Neutralization of TGF-β by Anti-TGF-β Antibody Attenuates Kidney Hypertrophy and the Enhanced Extracellular Matrix Gene Expression in STZ-Induced Diabetic Mice

Abstract

Diabetic nephropathy is characterized by renal hypertrophy, thickening of basement membranes, and accumulation of extracellular matrix in the glomerular mesangium and the interstitium. Our previous investigations have shown that high glucose concentration increases transforming growth factor (TGF)-beta1 mRNA in mesangial and proximal tubule cells and that treatment with anti-TGF-beta antibody results in prevention of the effects of high glucose on cell growth (e.g., induction of cellular hypertrophy) and the stimulation of collagen biosynthesis. We evaluated in vivo the functional role of the renal TGF-beta system in diabetic kidney disease by treatment of streptozotocin-induced diabetic mice with either a neutralizing monoclonal antibody against TGF-beta1, -beta2, and -beta3 (alphaT) or nonimmune murine IgG for 9 days. Diabetic mice given IgG demonstrated total kidney and glomerular hypertrophy, significantly elevated urinary TGF-beta1 protein, and increased mRNAs encoding TGF-beta1, type II TGF-beta receptor, alpha1(IV) collagen, and fibronectin. Treatment of diabetic mice with alphaT prevented glomerular hypertrophy, reduced the increment in kidney weight by approximately 50%, and significantly attenuated the increase in mRNA levels without having any effect on blood glucose. The antibody was without significant effect on mRNA levels in nondiabetic mice. This is the first demonstration that the early characteristic features of diabetic renal involvement, which include hypertrophy and increased matrix mRNAs, are largely mediated by increased endogenous TGF-beta activity in the kidney and that they can be significantly attenuated by treatment with neutralizing anti-TGF-beta antibodies.

Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease

“…Potential new therapeutic agents in the treatment of diabetic kidney disease: antagonists of the pathophysiologically altered transforming growth factor b (TGF-b) system For further explanation and references please see text cells is dependent on the autocrine action of TGF-b1 because neutralizing antibodies to TGF-b attenuate the rise [101]. Further, in vivo treatment of STZ-diabetic mice for 9 days with a neutralizing TGF-b1, TGF-b2, TGF-b3 antibody attenuated the increased renal TGF-b1 and TGF-b type IIR mRNA expressions and reduced the diabetes-associated renal/ glomerular growth and enhanced renal expression of collagen IV and fibronectin [102].…”

High glucose activates PKC-ζ and NADPH oxidase through autocrine TGF-β1 signaling in mesangial cells

“…Enhanced expression of TGF-␤ 1 , TGF-␤ receptors, TGF-␤ 1 bioactivity, and responsiveness to exogenous TGF-␤ 1 have been noted to occur in response to high glucose in glomerular mesangial cells grown in tissue culture, an in vitro model for the effects of high glucose (19,21,29,41,68,69). Furthermore, inhibiting TGF-␤ 1 attenuates the high glucoseinduced changes in gene expression in mesangial cells that lead to the accumulation of ECM both in vitro and in animal models of diabetic nephropathy (29,45,70,71).…”

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

“…In vitro, high-glucose culture induces TGF-␤1 mRNA or protein expression (12) at the transcriptional level (13). Moreover, intraperitoneal administration of neutralizing antibody to TGF-␤1 attenuates the increase in mRNA for collagen and fibronectin in the kidneys of streptozotocin (STZ)-induced diabetic mice (14) and preserves glomerular function in type 2 diabetic db/db mice (15). Furthermore, TGF-␤1 inhibition may ameliorate even established changes (16).…”