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A role for thromboxane in complement-mediated glomerular injury
Insights
The membrane attack complex (MAC) causes proteinuria in rat membranous nephropathy by damaging glomerular cells. This damage is partly mediated by thromboxane (Tx), a prostanoid synthesized in response to MAC.
Area of Science:
- Nephrology
- Immunology
- Complement System
Background:
- The membrane attack complex (MAC) of complement (C) activates prostaglandin (PG) and thromboxane (Tx) synthesis in nucleated cells.
- Glomerular epithelial cell injury and altered permeability in rat membranous nephropathy are mediated by the MAC.
Purpose of the Study:
- To investigate whether MAC-induced proteinuria is linked to glomerular prostanoid synthesis.
- To determine the role of thromboxane in MAC-mediated proteinuria.
Main Methods:
- Rat kidneys with planted antigen were perfused with C-fixing antibodies and human plasma to induce proteinuria.
- The effects of cyclooxygenase blockade (indomethacin) and thromboxane synthetase inhibition (OKY-046) on proteinuria and prostanoid excretion were examined.
- Inulin clearance was measured to assess renal hemodynamic changes.
Main Results:
- MAC activation led to heavy proteinuria.
- Indomethacin inhibited urinary PGE2 and reduced proteinuria, but also decreased inulin clearance.
- OKY-046 significantly reduced proteinuria and urinary TxB2 excretion without affecting inulin clearance.
Conclusions:
- Proteinuria in rat membranous nephropathy is caused by MAC-dependent glomerular epithelial injury.
- Thromboxane plays a significant role in mediating this proteinuria, independent of renal hemodynamic changes.
Abstract:
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.