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

  1. Fuad N Ziyadeh
  1. Renal-Electrolyte and Hypertension Division and Penn Center for Molecular Studies of Kidney Diseases, Department of Medicine, University of Pennsylvania School of Medicine Philadelphia, Pennsylvania
  2. Division of Nephrology, Department of Medicine, Thomas Jefferson University Philadelphia, Pennsylvania
  1. Address correspondence and reprint requests to Dr. Fuad N. Ziyadeh, Renal-Electrolyte & Hypertension Division, 700 Clinical Research Building, University of Pennsylvania, 422 Curie Blvd., Philadelphia, PA 19104-6144.

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)-β1 mRNA in mesangial and proximal tubule cells and that treatment with anti-TGF-β 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-β system in diabetic kidney disease by treatment of streptozotocin-induced diabetic mice with either a neutralizing monoclonal antibody against TGF-β1, -β2, and -β3 (αT) or nonimmune murine IgG for 9 days. Diabetic mice given IgG demonstrated total kidney and glomerular hypertrophy, significantly elevated urinary TGF-β1 protein, and increased mRNAs encoding TGF-β1, type II TGF-β receptor, α1(IV) collagen, and fibronectin. Treatment of diabetic mice with αT prevented glomerular hypertrophy, reduced the increment in kidney weight by ∼ 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-β activity in the kidney and that they can be significantly attenuated by treatment with neutralizing anti-TGF-β antibodies.

  • Received August 11, 1995.
  • Revision received November 29, 1995.
  • Accepted November 29, 1995.
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