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

虽然系膜细胞凋亡细胞死亡已被证明与系膜细胞有丝分裂在体内，并已建议作出至关重要的贡献，系膜细胞的数量在增殖性肾小球肾炎的恢复阶段的恢复，很少有人知道这两个明显相反的事件是如何调节肾小球肾炎。在这项研究中，我们已经证明，血小板衍生生长因子（PDGF）诱导的系膜细胞的促有丝分裂过程也剂量依赖性地导致细胞死亡的细胞凋亡的特征性细胞形态和DNA梯形的形成判断。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sunergistically刺激系膜细胞增殖。当我们关注LPA抑制细胞死亡的机制时，发现LPA增加bcl-xl的转录和蛋白水平，但不增加bcl-2或bax的转录和蛋白水平，而PDGF不改变这些凋亡相关基因的表达水平。bcl-xmRNA的反义寡核苷酸阻断了LPA与PDGF联合应用的存活效应和共促有丝分裂效应，使Bcl-xL蛋白含量降低。所有这些结果表明，肾小球系膜细胞死亡是复杂的PDGF诱导的有丝分裂反应，LPA作为一种生存因子，通过依赖于Bcl-xL的机制，保护肾小球系膜细胞死亡。我们认为这些发现可能对增生性肾小球肾炎的病理生理学进展有影响。

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.