Cytokines such as transforming growth factor-β (TGF-β) are peptide factors that regulate embryogenesis, development, inflammation, tissue repair, and carcinogenesis. Growing evidence indicates that dysregulation of cytokine actions may underlie the pathogenesis of serious autoimmune, degenerative, and fibrotic diseases. Studies in a model of acute mesangial proliferative glomerulonephritis show that overproduction of TGF-β is the cause of pathologic accumulation of extracellular matrix in the nephritic glomeruli. Transforming growth factor-β acts to increase matrix production, inhibit matrix degradation, and modulate matrix receptors in the glomerulonephritic rats. It may also play a role in the glomerular matrix build-up that is a central feature of diabetic nephropathy. Elevated expression of TGF-β mRNA and TGF-β protein were found in the glomeruli of diabetic rats along with increased levels of proteoglycans and other matrix components that are known to be induced by TGF-β. The study of human diabetic glomeruli has also shown markedly elevated levels of TGF-ft protein. Glomeruli from normal kidneys and nonprogressive kidney disorders were negative. The striking ability of TGF-β to cause exuberant matrix formation may be due to the fact that TGF-β can induce its own production by resident cells at a site of injury. Thus, the potential for TGF-β to do harm may be due to this autoinduction mechanism whereby TGF-β expression can become chronic, creating a vicious circle. As the role that TGF-ft plays in chronic fibrotic diseases becomes better understood, it is likely that TGF-β inhibitors will become important future drugs for treating these conditions. To date, TGF-β activity has been successfully blocked in the kidney, in the skin, and in the central nervous system by neutralizing antibodies. In each case, inhibiting TGFβ significantly decreased the accumulation of excessive extracellular matrix but did not interfere with normal tissue repair. Recently, it has been discovered that the proteoglycan decorin may be a natural regulator of TGF-β. Injection of recombinant human decorin into glomerulonephritic rats significantly blocked extracellular matrix build-up in the nephritic glomeruli and suppressed the development of proteinuria. Since decorin is a natural human compound that can be produced as a recombinant molecule, it is likely not to be immunogenic compared with antibodies. Decorin offers hope as a treatment for chronic diseases associated with the overproduction of TGF-β. © 1993, National Kidney Foundation. All rights reserved. All rights reserved.
