Sulforaphane attenuation of experimental diabetic nephropathy involves GSK-3 beta/Fyn/Nrf2 signaling pathway.
Sulforaphane (SFN), the bioactive component of cruciferous vegetables, is a potent indirect antioxidant. Oxidative stress and activation of glycogen synthase kinase 3beta (GSK3β) are two major contributors to the pathogenesis of diabetic nephropathy (DN). Here, we investigated whether and how SFN affected GSK3β in experimental models of DN in vivo and in vitro. SFN treatment obviously prevented the increase in urine albumin excretion, matrix expansion, transforming growth factor-β1 expression, fibronectin and type IV collagen deposition in the diabetic kidney. Simultaneously, the level of 8-oxo-deoxyguanosine, an indicator of oxidative damage, was markedly lowered in SFN-treated diabetic rats, together with a significant reduction in activity of the GSK-3β/Fyn axis and an evident activation of Nrf2 signaling. Similarly, antifibrotic effects of SFN, parallel to enhanced inhibitory Ser9-phosphorylation of GSK3β and Fyn/Nrf2 nuclear export/import, were observed in the cultured rat mesangial cells (RMC) exposed to high glucose. The salutary effects of SFN on high-glucose-stimulated RMC were abolished by overexpression of GSK3β while being rescued by lithium chloride, a well-known GSK3β inhibitor. Taken together, our findings suggested that SFN ameliorated experimental diabetic nephropathy, at least in part, via GSK3β/Fyn/Nrf2 signaling pathway.
Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China.
Guoguo
G
Shang
Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China.
Xinjun
X
Tang
Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China.
Pan
P
Gao
Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China.
Fanli
F
Guo
Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China.
Hongpeng
H
Liu
Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China.
Zhonghua
Z
Zhao
Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China.
Qi
Q
Chen
Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China.
Tao
T
Jiang
Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China.
Nong
N
Zhang
Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China. Electronic address: huili78@fudan.edu.cn.
Hui
H
Li
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000517:prevention & control*; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000517:prevention & control*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D017879:Isothiocyanates / Q000494:pharmacology*; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013454:Sulfoxides; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
D000975:Antioxidants; D024141:Collagen Type IV; D005353:Fibronectins; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D012333:RNA, Messenger; D013454:Sulfoxides; D053773:Transforming Growth Factor beta1; D000080242:8-Hydroxy-2'-Deoxyguanosine; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D003849:Deoxyguanosine; C016766:sulforaphane
Diabetic nephropathy; Fyn; Glycogen synthase kinase 3 beta; Mesangial cells; Nrf2; Sulforaphane