期刊
PHARMACOLOGICAL RESEARCH
卷 163, 期 -, 页码 -出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2020.105333
关键词
Diabetic nephropathy; Oxidative stress; Cx43; CKIP-1; Nrf2
资金
- National Natural Science Foundation of China [81770816, 81973375]
- Key Project of Natural Science Foundation of Guangdong Province, China [202081111100004]
- Youth Foundation of Guangdong Second Provincial General Hospital [YQ2018-008]
The study demonstrated that Cx43 could alleviate renal fibrosis in diabetic mice by activating the Nrf2 pathway, while CKIP-1 was found to play a crucial role in regulating this process. The interaction between Cx43 and CKIP-1, as well as their effects on Nrf2 signaling pathway, were investigated to provide experimental basis for potential therapeutic targets in diabetic renal fibrosis.
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.
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