Floege J, Eng E, Young B A, Couser W G, Johnson R J
Department of Medicine, University of Washington, Seattle.
Kidney Int. 1993 Feb;43(2):369-80. doi: 10.1038/ki.1993.55.
Proliferation and extracellular matrix (ECM) overproduction by glomerular mesangial cells characterizes many types of glomerulonephritis and often precedes the development of glomerulosclerosis. Heparin is a potent inhibitor of mesangial cell growth in vitro. We examined whether standard heparin can inhibit mesangial cell proliferation in vivo in the mesangioproliferative anti-Thy 1.1 nephritis. Untreated control rats were compared to rats infused with heparin either early (day -2 to 1) or late (day 2 to 5) after induction of anti-Thy 1.1 nephritis. The results show that heparin treatment significantly reduced mesangial cell proliferation regardless of when it was initiated. Heparin (either early or late treatment) also reduced mesangial basic fibroblast growth factor (bFGF) expression and platelet-derived growth factor (PDGF) receptor up-regulation as reflected by immunostaining, whereas PDGF B-chain expression was reduced only by late heparin treatment. Furthermore, heparin treatment markedly inhibited the mesangial matrix expansion for a variety of ECM proteins, including laminin, type I and IV collagen, fibronectin and entactin. Heparin did not affect the initial mesangiolysis, glomerular macrophage influx, deposition of anti-Thy 1.1 IgG or fibrinogen, or the glomerular platelet influx. These results suggest that heparin, via its antiproliferative rather than anticoagulant effect, can inhibit mesangial cell proliferation, overexpression of polypeptide growth factors, and ECM protein overproduction in vivo. The beneficial effect of heparin can be demonstrated even if treatment is initiated after the development of nephritis. By virtue of these properties, heparin may be an effective agent in the treatment of human mesangioproliferative disease and in the prevention of glomerulosclerosis.
肾小球系膜细胞的增殖和细胞外基质（ECM）过度产生是多种类型肾小球肾炎的特征，且常常先于肾小球硬化的发展。肝素在体外是系膜细胞生长的有效抑制剂。我们研究了标准肝素在系膜增生性抗Thy 1.1肾炎体内是否能抑制系膜细胞增殖。将未治疗的对照大鼠与在抗Thy 1.1肾炎诱导后早期（第-2天至第1天）或晚期（第2天至第5天）输注肝素的大鼠进行比较。结果显示，无论何时开始治疗，肝素治疗均显著降低系膜细胞增殖。肝素（早期或晚期治疗）还通过免疫染色反映出降低了系膜碱性成纤维细胞生长因子（bFGF）表达和血小板衍生生长因子（PDGF）受体上调，而仅晚期肝素治疗降低了PDGF B链表达。此外，肝素治疗显著抑制了多种ECM蛋白的系膜基质扩张，包括层粘连蛋白、I型和IV型胶原、纤连蛋白和巢蛋白。肝素不影响初始系膜溶解、肾小球巨噬细胞流入、抗Thy 1.1 IgG或纤维蛋白原沉积或肾小球血小板流入。这些结果表明，肝素通过其抗增殖而非抗凝作用，可在体内抑制系膜细胞增殖、多肽生长因子的过度表达以及ECM蛋白过度产生。即使在肾炎发展后开始治疗，肝素的有益作用也可得到证明。凭借这些特性，肝素可能是治疗人类系膜增生性疾病和预防肾小球硬化的有效药物。
