Emerging evidence suggests that transforming growth factor- (TGF-) is an important mediator of diabetic nephropathy. We showed previously that short-term treatment with a neutralizing monoclonal anti-TGF- antibody (␣T) 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 ␣T prevents renal insufficiency and glomerulosclerosis in the db͞db mouse, a model of type 2 diabetes that develops overt nephropathy. Diabetic db͞db mice and nondiabetic db͞m littermates were treated intraperitoneally with ␣T or control IgG, 300 g three times per week for 8 wk. Treatment with ␣T, but not with IgG, significantly decreased the plasma TGF-1 concentration without decreasing the plasma glucose concentration. The IgG-treated db͞db mice developed albuminuria, renal insufficiency, and glomerular mesangial matrix expansion associated with increased renal mRNAs encoding ␣1(IV) collagen and fibronectin. On the other hand, treatment with ␣T completely prevented the increase in plasma creatinine concentration, the decrease in urinary creatinine clearance, and the expansion of mesangial matrix in db͞db 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 ␣T treatment. We conclude that chronic inhibition of the biologic actions of TGF- with a neutralizing monoclonal antibody in db͞db mice prevents the glomerulosclerosis and renal insufficiency resulting from type 2 diabetes.
MSI status and PD-L1 expression are clinically actionable biomarkers for stratifying patients and predicting benefit from adjuvant chemotherapy after D2 gastrectomy for stage II/III gastric cancer.
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