Floege J, Eng E, Lindner V, Alpers C E, Young B A, Reidy M A, Johnson R J
Department of Medicine, University of Washington Medical Center, Seattle 98195.
J Clin Invest. 1992 Dec;90(6):2362-9. doi: 10.1172/JCI116126.
Mesangial injury and cell proliferation are frequent findings in various glomerular diseases in man. Previous studies have demonstrated that basic fibroblast growth factor (bFGF) is a potent mesangial cell mitogen in vitro. To further elucidate the role of bFGF in rat mesangial cell (RMC) proliferation, we examined whether RMC synthesize bFGF in vitro and whether bFGF is involved in mesangial proliferation in vivo. Cultured RMC expressed bFGF protein (23, 21.5, and 18 kD forms) and bFGF mRNA, and released biologically active bFGF into the culture medium after antibody- and complement-mediated injury. Normal rat glomeruli in vivo contained no detectable bFGF mRNA, but bFGF protein (23 and 21.5 kD) could be demonstrated, which immunolocalized to the mesangium. Glomerular bFGF decreased markedly during the acute phase of glomerulonephritis induced by anti-Thy 1.1 antibody, compatible with mesangial bFGF release after complement-mediated mesangiolysis. During the subsequent mesangial proliferative phase, glomerular bFGF protein and mRNA increased above normal. Intrarenal infusion of heparin did not affect the bFGF immunostaining of glomeruli at this stage, indicating a predominantly intracellular localization of the bFGF. The capability of bFGF to mediate proliferation in the anti-Thy 1.1 model was further supported by experiments in which intravenous bFGF given 24 h after a subnephritogenic dose of anti-Thy 1.1 antibody led to a 4.9- to 5.1-fold increase in glomerular cell proliferation (with > 60% of the cells identified as mesangial cells by double immunolabeling). No such increase was observed in normal rats injected with bFGF. These data show that mesangial cells produce and release bFGF after injury and that bFGF is mitogenic for injured mesangial cells in vivo. Release of mesangial cell bFGF thus may be an important mechanism involved in the initiation of mesangial cell proliferation in vivo.
肾小球系膜损伤和细胞增殖是人类各种肾小球疾病中的常见表现。以往研究表明，碱性成纤维细胞生长因子（bFGF）在体外是一种强大的系膜细胞促分裂原。为了进一步阐明bFGF在大鼠系膜细胞（RMC）增殖中的作用，我们检测了RMC在体外是否合成bFGF以及bFGF在体内是否参与系膜增殖。培养的RMC表达bFGF蛋白（23、21.5和18kD形式）和bFGF mRNA，并在抗体和补体介导的损伤后将生物活性bFGF释放到培养基中。正常大鼠体内肾小球未检测到bFGF mRNA，但可检测到bFGF蛋白（23和21.5kD），其免疫定位在系膜区。在抗Thy 1.1抗体诱导的肾小球肾炎急性期，肾小球bFGF明显减少，这与补体介导的系膜溶解后系膜bFGF释放一致。在随后的系膜增殖期，肾小球bFGF蛋白和mRNA高于正常水平。在此阶段，肾内注射肝素不影响肾小球的bFGF免疫染色，表明bFGF主要定位于细胞内。在抗Thy 1.1模型中，静脉注射bFGF（在亚致肾炎剂量的抗Thy 1.1抗体给药24小时后）导致肾小球细胞增殖增加4.9至5.1倍（通过双重免疫标记鉴定>60%的细胞为系膜细胞），这进一步支持了bFGF介导增殖的能力。在注射bFGF的正常大鼠中未观察到这种增加。这些数据表明，系膜细胞在损伤后产生并释放bFGF，并且bFGF在体内对损伤的系膜细胞具有促有丝分裂作用。因此，系膜细胞bFGF的释放可能是体内系膜细胞增殖启动的重要机制。
