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 thedb/dbmouse, a model of type 2 diabetes that develops overt nephropathy. Diabeticdb/dbmice and nondiabeticdb/mlittermates 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-β1 concentration without decreasing the plasma glucose concentration. The IgG-treateddb/dbmice 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 indb/dbmice. 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 indb/dbmice prevents the glomerulosclerosis and renal insufficiency resulting from type 2 diabetes.

The transcription factor Snail controls epithelial–mesenchymal transitions (EMT) by repressing E‐cadherin expression and other epithelial genes. However, the mechanisms involved in the regulation of Snail function are not fully understood. Here we show that lysyl‐oxidase‐like 2 and 3 (LOXL2 and LOXL3), two members of the lysyl‐oxidase gene family, interact and cooperate with Snail to downregulate E‐cadherin expression. Snail's lysine residues 98 and 137 are essential for Snail stability, functional cooperation with LOXL2/3 and induction of EMT. Overexpression of LOXL2 or LOXL3 in epithelial cells induces an EMT process, supporting their implication in tumor progression. The biological importance of LOXL2 is further supported by RNA interference of LOXL2 in Snail‐expressing metastatic carcinoma cells, which led to a strong decrease of tumor growth associated to increased apoptosis and reduced expression of mesenchymal and invasive/angiogenic markers. Taken together, these results establish a direct link between LOXL2 and Snail in carcinoma progression.