Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-ß antibody in db/db diabetic mice
Emerging evidence suggests that transforming growth factor-(TGF-β) is an important mediator of diabetic nephropathy. We showed previously that short-term treatment with a neutralizing monoclonal anti-TGF-antibody (αT) in streptozotocin-diabetic mice prevents early changes of renal hypertrophy and increased matrix mRNA. To establish that overactivity of the renal TGF-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, model of type 2 diabetes that develops overt nephropathy. Diabetic db/db mice and nondiabetic db/m littermates were treated intraperitoneally with α or control IgG, 300 µg three times per week for 8 wk. Treatment with αT, but not with IgG, significantly decreased the plasma TGF-β1 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 α 1(IV) collagen and fibronectin. On the other hand, treatment with α 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 α treatment. We conclude that chronic inhibition of the biologic actions of TGF-with neutralizing monoclonal antibody in db/db mice prevents the glomerulosclerosis and renal insufficiency resulting from type diabetes.
Recommended CitationZiyadeh, Fuad N.; Hoffman, Brenda B.; Han, Dong Cheol; Iglesias-de la Cruz, M. Carmen; Hong, Soon Won; Isono, Motohide; Chen, Sheldon; McGowan, Tracy A.; and Sharma, Kumar, "Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-ß antibody in db/db diabetic mice " (2000). Department of Medicine Faculty Papers. Paper 7.