A role for thromboxane in complement-mediated glomerular injury.
The membrane attack complex (MAC) of complement (C) has been shown to stimulate prostaglandin (PG) and thromboxane (Tx) synthesis in nucleated cells. Because glomerular epithelial cell injury and altered permeability in rat membranous nephropathy are mediated by the MAC, the authors examined whether MAC-induced proteinuria is linked to glomerular prostanoid synthesis. In kidneys containing non-nephritogenic, non-C-fixing gamma 2 sheep anti-Fx1A (planted antigen) that were perfused in vitro with C-fixing guinea pig anti-sheep IgG and a C source (fresh human plasma, 50% vol/vol in buffered bovine albumin), heavy proteinuria developed, reaching 4.27 +/- 1.20 mg/min/g at 100-120 minutes (n = 8). Cyclooxygenase blockade with 10(-4) M indomethacin (n = 6) inhibited urinary PGE2 excretion (569 +/- 47 to 124 +/- 18 pg/min/g, P less than 0.001) and lowered proteinuria (1.06 +/- 0.42 mg/min/g, P less than 0.001). Reduced protein excretion (0.88 +/- 0.12 mg/min/g, n = 6, P less than 0.001) also occurred with inhibition of Tx synthetase by OKY-046, 10(-4) M, a dose that was shown in separate perfusions to inhibit urinary TxB2 excretion by greater than 85%. Control kidneys, without planted antigen and perfused with anti-sheep IgG and plasma, excreted 0.30 +/- 0.05 mg protein/min/g (n = 6). Because inulin clearance was reduced by indomethacin, renal hemodynamic factors may have contributed to the reduction in proteinuria observed with this drug. However, insulin clearance was not significantly affected by OKY-046, implying that inhibition of Tx synthetase reduced proteinuria independently of changes in renal hemodynamics. Thus, proteinuria in rat membranous nephropathy is due to MAC-dependent glomerular epithelial injury and is mediated, in part, by Tx.
D000818:Animals; D002463:Cell Membrane Permeability; D015938:Complement Membrane Attack Complex; D003165:Complement System Proteins / Q000276:immunology*; D006224:Cricetinae; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D006439:Hemodynamics / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D007444:Inulin / Q000378:metabolism; D007668:Kidney / Q000098:blood supply; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology*; D011458:Prostaglandins E / Q000652:urine; D011507:Proteinuria / Q000276:immunology; D013929:Thromboxane B2 / Q000652:urine; D013931:Thromboxanes / Q000502:physiology*
D015938:Complement Membrane Attack Complex; D016861:Cyclooxygenase Inhibitors; D011458:Prostaglandins E; D013931:Thromboxanes; D013929:Thromboxane B2; D007444:Inulin; D003165:Complement System Proteins; D015232:Dinoprostone; D007213:Indomethacin