TY - JOUR
T1 - Complement C5b-9 complex activates phospholipases in glomerular epithelial cells
AU - Cybulsky, A. V.
AU - Salant, D. J.
AU - Quigg, R. J.
AU - Badalamenti, J.
AU - Bonventre, J. V.
PY - 1989
Y1 - 1989
N2 - In rat membranous nephropathy, formation of the C5b-9 membrane attack complex (MAC) leadss to proteinuria in association with glomerular visceral epithelial cell (GEC) injury. These alterations in GEC function and morphology might result from changes in intracellular free Ca2+ concentration ([Ca2+](i)) and activation of phospholipases. We demonstrate that in cultured rat GEC, antibody-directed formation of noncytolytic amounts of the MAC induced a rapid and sustained increase in [Ca2+](i) that was partly inhibited by ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tretraacetic acid (EGTA). The MAC elevated levels of inositol bis-(IP2) and trisphosphate (IP3), as well as 1,2-diacylglycerol (DAG) and phosphatidic acid (PA). In permeabilized GEC, IP3 released Ca2+ from intracellular stores. Cellular 45Ca2+ uptake was also increased by the MAC. Thus, in GEC, the MAC induced Ca2+ mobilization from intracellular stores secondary to activation of phospholipase C and production of IP3, as well as enhanced Ca2+ influx. In addition, C5b-9 stimulated release of arachidonic acid (AA), prostaglandin F(2α), and thromboxane A2. Indomethacin partially inhibited the increase in DAG levels observed with the MAC, whereas the prostaglandin H2/thromboxane A2 analogue U46619 elevated DAG, suggesting that an eicosanoid product of MAC-induced AA release may enhance the activation of phospholipase C. Activation of phospholipases by the MAC may lead to altered GEC function and thereby contribute to the pathophysiological changes that characterize complement-dependent rat membranous nephropathy.
AB - In rat membranous nephropathy, formation of the C5b-9 membrane attack complex (MAC) leadss to proteinuria in association with glomerular visceral epithelial cell (GEC) injury. These alterations in GEC function and morphology might result from changes in intracellular free Ca2+ concentration ([Ca2+](i)) and activation of phospholipases. We demonstrate that in cultured rat GEC, antibody-directed formation of noncytolytic amounts of the MAC induced a rapid and sustained increase in [Ca2+](i) that was partly inhibited by ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tretraacetic acid (EGTA). The MAC elevated levels of inositol bis-(IP2) and trisphosphate (IP3), as well as 1,2-diacylglycerol (DAG) and phosphatidic acid (PA). In permeabilized GEC, IP3 released Ca2+ from intracellular stores. Cellular 45Ca2+ uptake was also increased by the MAC. Thus, in GEC, the MAC induced Ca2+ mobilization from intracellular stores secondary to activation of phospholipase C and production of IP3, as well as enhanced Ca2+ influx. In addition, C5b-9 stimulated release of arachidonic acid (AA), prostaglandin F(2α), and thromboxane A2. Indomethacin partially inhibited the increase in DAG levels observed with the MAC, whereas the prostaglandin H2/thromboxane A2 analogue U46619 elevated DAG, suggesting that an eicosanoid product of MAC-induced AA release may enhance the activation of phospholipase C. Activation of phospholipases by the MAC may lead to altered GEC function and thereby contribute to the pathophysiological changes that characterize complement-dependent rat membranous nephropathy.
KW - 1,2-diacylglycerol
KW - arachidonic acid
KW - inositol phosphates
KW - intracellular free calcium concentration
KW - phospholipase C
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U2 - 10.1152/ajprenal.1989.257.5.f826
DO - 10.1152/ajprenal.1989.257.5.f826
M3 - Article
C2 - 2511764
AN - SCOPUS:0024381342
SN - 0002-9513
VL - 257
SP - F826-F836
JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
IS - 5 (26/5)
ER -