Kohno M, Yokokawa K, Horio T, Ikeda M, Kurihara N, Mandal A K, Takeda T
First Department of Internal Medicine, Osaka City University Medical School, Japan.
Kidney Int. 1994 Jan;45(1):137-42. doi: 10.1038/ki.1994.16.
The present study was designed to examine whether heparin inhibits basal or stimulated endothelin-1 production by arginine vasopressin (AVP) and platelet-derived growth factor (PDGF) in cultured rat mesangial cells. In addition, the reversibility of the heparin effect on mesangial cell endothelin-1 production was examined. AVP and PDGF stimulated endothelin-1 secretion in a concentration-dependent manner in these cells. Heparin (10 to 100 U/ml) exhibited concentration-related inhibition of AVP- and PDGF-stimulated endothelin-1 secretion. Heparin also had weak but significant inhibitory effects on basal endothelin-1 secretion in these cells. The protein kinase (PKC)-activating phorbor ester, phorbor myristate acetate (PMA), stimulated endothelin-1 secretion and heparin inhibited PMA-stimulated endothelin-1 secretion. In addition, the inhibitory effect of heparin was completely abolished in PKC-depleted mesangial cells. Mesangial cells which were exposed to a high concentration (100 U/ml) of heparin for 24 hours were capable of producing endothelin-1 after a short lag period of removal of heparin from the culture medium. These mesangial cells also showed recovery of responses to AVP and PDGF by secreting a significantly greater amount of endothelin-1 than the non-stimulated level. These results indicate that heparin potently inhibits mesangial cell endothelin-1 production, especially when stimulated by AVP or PDGF. This inhibitory effect of heparin is probably PKC dependent, and reversible.
本研究旨在检测肝素是否能抑制培养的大鼠系膜细胞中精氨酸加压素（AVP）和血小板衍生生长因子（PDGF）刺激的内皮素-1基础分泌或刺激分泌。此外，还检测了肝素对系膜细胞内皮素-1分泌作用的可逆性。AVP和PDGF在这些细胞中以浓度依赖的方式刺激内皮素-1分泌。肝素（10至100 U/ml）对AVP和PDGF刺激的内皮素-1分泌表现出浓度相关的抑制作用。肝素对这些细胞中的内皮素-1基础分泌也有微弱但显著的抑制作用。蛋白激酶（PKC）激活剂佛波酯、十四酰佛波醇乙酯（PMA）刺激内皮素-1分泌，而肝素抑制PMA刺激的内皮素-1分泌。此外，在PKC缺失的系膜细胞中，肝素的抑制作用完全消失。暴露于高浓度（100 U/ml）肝素24小时的系膜细胞，在从培养基中去除肝素后的短暂延迟期后能够产生内皮素-1。这些系膜细胞对AVP和PDGF的反应也有所恢复，分泌的内皮素-1量明显高于未刺激水平。这些结果表明，肝素能有效抑制系膜细胞内皮素-1的产生，尤其是在受到AVP或PDGF刺激时。肝素的这种抑制作用可能依赖于PKC，并且是可逆的。
