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FR167653 inhibits fibronectin expression and apoptosis in diabetic glomeruli and in high-glucose-stimulated mesangial cells.

Authors
 Dong-Sub Jung  ;  Jin Ji Li  ;  Seung-Jae Kwak  ;  Sun Ha Lee  ;  Jehyun Park  ;  Young Soo Song  ;  Tae-Hyun Yoo  ;  Seung Hyeok Han  ;  Jung Eun Lee  ;  Dong Ki Kim  ;  Sung Jin Moon  ;  Yu Seun Kim  ;  Dae Suk Han  ;  Shin-Wook Kang 
Citation
 AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, Vol.295(2) : 595-604, 2008 
Journal Title
 AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY 
ISSN
 1931-857X 
Issue Date
2008
MeSH
Animals ; Apoptosis/drug effects* ; Caspase 3/metabolism ; Cells, Cultured ; Cyclic AMP Response Element-Binding Protein/metabolism ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology* ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Fibronectins/metabolism* ; Glucose/pharmacology* ; Hyperglycemia/metabolism ; Hyperglycemia/pathology ; Kidney Glomerulus/drug effects ; Kidney Glomerulus/metabolism ; Kidney Glomerulus/pathology* ; Male ; Mesangial Cells/drug effects ; Mesangial Cells/metabolism ; Mesangial Cells/pathology* ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Pyrazoles/pharmacology* ; Pyridines/pharmacology* ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Streptozocin ; bcl-2-Associated X Protein/metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
Keywords
p38 mitogen-activated protein kinase ; fibrosis ; apoptosis ; diabetic nephropathy
Abstract
Previous in vitro studies suggest that the p38 MAPK pathway may be involved in the pathogenesis of diabetic nephropathy, but the consequences of the inhibition of the p38 MAPK pathway have not been well elucidated in diabetic (DM) glomeruli. This study was undertaken to investigate the effect of p38 MAPK inhibitor, FR167653, on fibronectin expression and apoptosis in DM glomeruli and in high-glucose-stimulated mesangial cells (MC). In vivo, 32 Sprague-Dawley rats were injected with diluent (control, N = 16) or streptozotocin intraperitoneally (DM, N = 16). Eight rats from each group were treated with FR167653 for 3 mo. In vitro, rat MC were exposed to medium containing 5.6 mM glucose or 30 mM glucose [high glucose (HG)] with or without 10(-6) M FR167653 for 24 h. Fibronectin mRNA and protein expression were determined by real-time PCR and Western blot, respectively. Western blot for apoptosis-related molecules, terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, and Hoechst 33342 staining were performed to determine apoptosis. FR167653 ameliorated the increases in fibronectin-to-GAPDH mRNA ratio and protein expression in DM glomeruli by 89 and 79% and in HG-stimulated MC by 70 and 91%, respectively (P < 0.05). Under diabetic conditions, Bcl-2 protein expression was decreased, whereas cleaved caspase-3 protein expression was increased (P < 0.05), and these changes were inhibited by FR167653 treatment. Apoptotic cells were also significantly increased in DM glomeruli and in HG-stimulated MC (P < 0.05), and FR167653 ameliorated these increases in apoptotic cells, both in vivo and in vitro. In conclusion, these findings suggest that the inhibition of the p38 MAPK pathway has a beneficial effect on the development of diabetic nephropathy by inhibiting the increase in fibronectin expression and apoptosis
Files in This Item:
T200800728.pdf Download
DOI
10.1152/ajprenal.00624.2007
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Shin Wook(강신욱) ORCID logo https://orcid.org/0000-0002-5677-4756
Kim, Dong Ki(김동기)
Kim, Yu Seun(김유선) ORCID logo https://orcid.org/0000-0002-5105-1567
Moon, Sung Jin(문성진)
Yoo, Tae Hyun(유태현) ORCID logo https://orcid.org/0000-0002-9183-4507
Lee, Jung Eun(이정은) ORCID logo https://orcid.org/0000-0003-0917-2872
Han, Dae Suk(한대석)
Han, Seung Hyeok(한승혁) ORCID logo https://orcid.org/0000-0001-7923-5635
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/106985
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