Effects of a Selective Thromboxane Synthetase Inhibitor OKY-046 on Experimental Diabetic Nephropathy

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Abstract
To examine the effects of endogenous thromboxane A2 on the development of diabetic nephropathy, we administered OKY-046, an inhibitor of thromboxane synthesis, to streptozotocin-induced diabetic rats. Animals were divided into three groups; nondiabetic control, diabetic, and diabetic with OKY-046, and were sacrificed 16 weeks after experimental procedures. The chronic oral administration of OKY-046 to diabetic rats significantly decreased plasma and urinary thromboxane B2 levels. Urinary protein excretion and serum glucose levels were significantly lower in the OKY-046-treated diabetic rats than in the untreated diabetics (60.8 ± 23.2 vs. 94.1 ± 33.4 mg/day in the 16th week, p < 0.05 and 424.4 ± 93.3 vs. 614.4 ± 102.3 mg/dl in the 16th week, p < 0.01, respectively). Platelet aggregation was inhibited by OKY-046. Blood urea nitrogen was unaffected. Ultrastructural examination revealed that the thickness of glomerular basement membrane was markedly thinner in the OKY-046-treated diabetic rats than in the untreated diabetics (197.4 ± 29.6 vs. 288.6 ± 46.9 nm, p < 0.01). These results suggest that thromboxane A2 may play an important role in the development and progression of diabetic nephropathy in rats.