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…
By F. Ziyadeh, B. B. Hoffman, D. Han, M. C. Cruz, Soon Won Hong, M. Isono, Sheldon Chen, Tracy A. McGowan, K. Sharma. Proceedings of the National Academy of Sciences of the United States of America, 2000
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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.
Subfields: Clinical Biochemistry, Molecular Biology, Nephrology
View Paper: https://www.semanticscholar.org/paper/8ba908151e7950526f0b30095460bf2b13d23992
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Citations in the corpus
- Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. (2012, background): “Direct support for the key role played by TGF-β in the development of diabetic nephropathy comes from studies where treatment with neutralizing monoclonal antibodies to TGF-β prevents glomerular hypertrophy, mesangial matrix expansion, and glomerulosclerosis and preserves renal function in streptozo”
- TGF-beta and fibrosis in different organs - molecular pathway imprints. (2009, background): “vity prevents the progression of renal failure in diabetes [57].”
- Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. (2013, background): “Moreover, suppression of TGF-b signaling reduced mesangial expansion and interstitial fibrosis in experimental T2DM nephropathy (Ziyadeh et al., 2000), which indicates that TGF-b may participate in the inhibition of inflammatory factors induced by T2DM.”
- Mechanisms of diabetic complications. (2013, background): “TGF- 1 is arguably the most potent inducer of tissue fibrosis, and chronic administration of a neutralizing TGF- 1 antibody improves renal function and structure in models of type 1 (537) and type 2 diabetes (691).”