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

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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.