CKIP-1 participates in the activation of Nrf2 signaling pathway by Cx43
and the regulation of diabetic renal fibrosis
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.