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

Yuri Miura; Atsuko Hayakawa; Shohei Kikuchi; Hiroki Tsumoto; Keitaro Umezawa; Yuko Chiba; Yurie Soejima; Motoji Sawabe; Koji Fukui; Yoshihiro Akimoto; Tamao Endo

doi:10.1016/j.abb.2019.108167

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

Arch Biochem Biophys. 2019 Dec 15:678:108167. doi: 10.1016/j.abb.2019.108167. Epub 2019 Nov 5.

Authors

Yuri Miura¹, Atsuko Hayakawa², Shohei Kikuchi³, Hiroki Tsumoto⁴, Keitaro Umezawa⁴, Yuko Chiba⁵, Yurie Soejima⁶, Motoji Sawabe⁶, Koji Fukui⁷, Yoshihiro Akimoto⁸, Tamao Endo⁴

Affiliations

¹ Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan. Electronic address: miura@center.tmig.or.jp.
² Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan; Department of Bioscience and Engineering, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama, 337-8570, Japan.
³ Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan; Department of Molecular Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
⁴ Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.
⁵ Department of Diabetes, Metabolism, and Endocrinology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.
⁶ Department of Molecular Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
⁷ Department of Bioscience and Engineering, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama, 337-8570, Japan.
⁸ Department Anatomy, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo, 181-8611, Japan.

PMID: 31704098
DOI: 10.1016/j.abb.2019.108167

Abstract

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.

Keywords: 2D-DIGE; Diabetic nephropathy; Fibrosis; Fumarate; Goto-Kakizaki rat; TCA cycle.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Citric Acid Cycle
Diabetic Nephropathies / metabolism*
Diabetic Nephropathies / pathology*
Down-Regulation
Fibrosis
Fumarates / metabolism*
Kidney / pathology*
Male
Rats

Substances

Fumarates