Heparin이 사구체 메산지움 세포의 중식 및 Endothelin 생성에 미치는 영향

Abstract

Glomerular mesangial cells have receptors to various growth factors and vasoactive peptides such as platelet-derived growth factor(PDGF), and endothelin(ET), which are important mediators for the progression of glomerular diseases. Heparin has been reported to have anti-proliferative effects in vascular smooth muscle cells and mesangial cells. Furthe- rmore, the treatment with heparin suppresses the progression of experimental mesangioproliferative glomerulonephritis. The present study was carried out to further ascertain inhibitory effects of heparin and possible mechanisms of its action, particularly in relation to the effect on ET production of mesangial cells. The effect of heparin on PDGF-stimulated proliferation was assessed by [H]thymidine uptake as well as the increase of number of cells, and ET production was evaluated in cultured rat mesangial cells. The results were as follows. 1) PDGF at a concentration of 10 ng/ml stimu- lated [Hjthymidine uptake significantly(mean S.D., 512.0 38.6 cpm/well vs. 3300.4±432.5, p<0.05), and also increased the number of cells significantly, compared to control(23.0±3.5 x10";/well vs. 66.5±8.9, p<0.05). 2) Heparin inhibited the PDGF(10ng/ml)-stimulated proliferation of mesangial cells in a dose-dependent manner(100 p g/ml, 3300.4±432.5cpm/well vs. 1452.5± 264.7, 66.5 ± 8.9 cpm/well vs. 20.0±6.5, p<0.05). 3) While N-desulfated heparin did not show the inhibitory effect on [H]thymidine uptake, the potency of intact heparin(100pg/ml) was 56.2±8.0% inhibition, which was similar to chondroitin sulfate(48.9±5.4%). N-desulfated N-acetylated he- parin showed 25.7±9.7% inhibition. 4) PDGF stimulated the production of ET in a dosedependent manner(25ng/ml, 4.2+0.7pg/ml/mg of protein vs 15.71.4, p<0,05). 5) Heparin inhibited the PDGF(25ng/ml)-stimulated ET production in a dose-dependent pattern(100pg/ ml, 12.6±3.5 vs. 2.5±1.1, p<0.05). From the above results, it is concluded that heparin has a significant inhibitory effect on proli- feration and ET production in mesangial cells, and this anti-proliferative effect of heparin appears to be related to the structure of heparin, especially N-sulfation. In conclusion, heparin may reduce glomerular injury through these inhibitory effects on mesangial cells, but the further studies such as in vivo experiments considering the anticoagulation effect are needed.