1. CKIP-1 acts downstream to Cx43 on the activation of Nrf2 signaling pathway to protect from renal fibrosis in diabetes.
- Author
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Yang Y, Li J, Zhang L, Lin Z, Xiao H, Sun X, Zhang M, Liu P, and Huang H
- Subjects
- Animals, Carrier Proteins genetics, Cells, Cultured, Connexin 43 genetics, Diabetes Mellitus, Experimental pathology, Diabetic Nephropathies pathology, Diabetic Nephropathies prevention & control, Fibrosis, Hydrogen Peroxide metabolism, Kidney metabolism, Kidney pathology, Male, Mesangial Cells metabolism, Mice, Inbred C57BL, Mice, Knockout, Rats, Sprague-Dawley, Signal Transduction, Superoxides metabolism, Mice, Rats, Carrier Proteins metabolism, Connexin 43 metabolism, Diabetes Mellitus, Experimental metabolism, Diabetic Nephropathies metabolism, NF-E2-Related Factor 2 metabolism
- Abstract
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. In this study, the effect of adenovirus-mediated Cx43 overexpression on renal fibrosis in CKIP-1
-/- diabetic mice was investigated. We found that 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. Cx43 overexpressed plasmid and CKIP-1 small interfering RNA were simultaneously transfected into glomerular mesangial cells and the result demonstrated that the effect of activation of Nrf2 signaling pathway by Cx43 was blocked by CKIP-1 depletion. The interaction between Cx43 and CKIP-1 was analyzed by immunofluorescence and immunoprecipitation assays. We found that Cx43 interacted with CKIP-1, and the interaction was weakened by high glucose treatment. Moreover, 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. According to the results, we preliminary infer that CKIP-1 acts downstream to CX43 on the activation of Nrf2 signaling pathway to protect from renal fibrosis in diabetes, 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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2021
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