAK pathway in those samples were examined by immunoblotting and immunohistochemistry.


Expression levels of p-FAK, p-Smad2/3 and p-LRP6 were significantly higher in the fibrotic wild-type UUO kidney on day 7 in comparison with the sham-operated control. However, p-FAK, but not p-Smad2/3 or p-LRP6, was significantly lower in the CCN2m/m UUO kidney compared with the wild-type UUO kidney (p-FAK/FAK: 1.1+/-0.1 vs. 2.6+/-0.4, p<0.01). Furthermore, mutant CCN2 showed significantly lower expression levels of p-Akt and total beta-catenin, which are considered downstream pathway proteins of pFAK, in the UUO kidney in comparison with the wild type (p-Akt/Akt: 0.1+/-0.1 vs. 0.6+/-0.2, p<0.03; beta catenin/GAPDH: 1.6+/-0.1 vs. 2.8+/-0.5, p<0.03). Immunohistochemistry revealed that FAK was activated in the tubular epithelium of the fibrotic wild-type UUO kidney, whereas these were significantly suppressed in the CCN2m/m UUO kidney.


CCN2 module-IV activates the FAK pathways in the tubular epithelium and, as a result, fibrosis is promoted in the UUO kidney. To prove this, primary tubular epithelial cells derived from CCN2m/m are being generated to examine the role of CCN2 module-IV in vitro.


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