Contribution of platelet thromboxane production to enhanced urinary excretion and glomerular production of thromboxane and to the pathogenesis of albuminuria in the streptozotocin-diabetic rat

Abstract

Previous studies have demonstrated that urinary thromboxane B 2 (TXB 2) excretion (U TXB2) and glomerular production of TXB 2 are enhanced in experimental diabetes and that selective inhibitors of TX synthesis prevent or delay the development of albuminuria. The present study was conducted to examine the contribution of platelet TXB 2 production to the enhancement of U TXB2 and glomerular TXB 2 production and to the pathogenesis of albuminuria in the partially insulin-treated moderately hyperglycemic (blood glucose, 200 to 400 mg/dL) streptozotocin-diabetic rat (SDR). Treatment of control rats or of SDR with diabetes of 5 months' duration with antiplatelet serum for 4 consecutive days reduced circulating platelet counts and serum TXB 2 generation, an index of platelet cyclooxygenase activity, by 80% or greater, but reduced U TXB2 excretion by only 30%. U TXB2 and glomerular production of TXB 2 of thrombocytopenic SDR remained markedly elevated compared with corresponding values from age-matched thrombocytopenic or platelet-replete, nondiabetic controls. Similarly, treatment of rats for 180 days with a dose of aspirin (ASA), which selectively inhibited platelet versus renal cyclooxygenase activity, reduced U TXB2 of both SDR and controls by 25% to 35%. The absolute reductions in U TXB2 induced by either ASA or thrombocytopenia in SDR were significantly greater than the absolute decrements in corresponding controls, suggesting that increased platelet TXB 2 production in SDR may contribute to the enhanced U TXB2. However, as in the thrombocytopenic SDR, U TXB2 and glomerular production of TXB 2 of SDR treated with ASA remained clearly above corresponding control values. Moreover, chronic ASA treatment failed to prevent the development of albuminuria in SDR. By contrast, 4′ (imidazol-1-yl) acetophenone, a selective inhibitor of TX synthesis given for 180 days at a dose that suppressed both platelet and glomerular TXB 2 production, prevented the development of albuminuria in SDR. The results indicate that platelets are not the major cellular source of increased U TXB2 or glomerular TXB 2 generation in SDR and that selective inhibition of platelet TXB 2 production does not prevent the development of albuminuria in this model. A pathogenetic role for local glomerular TX synthesis is suggested by the differential effects of ASA versus a TX synthetase inhibitor on glomerular TX production and on the development of albuminuria in SDR.