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Enhanced glycogen synthase kinase-3β activity mediates podocyte apoptosis under diabetic conditions

 Jisun Paeng  ;  Jae Hyun Chang  ;  Sun Ha Lee  ;  Bo Young Nam  ;  Hye-Young Kang  ;  Seonghun Kim  ;  Hyung Jung Oh  ;  Jung Tak Park  ;  Seung Hyeok Han  ;  Tae-Hyun Yoo  ;  Shin-Wook Kang 
 Apoptosis, Vol.19(12) : 1678-1690, 2014 
Journal Title
Issue Date
Albuminuria/metabolism ; Albuminuria/pathology ; Animals ; Apoptosis/drug effects* ; Apoptosis Regulatory Proteins/metabolism ; Diabetes Mellitus, Experimental/metabolism* ; Diabetes Mellitus, Experimental/pathology ; Glucose/pharmacology ; Glycogen Synthase Kinase 3/antagonists & inhibitors ; Glycogen Synthase Kinase 3/metabolism* ; Glycogen Synthase Kinase 3 beta ; Indoles/pharmacology ; Kidney Glomerulus/metabolism ; Kidney Glomerulus/pathology ; Male ; Oximes/pharmacology ; Phosphorylation ; Podocytes/drug effects ; Podocytes/metabolism ; Podocytes/pathology* ; Rats, Sprague-Dawley ; Signal Transduction ; Streptozocin ; Tyrosine/metabolism
GSK-3β ; Diabetic nephropathy ; Podocyte ; Apoptosis
Glycogen synthase kinase-3β (GSK-3β) is involved in the pathogenesis of various kidney diseases. This study was undertaken to examine the changes in GSK-3β activity in podocytes under diabetic conditions and to elucidate the functional role of GSK-3β in podocyte apoptosis. In vivo, 32 rats were injected with either diluent (n = 16, C) or with streptozotocin intraperitoneally (n = 16, DM), and 8 rats from each group were treated with 6-bromoindirubin-3'-oxime (BIO) for 3 months. In vitro, immortalized mouse podocytes were exposed to 5.6 mM glucose or 30 mM glucose (HG) with or without 10 μM BIO. Western blot analysis and TUNEL or Hoechst 33342 staining were performed to identify apoptosis. Urinary albumin excretion was significantly higher in DM rats, and this increase was significantly abrogated in DM rats by BIO treatment. The protein expression of Tyr216-phospho-GSK-3β was significantly increased in DM glomeruli and in cultured podocytes exposed to HG. Western blot analysis revealed that the protein expression of Bax and active fragments of caspase-3 were significantly increased, whereas phospho-Akt, β-catenin, and Bcl-2 protein expression were significantly decreased in DM glomeruli and HG-stimulated podocytes. Apoptosis, determined by TUNEL assay and Hoechst 33342 staining, was also significantly increased in podocytes under diabetic conditions. The changes in the expression of apoptosis-related molecules and the increase in the number of apoptotic cells in DM glomeruli as well as in HG-stimulated podocytes were significantly ameliorated by BIO. These findings suggest that enhanced GSK-3β activity within podocytes under diabetic conditions is associated with podocyte loss in diabetic nephropathy.
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1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Shin Wook(강신욱) ORCID logo https://orcid.org/0000-0002-5677-4756
Kang, Hye Young(강혜영)
Kim, Seonghun(김성훈)
Nam, Bo Young(남보영)
Park, Jung Tak(박정탁) ORCID logo https://orcid.org/0000-0002-2325-8982
Oh, Hyung Jung(오형중)
Yoo, Tae Hyun(유태현) ORCID logo https://orcid.org/0000-0002-9183-4507
Lee, Sun Ha(이순하)
Chang, Jae Hyun(장제현)
Paeng, Ji Sun(팽지선)
Han, Seung Hyeok(한승혁) ORCID logo https://orcid.org/0000-0001-7923-5635
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