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) F2 alpha, thromboxane (Tx) A2, the hydroxyeicosatetraenoic acids 12-HETE and 5-HETE, and the leukotrienes LTB4 and LTD4 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). PGF2 alpha, and TxA2 endoperoxide analog U-46619, and LTD4 significantly enhanced DNA synthesis [(as assessed by [3H]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 PGF2 alpha on IP3 generation was not blocked by the TxA2 receptor antagonist, SQ-29,548. PGF2 alpha was the most effective eicosanoid in inducing all three events, and concentrations that enhanced TdR incorporation (1 microM) also activated PLC and PKC. In contrast, concentrations of U-46619 and LTD4 which enhanced TdR incorporation (1 microM), also activated PLC, but were insufficient to also activate PKC. Our observations indicate that the growth-promoting effect of PGF2 alpha, U-46619, and LTD4 can best be correlated with PLC activation. In addition, PGF2 alpha does not mediate PLC activation through binding to the TxA2 receptor.
Kelefiotis
D
D
Department of Medicine, Medical College of Wisconsin, Milwaukee, USA.
Bresnahan
B A
BA
Stratidakis
I
I
Lianos
E A
EA
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D004247:DNA / Q000096:biosynthesis; D004075:Diglycerides / Q000378:metabolism; D015237:Dinoprost / Q000494:pharmacology; D015777:Eicosanoids / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D007975:Leukotriene B4 / Q000494:pharmacology; D017998:Leukotriene D4 / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism
D004075:Diglycerides; D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; D007975:Leukotriene B4; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D013928:Thromboxane A2; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D017998:Leukotriene D4; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D004247:DNA; D015237:Dinoprost; D011493:Protein Kinase C; D010738:Type C Phospholipases