Cell biological control of chronic glomerulonephritis -Analysis of signal transduction molecules in pletelets and glomerular cells-

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Angiotensin II ( AII ) causes the contraction and proliferation of msangial cells, both of which are important in etiology and pathophysiology of chronic glomerulonephritis. Recently lines of evidenc have revealed thath the activation of phosphoinositide cycle ( PI cycle ) is a common signal transduction mechanism in the action of Ca-mobilizing hormones including AII. The possibility has been suggested that the modulation of PI metabolism leads to the discovery of new therapy for chronic glomerulonephritis. Unfortunately, the proeviously published methods for the measurement of inositol phosphates ( IPs ), which should provide direct evidence for activated PI cycle, i.e., phospholipase C-catalyzed hydrolysis of phosphatidylinositol 4,5-bisphosphate, had some disadvantages.In this research project, therefore, we developed the new high performance liquid chromatography ( HPLC ) method, by which we could evaluate AII-induced changes in IPS in cultured rat mesangial cells. The newly develo … More ped HPLC method has enable us to analyze the change in IPs including inositol 1,4,5-trisphosphate ( Ins(1,4,5)P_3 ), inositol 1,3,4-trisphosphate ( Ins(1,3,4)P_3 ), inositol 1,3,4,5-tetrakisphosphate ( Ins(1,3,4,5)P_4 ), inositol pentakisphosphate ( IP_5 ) and inositol hexakisphosphate ( IP_6 ).When the cells were treated with 10-7 M AII, the increase of Ins(1,4,5)P_3 was very rapid and transient. The increase of Ins(1,3,4,5)P_4 was also rapid and remained increased for up to 60 sec. The increase of Ins(1,3,4)P_4 followed their increases. Inositol monophosphate and inositol bisphosphate also increased within 30 sec and 5 sec, respectively. Neither IP_5 nor IP_6 was increased by AII. AII-induced increase of IP_1, IP_2 and inositol trisphosphate showed dose-dependency and were completely inhibited by saralasin, the competitive inhibitor for AII.From these results, we suggest that in cultured rat mesangial cells PI cycle including inositol tris- and tetrakisphosphate pathway is the signal transduction mechanism for AII, which may be coupled with the contraction and proliferation ff the cells. Less