Recently, it has been demonstrated that the production of prostaglandins and thromboxane is increased in patients with chronic glomerulonephritis and lupus nephritis. We recently demonstrated that thromboxane A 2 delayed the clearance of heat-aggregated bovine serum albumin deposited in glomeruli. In the present study, we investigated the effect of thromboxane A 2 on the clearance of macromolecules in nephritic glomeruli. First, we attempted to clarify the conditions for the clearance of heat-aggregated bovine serum albumin in nephritic glomeruli, using glomeruli isolated from control and anti-glomerular basement membrane nephritic mice. Heat-aggregated bovine serum albumin was injected twice into each mouse. The glomeruli were then isolated and incubated in culture medium. The heat-aggregated bovine serum albumin content of control glomeruli gradually diminished with incubation time up to 24 h. The heat-aggregated bovine serum albumin content of nephritic glomeruli was 69% higher than that of control glomeruli at 24 h incubation. The production of thromboxane B 2 (the stable metabolite of thromboxane A 2) in nephritic glomeruli showed about a sevenfold increase compared with control. DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid hydrochloride], a thromboxane A 2 synthase inhibitor, and KT2-962 [sodium 3-(4-(4-chlorophenyl-butylsulfonamido) butyl)-6-isopropylazulene-1-sulfonate], a selective thromboxane A 2 receptor antagonist, significantly reduced the heat-aggregated bovine serum albumin content in nephritic glomeruli. Normal glomeruli treated with U-46619 [15 S-hydroxy-11a,9a-(epoxymethano)prosta-5Z,13E-dienoic acid], a stable analogue of thromboxane A 2, had significantly more heat-aggregated bovine serum albumin than control glomeruli. We next investigated whether thromboxane A 2 could affect the uptake/disposal of heat-aggregated bovine serum albumin by cultured rat mesangial cells. U-46619 significantly enhanced the uptake and inhibited the disposal of heat-aggregated bovine serum albumin by mesangial cells. Finally, we performed experiments to elucidate the role of the thromboxane A 2 receptor (TP receptor) in the clearance of heat-aggregated bovine serum albumin using TP-deficient mice. The glomerular heat-aggregated bovine serum albumin content of TP-receptor knockout [TP(−/−)] mice was lower than that of wild-type [WT(+/+)] mice. U-46619 dose dependently increased the uptake of heat-aggregated bovine serum albumin by mesangial cells in WT(+/+) mice, but not in the TP(−/−) mice. These findings suggest that thromboxane A 2 retards the clearance of aggregated protein in nephritic glomeruli and may contribute to the pathophysiology of glomerulonephritis.