Dual effect of lysophosphatidic acid on proliferation of glomerular mesangial cells

Among the variety of factors able to contribute to mesangial hypertrophy by altering mesangial cell growth, lysophosphatidic acid (LPA) is the focus of increasing attention. It is produced in plasma following platelet activation, as well as by mesangial cells stimulated by secretory phospholipase A(2). As mitogenic/antimitogenic properties of LPA are already described in a variety of cells, knowledge of its specific actions on mesangial cells is of potential interest regarding the pathophysiology of glomerulus damage in situ. We tested the effect of LPA on cultured rat mesangial cell growth. At 10 to 20 mu M, LPA stimulated thymidine incorporation as well as phosphorylation of mitogen-activated protein kinases (MAP-kinases) p42-p44 in dose- and time-dependent manner, which demonstrated a positive effect on cell proliferation. However, higher concentrations of LPA (100 mu M) were unable to stimulate thymidine incorporation and partly inhibited the proliferative effect as well as p42-p44 phosphorylation evoked by serum. Finally, whereas lysophosphatidylcholine (10 to 20 mu M) was lytic for mesangial cells, no cell lysis could be detected at the highest concentrations of LPA. Taken together, these results suggest that LPA exerts a dual effect on mesangial cell proliferation, which could be due to activation of distinct specific signaling pathways, in dose-dependent fashion. Specific actions of LPA able to modify mesangial cell proliferation in a positive or negative manner are also likely to influence the pathophysiological processes involved in the progression of glomerulosclerosis in the kidney.