IMMUNE-MEDIATED MESANGIAL CELL INJURY - BIOSYNTHESIS AND FUNCTION OF PROSTANOIDS

We studied the formation of cyclo-oxygenase products in a rat model of mesangial cell injury, in order to determine a possible role of prostaglandin E2 (PGE2), prostaglandin I2 (determined as 6-keto-PGF(1α)) and thromboxane A2 (TxA2) in immune-mediated glomerular disease. Selective immune-mediated mesangial cell injury was induced by i.v. administration of a rabbit anti-rat thymocyte antiserum (ATS). Intravenous ATS leads to immune deposits in the mesangium followed by mesangiolysis and the infiltration of polymorphonuclear granulocytes and monocytes. Glomerular TxB2 formation two hours (292 ± 27 pg/mg/min) and 48 hours (396 ± 69 pg/mg/min) following antibody was significantly (P < 0.05) higher compared to animals receiving non-antibody rabbit IgG (TxB2: 2 hr 143 ± 13; 48 hr 171 ± 32 pg/mg/min). Treatment with cobra venom factor (CVF) and the reduction of glomerular monocyte infiltration inhibited the increase of glomerular TxB2 formation significantly. Depletion of granulocytes with a rabbit anti-rat granulocyte serum had no effect on glomerular prostanoid formation following ATS. Glomerular PGF2 and 6-keto PGF(1α) production was not altered following ATS. Inulin clearance in rats with immune-mediated mesangial cell injury was significantly (P < 0.001) lower at two hours (456 ± 24 μl/min/100 g body wt) and 48 hours (433 ± 54 μl/min/100 g body wt) compared to their corresponding control animals which were treated with non-antibody IgG (2 hr: 914 ± 51; 48 hr: 694 ± 79 μl/min/100 g body wt). Pretreatment of rats with indomethacin (Indo) or with the thromboxane synthetase inhibitor UK 38485 prevented the decrease in inulin clearance following ATS at two hours (Indo: 800 ± 67; UK 38485: 923 ± 115) and at 48 hours (Indo: 697 ± 60; UK 38485: 654 ± 99). The data demonstrate that selective, immune-mediated mesangial cell injury in rats is associated with increased glomerular TxB2 formation. Complement and monocyte/macrophage depletion reduces TxB2 production. The fall in inulin clearance following ATS is ameliorated when the rats receive indomethacin or the Tx synthetase inhibitor UK 38485. Thus, elevated TxB2 formation might mediate the reduction in GFR in this model of glomerular immune injury.