HEMODYNAMIC ROLES OF THROMBOXANE-A2 AND PROSTAGLANDIN-E2 IN GLOMERULONEPHRITIS

Abstract

Eicosanoid metabolites may play a role in the pathophysiology of nephrotoxic serum nephritis (NSN), a model of immune renal disease. The relative importance of vasoconstrictor [thromboxane A2 (TX)A2] and vasodilator [prostaglandin E2 (PG)E2] eicosanoids as mediators of hemodynamic and renal functional changes was examined. Glomerular filtration rate (GFR; inulin clearance), and renal plasma flow (RPF; p-aminohippurate clearance/extraction) were measured in rats on day 1 and day 14 of NSN. Specific inhibitors of TXA2 synthesis and receptor binding, and cyclooxygenase inhibitors were used to determine the relative roles of TXA2 and PGE2. In vitro glomerular production of radioimmunoassayable PGE2 and TXB2 were measured after clearances. At 1 day GFR is decreased compared to control, 1.9 .+-. 0.2 vs. 2.6 .+-. 0.2 ml/min. RPF is numerically increased, 10.0 .+-. 1.0 vs. 7.0 .+-. 0.6 ml/min. By 14 days GFR is normal, 2.2 .+-. 0.2 ml/min, as a consequence of signficantly increaced RPF, 11.7 .+-. 1.0 ml/min. Glomerular production of PGE2 and TXB2 was increased 11- and 15-fold, respectively, at both 1 and 14 days. Pretreatment with OKY-1581, or acute treatment with UK-38, 485, both inhibitors of TXA2 synthesis, had no effect on GFR or RPF in NSN rats. Addition of EP 092, a TXA2 receptor antagonist was similarly without effect. In contrast, acute treatment with the cyclooxygenase inhibitors meclofenamate or indomethacin resulted in a 50% decrease in both RPF and GFR; these inhibitors had no effect in control rats. PGE2 (vasodilator) is of greater relative significance than TXA2 (vasoconstrictor) with respect to renal function in the NSN rat at 1 and 14 days.