Thromboxane A2, prostaglandins, and mesangial cell proliferation.

Much work has recently focused upon the cellular involvement of the mesangium in glomerular inflammation and fibrosclerosis. A host of mediators of inflammation have been identified and their actions studied in mesangial cell cultures [1]. The recent identification of functional receptors for prostaglandins (PG) and thromboxane A2 (TxA2) in cultured glomerular mesangial cells [2, 3] has prompted us and others to examine the relevance of these arachidonate (AA) metabolites to mesangial pathophysiology. We investigated whether exogenous eicosanoids (that is, 20°C atoms unsaturated lipids), in addition to their contractile (PGF2, TxA2) or relaxant (PGE2, PGI2) effects on mesangial cells, affect protein synthesis and growth rates in culture. The implications of such effects would be severalfold. First, AA metabolism occurs in normal glomerular cells, both in culture and in vivo [4]. Binding of prostanoids to mesangial or neighboring glomerular cells may modulate their functional behavior. Leukocytes and platelets also express functional receptors for AA metabolites, and may hence be recruited by and respond to such diffusible mediators. Second, AA metabolism is enhanced by vasoconstrictors, cytokines and growth factors released at the site of inflammation [5, 6]. This may, in turn, regulate the activity of these primary agents on target cells. Unlike growth factors or cytokines, the release of prostanoids can occur within seconds of application of stimuli, not requiring protein synthesis. In turn, induction of key enzymes in the metabolism of AA has been described in cytokine-activated cells. Thus, long-term regulation of prostanoid biosynthesis can also occur during chronic exposure to inflammatory polypeptide mediators [6]. Third, pharmacologic manipulation of PG and TxA2 synthesis or binding to cellular targets is well established, unlike growth factors and cytokines, at present. Several agents can therefore be employed as tools for dissecting out the relative contribution of eicosanoids to primary events in the progression of renal injury, such as glomerular hypertrophy, hypercellularity, and fibrosclerosis.