[Inhibition of mesangial cell proliferation and mesangial matrix expansion by antisense oligodeoxynucleotide targeting preproendothelin-1 mRNA in vivo].

OBJECTIVE

To investigate the effect of endothelin-1 (ET-1) on mesangial cells(MC) proliferation and mesangial matrix expansion in vivo.

METHODS

Antisense oligodeoxynucleotide(As-ODN) and its control sequences, sense oligodeoxynucleotide(Se-ODN) and mismatch oligodeoxynucleotide(Mis-ODN), targeting pre-proendothelin-1 mRNA (ppET-1) were delivered into the kidney of rats with mesangioproliferative glomerulonephritis (MsPGN) model respectively at day 2 by lipofectin-mediated gene transfer method. The efficiency of transfer of ODNs into MC was examined with biotinylated As-ODN staining. Four days after the rats were sacrificed, the influence of ODNs on ET-1 production by glomeruli was tested with radioimmunoassay(RIA). The action of ODNs on MC proliferation and mesangial matrix expansion was evaluated with quantitative pathologic analysis.

RESULTS

ODNs were transferred into MC in vivo. The glomerular ET-1 production was decreased by As-ODN [(32 +/- 19) ng/g, P < 0.05] with reduction of mesangial cell proliferation [(0.82 +/- 0.04)/100 micron 2, P < 0.05] and mesangial matrix expansion[(12.8 +/- 1.6)%, P < 0.05], where Se-ODN and Mis-ODN did not show any effect on all of these.

CONCLUSIONS

Specific inhibition of ET-1 gene expression leads to reduction of proliferation of mesangial cell and expansion of mesangial matrix in rats with MsPGN model. ET-1 is one of the important inflammatory mediators which can stimulate MC proliferation and mesangial matrix expansion in vivo.