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Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice

Authors
 Fuad N. Ziyadeh  ;  Brenda B. Hoffman  ;  Dong Cheol Han  ;  M. Carmen Iglesias-de la Cruz  ;  Soon Won Hong  ;  Motohide Isono  ;  Sheldon Chen  ;  Tracy A. McGowan  ;  Kumar Sharma 
Citation
 Proceedings of the National Academy of Sciences of the United States of America, Vol.97(14) : 8015-8020, 2000 
Journal Title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN
 0027-8424 
Issue Date
2000
MeSH
Animals ; Antibodies, Monoclonal/therapeutic use* ; Carrier Proteins/genetics ; Diabetes Mellitus, Type 2/complications* ; Disease Models, Animal ; Extracellular Matrix/drug effects* ; Extracellular Matrix Proteins/biosynthesis ; Glomerular Mesangium/drug effects* ; Glomerular Mesangium/pathology ; Mice ; Mice, Mutant Strains ; Protein-Serine-Threonine Kinases ; Receptors, Cell Surface* ; Receptors, Leptin ; Receptors, Transforming Growth Factor beta/biosynthesis ; Renal Insufficiency/etiology ; Renal Insufficiency/prevention & control* ; Transforming Growth Factor beta/immunology* ; Up-Regulation
Abstract
Emerging evidence suggests that transforming growth factor-beta (TGF-beta) is an important mediator of diabetic nephropathy. We showed previously that short-term treatment with a neutralizing monoclonal anti-TGF-beta antibody (alphaT) in streptozotocin-diabetic mice prevents early changes of renal hypertrophy and increased matrix mRNA. To establish that overactivity of the renal TGF-beta system mediates the functional and structural changes of the more advanced stages of nephropathy, we tested whether chronic administration of alphaT prevents renal insufficiency and glomerulosclerosis in the db/db mouse, a model of type 2 diabetes that develops overt nephropathy. Diabetic db/db mice and nondiabetic db/m littermates were treated intraperitoneally with alphaT or control IgG, 300 microgram three times per week for 8 wk. Treatment with alphaT, but not with IgG, significantly decreased the plasma TGF-beta1 concentration without decreasing the plasma glucose concentration. The IgG-treated db/db mice developed albuminuria, renal insufficiency, and glomerular mesangial matrix expansion associated with increased renal mRNAs encoding alpha1(IV) collagen and fibronectin. On the other hand, treatment with alphaT completely prevented the increase in plasma creatinine concentration, the decrease in urinary creatinine clearance, and the expansion of mesangial matrix in db/db mice. The increase in renal matrix mRNAs was substantially attenuated, but the excretion of urinary albumin factored for creatinine clearance was not significantly affected by alphaT treatment. We conclude that chronic inhibition of the biologic actions of TGF-beta with a neutralizing monoclonal antibody in db/db mice prevents the glomerulosclerosis and renal insufficiency resulting from type 2 diabetes.
Files in This Item:
T200003085.pdf Download
DOI
10.1073/pnas.120055097
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/22282913/171845
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