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Increased Glomerular and Tubular Expression of Transforming Growth Factor-β1, Its Type II Receptor, and Activation of the Smad Signaling Pathway in the db/db Mouse

Authors
 Soon Won Hong  ;  Motohide Isono  ;  Sheldon Chen  ;  M. Carmen Iglesias-de la Cruz  ;  Dong Cheol Han  ;  Fuad N. Ziyadeh 
Citation
 AMERICAN JOURNAL OF PATHOLOGY, Vol.158(5) : 1653-1663, 2001 
Journal Title
AMERICAN JOURNAL OF PATHOLOGY
ISSN
 0002-9440 
Issue Date
2001
MeSH
Animals ; Binding Sites ; Cell Nucleus/metabolism ; DNA-Binding Proteins/metabolism* ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Gene Expression ; Glomerular Mesangium/metabolism* ; Glomerular Mesangium/pathology ; Glomerular Mesangium/ultrastructure ; Immunohistochemistry ; In Situ Hybridization ; Kidney Tubules/metabolism* ; Kidney Tubules/pathology ; Mice ; Mice, Inbred C57BL ; Microscopy, Electron ; Nuclear Proteins/metabolism ; Protein Binding ; Protein-Serine-Threonine Kinases ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Receptor, Transforming Growth Factor-beta Type II ; Receptors, Transforming Growth Factor beta/genetics* ; Receptors, Transforming Growth Factor beta/metabolism ; Signal Transduction ; Smad3 Protein ; Trans-Activators/metabolism* ; Transforming Growth Factor beta/genetics* ; Transforming Growth Factor beta/metabolism ; Transforming Growth Factor beta1
Abstract
Activation of the renal transforming growth factor-β (TGF-β) system likely mediates the excess production of extracellular matrix in the diabetic kidney. To establish the role of the TGF-β system in type 2 diabetic nephropathy, we examined the intrarenal localization and expression of the TGF-β1 isoform, the TGF-β type II receptor, and the Smad signaling pathway in the 16-week-old db/db mouse, a genetic model of type 2 diabetes that exhibits mesangial matrix expansion, glomerular basement membrane thickening, and renal insufficiency that closely resemble the human disease. Compared with its nondiabetic db/m littermate, the db/db mouse showed significantly increased TGF-β1 mRNA expression by in situ hybridization in both glomerular and tubular compartments. Likewise, TGF-β1 protein, by immunohistochemical staining, was increased in both renal compartments, but the fractional expression of TGF-β1 protein was less than that of the mRNA in the glomerulus. In situ hybridization and immunohistochemical staining for the TGF-β type II receptor revealed concordant and significant increases of both mRNA and protein in the glomerular and tubular compartments of diabetic animals. Finally, immunohistochemistry showed preferential accumulation of Smad3 in the nuclei of glomerular and tubular cells in diabetes. The complementary technique of Southwestern histochemistry using a labeled Smad-binding element demonstrated increased binding of nuclear proteins to Smad-binding element, indicating active signaling downstream of the TGF-β stimulus. We therefore propose that the TGF-β system is up-regulated at the ligand, receptor, and signaling levels throughout the renal cortex in this animal model of type 2 diabetes. Our findings suggest that the profibrotic effects of TGF-β may underlie the progression to glomerulosclerosis and tubulointerstitial fibrosis that characterize diabetic nephropathy.
Files in This Item:
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Hong, Soon Won(홍순원) ORCID logo https://orcid.org/0000-0002-0324-2414
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/142949
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