Physiological role for enhanced renal thromboxane production in murine lupus nephritis

Abstract

To investigate the physiologic significance of enhanced renal thromboxane production in murine lupus nephritis, we measured renal hemodynamics and eicosanoid production in MRL- lpr/lpr mice from 8 to 20 weeeks of age. Over this age range, MRL- lpr/lpr mice develop an autoimmune disease with nephritis similar to huma systemic lupus erythematosus (SLE). In these studies, glomerular filtration rate (GFR) and PAH clearance (C PAH) decreased progressively with age in MRL- lpr/lpr mice, but not in controls. This impairment of renal hemodynamics was associated with increased renal thromoboxane production, as well as increased excretion of both thromboxane B 2 (T×B 2) and 2,3-dinor T×B 2 in urine. There was an inverse correlation between renal thromboxane production in MRL- lpr/lpr mice and both GFR and C PAH. Furthermore, there were positive correlations between thromboxane production by the kidney and both the severity of renal hispathology and serum anti-DNA antibody levels measured in individual animals. Enhanced urinary excretion of T×B 2 and the development of renal dysfunction also conincidede temporally with the appearance of increased levels of interleukin 1β (IL-1β) mRNA in renal cortex. Acute administration of the specific thromboxane receptor antagonist GR32191 to MRL- lpr/lpr mice restored GFR to normal in early stages of the autoimmune disease. However, in animals with more advanced nephritis, the effect of acute thromboxane receptor blockade on renal hemodynamics was less marked. We conclude that thromboxane A 2 is an important mediator of reversible renal hemodynamic impairment in murine lupus, especially in the early phase of disease.