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CKIP-1 participates in the activation of Nrf2 signaling pathway by Cx43 and the regulation of diabetic renal fibrosis
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  • Heqing Huang,
  • Yan Yang,
  • Zeyuan Lin,
  • Haiming Xiao,
  • Xiaohong Sun,
  • Peiqing Liu
Heqing Huang
Sun Yat-Sen University
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Yan Yang
Sun Yat-Sen University
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Zeyuan Lin
Sun Yat-Sen University
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Haiming Xiao
Sun Yat-Sen University
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Xiaohong Sun
Sun Yat-Sen University
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Peiqing Liu
Sun Yat-Sen University
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Abstract

Abstract Background and Purpose We previously reported that both Cx43 and CKIP-1 attenuated diabetic renal fibrosis via the activation of Nrf2 signaling pathway. However, whether CKIP-1, a scaffold protein, participates in regulating the activation of Nrf2 signaling pathway by Cx43 remains to be elucidated. Experimental Approach The effect of adenovirus-mediated Cx43 overexpression on renal fibrosis in CKIP-1−/− diabetic mice was investigated. Cx43 overexpressed plasmid and CKIP-1 small interfering RNA were simultaneously transfected into GMCs and the activity of Nrf2 signaling pathway was observed. The interaction between Cx43 and CKIP-1 was analyzed by immunofluorescence and immunoprecipitation assays. Key Results Overexpression of Cx43 could significantly alleviate renal fibrosis by activating the Nrf2 pathway in diabetic mice, but have no obvious effect in CKIP-1−/− diabetic mice. The effect of activation of Nrf2 signaling pathway by Cx43 was blocked by CKIP-1 depletion. Cx43 interacted with CKIP-1, and the interaction was weakened by high glucose treatment. Cx43 regulated the expression of CKIP-1 and the interaction of CKIP-1 with Nrf2 via Cx43 carboxyl terminus (CT) domain, thereby activating Nrf2 signaling pathway. Conclusion and Implications CKIP-1 participates in regulating the activation of Nrf2 signaling pathway by Cx43, the mechanism of which might be related to the interaction of CKIP-1 with Nrf2 through Cx43 CT. Our study provides further experimental basis for targeting the Cx43-CKIP-1-Nrf2 axis to resist diabetic renal fibrosis.