Bimodal effects of platelet-derived growth factor on rat mesangial cell proliferation and death, and the role of lysophosphatidic acid in cell survival

Although mesangial cell death has been shown to be correlated with mesangia l cell mitosis in vivo, little is known about how these two apparently oppo site events are regulated. We show that the addition of platelet-derived gr owth factor (PDGF; 10-50 ng/ml) to primary cultured rat mesangial cells for 24 h caused continuous proliferation along with simultaneous cell death. T his process was accompanied by the fragmentation of DNA into nucleosomal ol igomers, the development of apoptotic morphological changes in the nucleus, and increased expression of p53. Accumulation of lactate dehydrogenase (LD H) was also observed in the culture medium, suggesting that both apoptosis and necrosis are involved in the cell death mechanisms observed. We also ob served that addition of 30 muM lysophosphatidic acid (LPA) to the culture m edium greatly suppressed PDGF-induced cell death, leading to synergisticall y enhanced mesangial cell proliferation. DNA fragmentation, p53 expression and LDH release were all suppressed by LPA. We suggest that PDGF is a bifun ctional molecule in mesangial cells that evokes both cell proliferation and cell death simultaneously, whereas LPA is a survival factor. We speculate that PDGF and LPA may play important roles in the progression or exacerbati on of proliferative glomerulonephritis.