The present study examined the role of thromboxane (TX) in the initiation and progression of glomerular injury in diabetic rats, as reflected by albuminuria and glomerular histology. Urinary thromboxane and albumin excretion (UTX and UAlb) were elevated by four months after induction of diabetes in the moderately hyperglycemic (200 to 400 mg/dl glucose) streptozotocin diabetic rat (SDR) compared to age-matched control rats. UTX and UAlb both increased progressively in SDR over the seven month period of study. Glomerular TX production, glomerular volume, fractional and absolute mesangial volume and glomerular basement membrane (GBM) width were also increased after seven months in SDR compared to control. Treatment of SDR with a thromboxane synthetase inhibitor (TXI) 4' (imidazol-l-yl) acetophenone (100 mg/kg/day) for seven months beginning at the time of induction of diabetes prevented the increases in UTX, UAlb, glomerular TX production, glomerular volume and mesangial volume and attenuated, but did not prevent, GBM thickening. When the same dose of the TXI was begun five months after induction of diabetes and continued for two months, UTX and ex vivo glomerular TX production were reduced by only 60% compared to untreated SDR and remained higher than corresponding values in control rats. Delayed treatment with the TXI alone did not alter UAlb compared to untreated SDR. By contrast, treatment of five month albuminuric SDR for only two months with the TXI plus the TX receptor antagonist (TXRA) Bay U3405 (5 mg/kg/day) prevented a further increase in UAlb, and reduced fractional albumin clearance and mesangial volume compared to values in untreated SDR. Combined treatment with the TXI and TXRA had no effect on GBM width or glomerular volume compared to values in untreated SDR. The results support roles for TX in the initiation of, and for TX and/or endoperoxides in the progression of glomerular injury in SDR.