title: Renal improvement by zinc in diabetic mice is associated with glucose metabolism signaling mediated by metallothionein and Akt, but not Akt2.
abstract: Human epidemiological and animal studies have shown the beneficial effect of zinc supplementation on mitigating diabetic nephropathy. However, the mechanism by which zinc protects the kidney from diabetes remains unknown. Here we demonstrate the therapeutic effects of zinc on diabetes-induced renal pathological and functional changes. These abnormalities were found in both transgenic OVE26 and Akt2-KO diabetic mouse models, accompanied by significant changes in glucose-metabolism-related regulators. The changes included significantly decreased phosphorylation of Akt and GSK-3β, increased phosphorylation of renal glycogen synthase, decreased expression of hexokinase II and PGC-1α, and increased expression of the Akt negative regulators PTEN, PTP1B, and TRB3. All of these were significantly prevented by zinc treatment for 3 months. Furthermore, zinc-stimulated changes in glucose metabolism mediated by Akt were actually found to be metallothionein dependent, but not Akt2 dependent. These results suggest that the therapeutic effects of zinc in diabetic nephropathy are mediated, in part, by the preservation of glucose-metabolism-related pathways via the prevention of diabetes-induced upregulation of Akt negative regulators. Given that zinc deficiency is very common in diabetics, this finding implies that regularly monitoring zinc levels in diabetic patients, as well as supplementing if low, is important in mitigating the development of diabetic nephropathy.
authors.affiliation: First Hospital, Jilin University, Jilin 130021, China; Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, KY 40202, USA.
authors.forename: Weixia
authors.initials: W
authors.lastname: Sun
authors.affiliation: Second Hospital, Jilin University, Jilin 130041, China.
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, KY 40202, USA; Second Hospital, Jilin University, Jilin 130041, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Miao
authors.affiliation: Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, KY 40202, USA; China-Japan Union Hospital, Jilin University, Jilin 130031, China.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: First Hospital, Jilin University, Jilin 130021, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, KY 40202, USA; Norman Bethune Medical College, Jilin University, Jilin 130021, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xin
authors.affiliation: Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, KY 40202, USA.
authors.forename: Shirong
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, KY 40202, USA.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Epstein
authors.affiliation: First Hospital, Jilin University, Jilin 130021, China. Electronic address: fuyaowen@medmail.com.cn.
authors.forename: Yaowen
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, KY 40202, USA. Electronic address: L0cai001@louisville.edu.
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
mesh_terms: D000818:Animals; D003928:Diabetic Nephropathies / Q000178:diet therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008668:Metallothionein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015032:Zinc / Q000008:administration & dosage* / Q000172:deficiency
chemical_list: D008668:Metallothionein; C494921:AKT2 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D005947:Glucose; D015032:Zinc
keywords: Akt, GSK-3β, Akt2 gene defect; Diabetic nephropathy; Free radicals; Metallothionein; Zinc