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Role of lysophosphatidic acid in the growth and apoptosis induced by platelet-derived growth factor in primary cultured rat mesangial cells

溶血磷脂酸在血小板源性生长因子诱导原代培养大鼠系膜细胞生长和凋亡中的作用

基本信息

批准号：
10670981
负责人：
NAGANO Chiyoko
金额：
$ 2.05万
依托单位：
TOHOKU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

Although mesangial apoptotic cell death has been shown to correlate with mesangial cell mitosis in vivo and has been suggested to make crucial contribution to the restoration of the number of mesangial cells in the recovery phase of proliferative glomerulonephritis, little is known how these two apparently opposite events are regulated in glomerulonephritis. In this study, we have demonstrated that the platelet-derived growth factor (PDGF)-induce mitogenic process for mesangial cells also dose-dependently led to cell death by apoptosis as judged by characteristic cell morphology and DNA ladder formation. On the other hand, when lysophosphatidic acid (LPA) co-acted with PDGF, cell death was significantly suppressed, leading to sunergistically stimulated mesangial cell proliferation. When we focused on the mechanisms of inhibition of cell death mediated by LPA, it was found that LPA increased transcript and protein level of bcl-xl but not of bcl-2 or bax, whereas PDGF did not change the levels of these apoptosis-related gene expressions. Antisense oligonucleotide against bcl-x mRNA abolished both the survival effect and the co-mitogenic effect of LPA in combination with PDGF with the reduction in Bcl-xL protein content. All of these results indicate that mesangial cell death is complicated by PDGF-induced mitogenic responses and that LPA acts as a survival factor, protecting mesangial against cell death through a mechanism dependent on Bcl-xL. We suggest the possible implications of these findings for the pathophysiology of the progression of proliferative glomerulonephritis.

尽管系膜细胞凋亡与系膜细胞有丝分裂相关，并在增殖性肾小球肾炎恢复期系膜细胞数量的恢复中起重要作用，但这两个明显相反的事件在肾小球肾炎中是如何调节的，目前尚不清楚。在这项研究中，我们已经证明了血小板衍生生长因子(PDGF)诱导的系膜细胞有丝分裂过程也以剂量依赖的方式通过细胞形态和DNA梯带的形成而导致细胞死亡。另一方面，当溶血磷脂酸(LPA)与PDGF共同作用时，细胞死亡被显著抑制，导致阳光刺激的系膜细胞增殖。当我们重点研究LPA抑制细胞死亡的机制时，我们发现LPA增加了bclxl的转录和蛋白水平，但不增加bcl2和bax的表达，而PDGF不改变这些凋亡相关基因的表达水平。BCL-x反义寡核苷酸可阻断LPA与PDGF联合应用的存活效应和协同促有丝分裂作用，同时降低BclxL蛋白含量。所有这些结果表明，PDGF诱导的有丝分裂反应使系膜细胞死亡复杂化，LPA作为一种生存因子，通过依赖于Bcl-xL的机制保护系膜细胞免受细胞死亡的影响。我们认为这些发现可能对增殖性肾小球肾炎进展的病理生理学有影响。