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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
- Source :
- Proceedings of the National Academy of Sciences of the United States. July 5, 2000, Vol. 97 Issue 14, 8015
- Publication Year :
- 2000
-
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 ([Alpha]T) 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 [Alpha]T 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 [Alpha]T or control IgG, 300 [micro]g three times per week for 8 wk. Treatment with [Alpha]T, but not with IgG, significantly decreased the plasma TGF-[Beta] 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 [Alpha]1(IV) collagen and fibronectin. On the other hand, treatment with [Alpha]T 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 [Alpha]T 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.
Details
- ISSN :
- 00278424
- Volume :
- 97
- Issue :
- 14
- Database :
- Gale General OneFile
- Journal :
- Proceedings of the National Academy of Sciences of the United States
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.63715768