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

Abstract

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.

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

“…14 In one study, the ID11 antibody reduced mesangial sclerosis, although proteinuria was not significantly improved. 12 The timing of anti-TGF-␤ administration also affects outcomes in streptozotocin-treated rats with early treatment (27 to 52 weeks) but not late treatment (52 to 61 weeks), having significant beneficial effects on glomerulosclerosis and proteinuria. 61 The present findings are unusual in that mesangial sclerosis was not affected by LSKL treatment but albuminuria was reduced.…”

“…10 Increased expression of TGF-␤ in glomeruli is documented in diabetic patients and in animal models. [11][12][13] Treatment of diabetic mice with neutralizing antibodies to TGF-␤ reduces mesangial matrix expansion, with differential effects on proteinuria, depending on the specific anti-TGF-␤ antibody used. 12,14 -16 Thus, TGF-␤ has been considered as a therapeutic target for the treatment of diabetic nephropathy.…”

Angiotensin II induces human TGF-β1 promoter activation: similarity to hyperglycaemia

“…The prosclerotic cytokine transforming growth factor beta (TGF-β1) has been implicated as an important downstream mediator in the progression of the renal pathological changes occurring in diabetic patients which lead to glomerular and tubular basement membrane thickening, mesangial matrix expansion, and glomerulosclerosis [13,15,15,16,17,18]. Numerous studies including data from our own laboratory indiStudies have provided evidence that angiotensin-converting enzyme inhibitors and angiotensin-receptor antagonists attenuate diabetic glomerulosclerosis and slow the progression of diabetic kidney disease [1, 2, cate that hyperglycemia induces an increase in TGF-β1 protein and mRNA expression in experimental and human diabetes [15,19,20,21] and in cultured mesangial cells [22,23,24].…”

Current concepts in radiation enteritis and implications for future clinical trials

“…Long-term administration of TGF-␤1 antibody also prevented the deposition of collagen and fibronectin in the kidneys of diabetic db/db mice. 85 In addition, the fall in the glomerular filtration rate observed in untreated animals was suppressed by the antibody. In situ hybridization studies showed increased TGF-␤1 levels in both glomerular and tubular components of db/db mouse kidneys.…”