We examined the effect of glomerular
immune complex (IC) deposition on glomerular
eicosanoid synthesis and the role of the
eicosanoids in glomerular pathophysiology. Rats received daily 10 mg i.v.
injections of native bovine
gamma-globulin (NBGG) or cationic bovine
gamma-globulin (CBGG) for 21 days; age-matched controls were maintained. Immunofluorescence and electron microscopy showed mesangial deposits of IC in the NBGG group and capillary wall deposits in the CBGG group, without light or electron microscopic evidence of leukocyte infiltration. One week after the last
antigen dose, GFR was similar in all three groups, but RPF increased in the rats given CBGG; (8.37 +/- 0.90 vs. control 5.54 +/- 0.56 ml/min, P less than 0.05). Glomerular synthesis of
prostaglandin E2 (
PGE2) and
thromboxane B2 (TxB2) was normal in animals that received NBGG. Rats given CBGG had increased glomerular production of
PGE2, (2.23 +/- 0.37 vs. control 1.03 +/- 0.16 ng/mg glomerular dry wt, P less than 0.05) and TxB2 (3.12 +/- 0.50 vs. control 0.48 +/- 0.07 ng/mg glomerular dry wt, P less than 0.001).
Proteinuria only developed in the rats given CBGG, 86.6 +/- 18 mg/24 hr, which correlated with glomerular TxA2 synthesis, r = 0.82, P = 0.01. Acute administration of the TxA2 synthesis inhibitor,
UK-38,485, and a TxA2 receptor antagonist,
EP-092, to rats given CBGG did not affect GFR or RPF. The
cyclo-oxygenase inhibitor,
indomethacin, reduced both GFR and RPF by up to 40% in CBGG-immunized rats.
Oral administration of
UK-38,485 for six days to nephrotic rats did not result in a statistically significant reduction of
proteinuria despite 85% inhibition of glomerular TxB2. We conclude that cationic
antigen induces a glomerular disease pathologically similar to
membranous nephropathy. The increment of RPF is most probably due to increased glomerular
PGE2. The increased TxA2 has no effect on glomerular hemodynamics and probably is not a component in the pathogenesis of
proteinuria.