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  • Title: Electroporation-mediated PDGF receptor-IgG chimera gene transfer ameliorates experimental glomerulonephritis.
    Author: Nakamura H, Isaka Y, Tsujie M, Akagi Y, Sudo T, Ohno N, Imai E, Hori M.
    Journal: Kidney Int; 2001 Jun; 59(6):2134-45. PubMed ID: 11380815.
    Abstract:
    BACKGROUND: Mesangial cell proliferation and phenotypic alteration occur in an early phase of glomerular injury and precede increased extracellular matrix accumulation. A critical growth factor responsible for mesangial proliferation is platelet-derived growth factor (PDGF), which has proved to be a potent mitogen. METHODS: We generated a chimeric cDNA encoding an extracellular domain of the beta-PDGF receptor fused with IgG-Fc, termed PDGFR/Fc, and examined the feasibility of gene therapy targeting PDGF using PDGFR/Fc. RESULTS: Chimeric PDGFR/Fc molecule completely inhibited the tyrosine phosphorylation of beta-PDGF receptors and cellular proliferation induced by PDGF in vitro. We then introduced the PDGFR/Fc expression vector into the muscle of anti-Thy-1 model of glomerulonephritic rats by electroporation. The plasma concentration of chimeric PDGFR/Fc levels was 244.4 +/- 89.8 ng/mL four days after transfection. On day 5, PDGFR/Fc gene transfer significantly reduced the number of PCNA-positive cells and glomerular cell numbers by 59.6 and 23.2%, respectively. Northern blot analysis demonstrated that glomerular mRNA levels of alpha-smooth muscle action, transforming growth factor-beta 1, and type I collagen were also suppressed on days 5 and 7 by the PDGFR/Fc transfection. There was a significant reduction in the matrix score of the transfected nephritic rats (2.91 +/- 0.75 and 2.06 +/- 0.95; disease control group vs. treated group, P < 0.001). CONCLUSION: These results suggest that gene therapy by the manipulation of PDGF action using electroporation-mediated PDGFR/Fc gene transfer to the skeletal muscle might be a useful treatment for mesangioproliferative glomerulonephritis.
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