Fumarate accumulation involved in renal diabetic fibrosis in Goto-Kakizaki rats

• Published in: Archives of biochemistry and biophysics 2019-12, Vol.678, p.108167-108167, Article 108167
• Main Authors: Miura, Yuri, Hayakawa, Atsuko, Kikuchi, Shohei, Tsumoto, Hiroki, Umezawa, Keitaro, Chiba, Yuko, Soejima, Yurie, Sawabe, Motoji, Fukui, Koji, Akimoto, Yoshihiro, Endo, Tamao
• Format: Article
• Language: English
• Subjects: 2D-DIGE; Animals; Citric Acid Cycle; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Diabetic nephropathy; Down-Regulation; Fibrosis; Fumarate; Fumarates - metabolism; Goto-Kakizaki rat; Kidney - pathology; Male; Rats; TCA cycle
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2019.108167

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. [Display omitted] •Protein profiles of Goto-Kakizaki (GK) rat's kidney were compared with Wistar rats.•Abnormalities of glucose metabolism caused fumarate accumulation in GK kidneys.•Fumarate accumulation upregulated HIF-1α and TGF-β1, leading to fibrosis.