EICOSANOID-INDUCED GROWTH AND SIGNALING EVENTS IN RAT GLOMERULAR MESANGIAL CELLS

Renal glomerular injury frequently results in proliferation of a specialized supporting cell of the glomerular capillary known as the mesangial cell. In various forms of renal injury there is enhanced glomerular synthesis of specific eicosanoids of the arachidonic cyclooxygenase and lipoxygenase pathways including prostaglandin (PG) F-2 alpha, thromboxane (Tx) A(2), the hydroxyeicosatetraenoic acids 12-HETE and 5-HETE, and the leukotrienes LTB(4) and LTD(4) and attempts have been made to link these eicosanoids with injury-induced mesangial cell growth. In this study, the growth promoting effect of these eicosanoids on glomerular mesangial cells was correlated with activation of two growth regulatory enzymes: phospholipase C (PLC) and protein kinase C (PKC). PGF(2 alpha), and TxA(2) endoperoxide analog U-46619, and LTD(4) significantly enhanced DNA synthesis [(as assessed by [H-3]thymidine (TdR) incorporation)] in relatively quiescent (0.5% serum) mesangial cells, activated PLC [as assessed by increased 1,4,5-inositol tris-phosphate (IP3) generation and diacylglycerol (DAG) synthesis], and activated PKC (as assessed by translocation of the enzyme activity from the cytosol to the membrane). The effect of PGF(2 alpha) on IP3 generation was not blocked by the TxA(2) receptor antagonist, SQ-29,548. PGF(2 alpha) was the most effective eicosanoid in inducing all three events, and concentrations that enhanced TdR incorporation (1 mu M) also activated PLC and PKC. In contrast, concentrations of U-46619 and LTD(4) which enhanced TdR incorporation (1 mu M), also activated PLC, but were insufficient to also activate PKC. Our observations indicate that the growth-promoting effect of PGF(2 alpha), U-46619, and LTD(4) can best be correlated with PLC activation. In addition, PGF(2 alpha) does not mediate PLC activation through binding to the TxA(2) receptor.