Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 102, Issue -, Pages 77-86Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2016.11.015
Keywords
Oxidative stress; Renal fibrosis; Diabetic nephropathy; Connexin43; c-Src; Nrf2/ARE pathway
Funding
- National Natural Science Foundation of China [81402984, 81373457, 81573477]
- Natural Science Foundation of Hainan Province [20158309]
- Doctoral Program of the Ministry of Education of China [20130171110097]
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Nrf2/ARE signaling pathway is a crucial cellular defense system to cope with oxidative stress, which is adaptively activated, in diabetic condition that is not efficient enough to resist the oxidative stress provoked by hyperglycemia. We have previously demonstrated that Connexin43 (Cx43) attenuates renal fibrosis through c-Src. However, the underlying mechanisms need to be further clarified. It has been reported that Cx43 possesses the ability of anti-oxidative. The current study aimed to determine if Cx43 exerts protective effects on renal fibrosis in diabetes via activation of Nrf2/ARE pathway and explore the underlying molecular mechanisms. The following findings were observed: (1) Cx43 expression decreased and c-Src activity increased in kidneys of diabetic animals; (2) Over-expressed Cx43 in high glucose treated GMCs inhibited protein levels of FN, ICAM-1 and TGF-beta 1; (3) Nrf2/ARE signaling adaptively responded to high glucose treatment in GMCs; (4) Cx43 reduced ROS generation by boost Nrf2/ARE signaling under high glucose condition; (5) Inhibition of c-Src activity promoted nucleus accumulation of Nrf2; (6) Over-expressed Cx43 inhibited c-Src activity and the interaction between c-Src and Nrf2 in GMCs cultured in high glucose. Thus we propose that Cx43 might enhance the activation of Nrf2/ARE pathway by means of inhibiting c-Src activity to hinder the nuclear export of Nrf2, and then reduce expression of FN, ICAM-1, TGF-beta 1, ultimately attenuating renal fibrosis in diabetes.
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