Hyperglycemia and Diabetic Kidney Disease: The Case for Transforming Growth Factor–β as a Key Mediator
- Department of Medicine, Division of Nephrology, Thomas Jefferson University Philadelphia, Pennsylvania
- Department of Medicine, Renal-Electrolyte and Hypertension Division and Penn Center for Molecular Studies of Kidney Diseases, University of Pennsylvania, School of Medicine Philadelphia, Pennsylvania
- 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.
Renal cells are a rich source of transforming growth factor (TGF)-β, and they serve as targets for its actions. Our hypothesis that activation of the TGF-β system in the kidney is implicated in the development of diabetic renal disease stems from the close similarity of actions of TGF-β and high ambient glucose on renal cell growth and extracellular matrix metabolism. Proximal tubule cells and glomerular mesangial cells cultured in high glucose concentration express increased TGF-β1 mRNA and protein levels, and treatment with anti-TGF-β antibodies results in prevention of the effects of high glucose to induce cellular hypertrophy and stimulate collagen biosynthesis. Several in vivo studies by different groups of investigators have reported overexpression of TGF-β in the glomeruli in human and experimental diabetes. We have also observed that the development of renal hypertrophy in the insulin-dependent diabetic BB rat and NOD mouse is associated with increased expression of TGF-β1 in the kidney and that short-term administration of antibodies capable of neutralizing the activity of TGF-β in the streptozotocin mouse model of diabetes results in attenuation of whole kidney and glomerular hypertrophy and overexpression of mRNAs encoding matrix components. Together, these findings are consistent with the hypothesis that the diabetic state stimulates TGF-β expression in the kidney and that in turn this growth factor may mediate, in an autocrine/paracrine manner, some of the principal early manifestations of diabetic renal disease. Demonstrating a causal link between upregulation of glomerular TGF-β and the subsequent development of diabetic glomerulosclerosis will require long-term interventional studies designed to intercept the TGF-β system in the kidney.
- Received April 12, 1995.
- Revision received June 29, 1995.
- Accepted June 29, 1995.
- Copyright © 1995 by the American Diabetes Association