To investigate the role of
thromboxane A2 (TxA2) in murine lupus, we assessed the effects of the specific
thromboxane receptor antagonist
GR32191 on
immune complex glomerulonephritis in MRL-lpr/lpr mice. Forty mg/kg/day
GR32191 was given by twice daily
subcutaneous injection for eight weeks beginning at 12 weeks of age. This dose completely blocked the renal vasoconstriction produced by the
thromboxane agonist
U46619. After eight weeks of treatment, both glomerular filtration rate (GFR) (8.9 +/- 0.6 vs. 6.8 +/- 1.1 ml/min/kg; P less than 0.05) and PAH clearance (CPAH) (37.4 +/- 2.5 vs. 29.9 +/- 3.3 ml/min/kg; P less than 0.05) were significantly higher in mice given
GR32191 compared to vehicle treated animals. Administration of
GR32191 also reduced
proteinuria from 18.1 +/- 11.6 to 3.7 +/- 1.3 mg/24 hours (P less than 0.05). In
GR32191 treated MRL-lpr/lpr mice, renal hemodynamic function and
proteinuria were not significantly different from congenic MRL-+/+ controls.
Thromboxane receptor blockade had striking affects on renal histomorphology reducing both hyaline thrombi in glomeruli (P = 0.022) and interstitial
inflammation (P = 0.006). Glomerular crescents and severity of
vasculitis also tended to be reduced in mice receiving the
thromboxane receptor antagonist. The overall histopathologic score in mice given
GR32191 was significantly lower than vehicle treated animals (4.7 +/- 0.5 vs. 8.4 +/- 1.5; P = 0.016). These effects of
GR32191 were associated with decreased excretion of
thromboxane B2 (TxB2) in urine (292 +/- 37 vs. 747 +/- 155 pg/24 hr; P less than 0.005) as well as a modest reduction in glomerular deposits of
IgG (semiquantitative score 2.6 +/- 0.2 vs. 3.5 +/- 0.2; P less than 0.02). Thus, chronic
thromboxane receptor blockade markedly altered the course of renal disease in MRL-lpr/lpr mice, suggesting that TxA2 is an important mediator of renal dysfunction and injury in this murine model of
lupus nephritis.