Normotensive rats of the Milan strain (MNS) spontaneously develop focal glomerulosclerosis. In order to explore the contribution of glomerular thromboxane (TX) A2 synthesis to the development of the disease, we have characterized the time course of renal functional and biochemical changes, and their modification by long-term treatment with a TX-synthase inhibitor. Oral administration (150 mg.kg-1 from 1 to 14 months of age) of FCE 22178 suppressed enhanced glomerular TXB2 production at all experimental times (mean inhibition 80%) and proteinuria (varying between 27.1 and 73.0%) while preserving renal blood flow and glomerular filtration rate. These effects of TX-synthase inhibition were seen in the absence of any statistically significant changes in systemic blood pressure. Moreover, FCE 22178 had no antihypertensive effects in hypertensive rats of the Milan strain (MHS) nor in spontaneously hypertensive rats (SHR). Treatment also prevented the age-related hypoalbuminemia and hyperlipidemia observed in control MNS and significantly (P less than 0.01) reduced glomerular histologic damage, as demonstrated by light microscopy studies and measurement of sclerotic area. We conclude that: 1) MNS rats provide an animal model of long-lasting proteinuria characterized by an age-related increase in glomerular TXB2 production paralleled by progressive loss of renal structural integrity and function and by a secondary dyslipidemia; 2) pharmacological inhibition of glomerular TX-synthase attenuates the structural as well as the functional expression of kidney disease, without a primary effect on systemic blood pressure. These data are suggestive of an important modulating role of TXA2 in the progression of MNS renal disease.