TY - JOUR
T1 - Fumarate accumulation involved in renal diabetic fibrosis in Goto-Kakizaki rats
AU - Miura, Yuri
AU - Hayakawa, Atsuko
AU - Kikuchi, Shohei
AU - Tsumoto, Hiroki
AU - Umezawa, Keitaro
AU - Chiba, Yuko
AU - Soejima, Yurie
AU - Sawabe, Motoji
AU - Fukui, Koji
AU - Akimoto, Yoshihiro
AU - Endo, Tamao
N1 - Funding Information:
This study was supported in part by the Novartis Foundation (Japan) [Novartis Research Grants 2018] to YM. Appendix A
Funding Information:
This study was supported in part by the Novartis Foundation (Japan) [Novartis Research Grants 2018] to YM.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/12/15
Y1 - 2019/12/15
N2 - The Goto-Kakizaki (GK) rat is a spontaneous animal model of type 2 diabetes and early stage of diabetic nephropathy. However, the pathophysiological mechanisms contributing to the progression of diabetic nephropathy in GK rats remain unclear. Kidneys from 15-week old male diabetic GK/Jcl rats and age-matched Wistar rats, which have the same genetic background as GK rats, were used. Proteomic analyses of GK and Wistar kidneys were performed using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Differentially expressed proteins in GK rats were subjected to pathway analysis, and expression levels of hypoxia inducible factor 1α (HIF-1α) and transforming growth factor-β1 (TGF-β1), and fumarate accumulation in GK kidneys were examined. Azan staining and immunohistochemical staining of α-smooth muscle actin were performed in relation to fibrosis in GK kidneys. Proteomic analysis using 2D-DIGE, analysis of fumarate content, and expression analysis of HIF-1α, TGF-β1, and α-smooth muscle actin of GK rat's kidney, suggested the mechanism of fibrosis characterized as two stages in diabetic nephropathy of GK rats. Abnormalities of glucose metabolism such as elevated levels of 2-oxoglutarate dehydrogenase and reduction of fumarate hydratase caused the accumulation of fumarate followed by the upregulation of HIF-1α and TGF-β1 leading to fibrosis in diabetic nephropathy. Alterations in proteins involved in the tricarboxylic acid cycle are associated with fibrosis through fumarate accumulation in diabetic nephropathy of GK rats.
AB - The Goto-Kakizaki (GK) rat is a spontaneous animal model of type 2 diabetes and early stage of diabetic nephropathy. However, the pathophysiological mechanisms contributing to the progression of diabetic nephropathy in GK rats remain unclear. Kidneys from 15-week old male diabetic GK/Jcl rats and age-matched Wistar rats, which have the same genetic background as GK rats, were used. Proteomic analyses of GK and Wistar kidneys were performed using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Differentially expressed proteins in GK rats were subjected to pathway analysis, and expression levels of hypoxia inducible factor 1α (HIF-1α) and transforming growth factor-β1 (TGF-β1), and fumarate accumulation in GK kidneys were examined. Azan staining and immunohistochemical staining of α-smooth muscle actin were performed in relation to fibrosis in GK kidneys. Proteomic analysis using 2D-DIGE, analysis of fumarate content, and expression analysis of HIF-1α, TGF-β1, and α-smooth muscle actin of GK rat's kidney, suggested the mechanism of fibrosis characterized as two stages in diabetic nephropathy of GK rats. Abnormalities of glucose metabolism such as elevated levels of 2-oxoglutarate dehydrogenase and reduction of fumarate hydratase caused the accumulation of fumarate followed by the upregulation of HIF-1α and TGF-β1 leading to fibrosis in diabetic nephropathy. Alterations in proteins involved in the tricarboxylic acid cycle are associated with fibrosis through fumarate accumulation in diabetic nephropathy of GK rats.
KW - 2D-DIGE
KW - Diabetic nephropathy
KW - Fibrosis
KW - Fumarate
KW - Goto-Kakizaki rat
KW - TCA cycle
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U2 - 10.1016/j.abb.2019.108167
DO - 10.1016/j.abb.2019.108167
M3 - Article
C2 - 31704098
AN - SCOPUS:85074892673
SN - 0003-9861
VL - 678
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
M1 - 108167
ER -