Development of Gene Therapy for Progrssive Glomerular Diseases

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Action of various growth factors in pathophysiological condition in the process of progressive renal diseases has been demonstrated by several lines of evidences. The up-regulation of transforming growth factor-beta (TGF-beta) and Platelet-derived growth factor (PDGF) as well as their receptors are observed in glomerular and tubulointerstitial lesions in experimental and human glomerulonephritis. In experimental animals, overproduction of TGF-beta by gene transfection to kidney or transgenic mouse carrying TGF-beta gene causes glomerulosclerosis. These evidences which support the pivotal role of growth factor prompt us to intervene the development of glomerulosclerosis by gene technology. To inhibit the action of TGF-beta or PDGF we created the expression plasmids for extracellular domain of receptor-immunoglobulin Fc chimera. The purified TGF-betaR-Fc, which was obtained from cultured COS cells, inhibited the suppression of cell growth and extracellular matrix synthesis by TGF-beta. We transfected the expression vector for TGFbeta-R-Fc to the gluteal muscle of the anti-Thy 1 glomerulonephritis by HVJ-liposome method. The synthesized TGF-betaR-Fc accumulated to the kidney through the systemic circulation. Consequently, the glomerular TGF-betamRNA were suppressed and the extracellular matrix accumulation was concomitantly reduced. Similarly, The purified betaPDGFR-Fc inhibited cell proliferation induced by PDGF-B.Transfected betaPDGF-Fc into skeletal muscle suppressed PCNA expression and the cell number of glomerulus in comparable with reduction of ECM accumulation. These results suggest that the molecular intervention by growth factor receptor-Fc chimera may be feasible for the therapy of glomerulosclerosis.