title: Metallothionein deficiency exacerbates diabetic nephropathy in streptozotocin-induced diabetic mice.
abstract: Oxidative stress and inflammation play important roles in diabetic complications, including diabetic nephropathy. Metallothionein (MT) is induced in proximal tubular epithelial cells as an antioxidant in the diabetic kidney; however, the role of MT in renal function remains unclear. We therefore investigated whether MT deficiency accelerates diabetic nephropathy through oxidative stress and inflammation. Diabetes was induced by streptozotocin injection in MT-deficient (MT(-/-)) and MT(+/+) mice. Urinary albumin excretion, histological changes, markers for reactive oxygen species (ROS), and kidney inflammation were measured. Murine proximal tubular epithelial (mProx24) cells were used to further elucidate the role of MT under high-glucose conditions. Parameters of diabetic nephropathy and markers of ROS and inflammation were accelerated in diabetic MT(-/-) mice compared with diabetic MT(+/+) mice, despite equivalent levels of hyperglycemia. MT deficiency accelerated interstitial fibrosis and macrophage infiltration into the interstitium in the diabetic kidney. Electron microscopy revealed abnormal mitochondrial morphology in proximal tubular epithelial cells in diabetic MT(-/-) mice. In vitro studies demonstrated that knockdown of MT by small interfering RNA enhanced mitochondrial ROS generation and inflammation-related gene expression in mProx24 cells cultured under high-glucose conditions. The results of this study suggest that MT may play a key role in protecting the kidney against high glucose-induced ROS and subsequent inflammation in diabetic nephropathy.
authors.affiliation: Depts. of Medicine and Clinical Science and Diabetic Nephropathy, Okayama Univ. Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. daiogawa@md.okayama-u.ac.jp.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tachibana
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogawa
authors.forename: Norio
authors.initials: N
authors.lastname: Sogawa
authors.forename: Masato
authors.initials: M
authors.lastname: Asanuma
authors.forename: Ikuko
authors.initials: I
authors.lastname: Miyazaki
authors.forename: Naoto
authors.initials: N
authors.lastname: Terami
authors.forename: Takashi
authors.initials: T
authors.lastname: Hatanaka
authors.forename: Chikage Sato
authors.initials: CS
authors.lastname: Horiguchi
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nakatsuka
authors.forename: Jun
authors.initials: J
authors.lastname: Eguchi
authors.forename: Jun
authors.initials: J
authors.lastname: Wada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
authors.forename: Kohji
authors.initials: K
authors.lastname: Takei
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation; D007668:Kidney / Q000166:cytology / Q000473:pathology; D008264:Macrophages / Q000502:physiology; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C491054:Mt2 protein, mouse; D017382:Reactive Oxygen Species; C525355:metallothionein-1, mouse; D008668:Metallothionein
keywords: diabetic nephropathy; inflammation; metallothionein; oxidative stress; reactive oxygen species