title: GSK-3β inhibitor attenuates urinary albumin excretion in type 2 diabetic db/db mice, and delays epithelial-to-mesenchymal transition in mouse kidneys and podocytes.
abstract: The mechanism underlying epithelial‑to‑mesenchymal transition (EMT) caused by high glucose (HG) stimulation in diabetic nephropathy (DN) remains to be fully elucidated. The present study investigated the effects of HG on EMT and the activity of glycogen synthase kinase 3β (GSK‑3β) in podocytes and the kidneys of db/db mice, and assessed the effects of (2'Z, 3'E)‑6‑bromoindirubin‑3'‑oxime (BIO), an inhibitor of GSK‑3β, on EMT and glomerular injury. The resulting data showed that the activity of GSK‑3β was upregulated by HG and downregulated by BIO in the podocytes and the renal cortex. The expression levels of epithelial markers, including nephrin, podocin and synaptopodin, were decreased by HG and increased by BIO, whereas the reverse were true for mesenchymal markers, including α‑smooth muscle actin (α‑SMA) and fibronectin. The expression levels of β‑catenin and Snail, in contrast to current understanding of the Wnt signaling pathway, were increased by HG and decreased by BIO. In addition, expression of the vitamin D receptor (VDR) was decreased by HG and increased by BIO. In conclusion, the present study revealed that the mechanism by which BIO inhibited HG‑mediated EMT in podocytes and the renal cortex was primarily due to the VDR. Treatment with BIO protected renal function by maintaining the integrity of the filtration membrane and decreasing UAE, but not by regulating blood glucose. Therefore, GSK‑3β may be used as a sensitive biomarker of DN, and its inhibition by BIO may be effective in the treatment of DN.
authors.affiliation: Henan Food and Drug Administration, Zhengzhou, Henan 450012, P.R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Wan
authors.affiliation: Pharmaceutical College, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450012, P.R. China.
authors.forename: Dong-Wei
authors.initials: DW
authors.lastname: Liu
authors.affiliation: School of Life Science and Technology, Henan Institute of Science and Technology, Xinxiang, Henan 453003, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Food Science, Henan Institute of Science and Technology, Xinxiang, Henan 453003, P.R. China.
authors.forename: Hai-Zhen
authors.initials: HZ
authors.lastname: Mo
authors.affiliation: Department of Food Science, Henan Institute of Science and Technology, Xinxiang, Henan 453003, P.R. China.
authors.forename: Ben-Guo
authors.initials: BG
authors.lastname: Liu
authors.affiliation: Modern Education Technology Center, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Chen
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450012, P.R. China.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Lu
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450012, P.R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450012, P.R. China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450012, P.R. China.
authors.forename: Ying-Jin
authors.initials: YJ
authors.lastname: Qiao
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450012, P.R. China.
authors.forename: Zhang-Suo
authors.initials: ZS
authors.lastname: Liu
authors.affiliation: Pharmaceutical College, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Guang-Rui
authors.initials: GR
authors.lastname: Wan
mesh_terms: D000818:Animals; D015415:Biomarkers; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight; D002461:Cell Line, Transformed; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000652:urine; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000652:urine; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D015870:Gene Expression; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D011507:Proteinuria
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D000071679:Glycogen Synthase Kinase 3 beta