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

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Authors
Jung, Dong-Sub; Li, Jin Ji; Kwak, Seung-Jae; Lee, Sun Ha; Park, Jehyun; Song, Young Soo; Yoo, Tae-Hyun; Han, Seung Hyeok; Lee, Jung Eun; Kim, Dong Ki; Moon, Sung Jin; Kim, Yu Seun; Han, Dae Suk; Kang, Shin-Wook
Issue Date
2008-06-06
Publisher
American Physiological Society
Citation
Am J Physiol Renal Physiol. 295(2):F595-F604
Keywords
AnimalsApoptosis/*drug effectsCaspase 3/metabolismCells, CulturedCyclic AMP Response Element-Binding Protein/metabolismDiabetes Mellitus, Experimental/metabolism/*pathologyDose-Response Relationship, DrugEnzyme Inhibitors/pharmacologyFibronectins/*metabolismGlucose/*pharmacologyHyperglycemia/metabolism/pathologyKidney Glomerulus/drug effects/metabolism/*pathologyMaleMesangial Cells/drug effects/metabolism/*pathologyProto-Oncogene Proteins c-bcl-2/metabolismPyrazoles/*pharmacologyPyridines/*pharmacologyRNA, Messenger/metabolismRatsRats, Sprague-DawleySignal Transduction/drug effectsStreptozocinbcl-2-Associated X Protein/metabolismp38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
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.
ISSN
0363-6127 (Print)
http://dx.doi.org/10.1152/ajprenal.00624.2007
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18524857
http://ajprenal.physiology.org/cgi/reprint/295/2/F595.pdf
Language
English
URI
http://hdl.handle.net/10371/68248
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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