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

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

Research output: Contribution to journalArticlepeer-review

745 Scopus citations

Abstract

Emerging evidence suggests that transforming growth factor-β (TGF-β) is an important mediator of diabetic nephropathy. We showed previously that short-term treatment with a neutralizing monoclonal anti-TGF-β antibody (αT) in streptozotocin-diabetic mice prevents early changes of renal hypertrophy and increased matrix mRNA. To establish that overactivity of the renal TGF-β system mediates the functional and structural changes of the more advanced stages of nephropathy, we tested whether chronic administration of αT 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 αT or control IgG, 300/μg three times per week for 8 wk. Treatment with αT, but not with IgG, significantly decreased the plasma TGF-βI 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 α1(IV) collagen and fibronectin. On the other hand, treatment with αT 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 αT treatment. We conclude that chronic inhibition of the biologic actions of TGF-β with a neutralizing monoclonal antibody in db/db mice prevents the glomerulosclerosis and renal insufficiency resulting from type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)8015-8020
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number14
DOIs
StatePublished - Jul 5 2000

ASJC Scopus subject areas

  • General

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