Functional significance of renal prostacyclin and thromboxane A2 production in patients with systemic lupus erythematosus.

Abstract

We have examined the urinary excretion of stable immunoreactive eicosanoids in 23 female patients with systemic lupus erythematosus (SLE), 16 patients with chronic glomerular disease (CGD), and 20 healthy women. SLE patients had significantly higher urinary thromboxane B2 (TXB2) and prostaglandin (PG) E2 excretion and significantly lower 6-keto-PGFI. than did healthy women. In contrast, CGD patients only differed from controls for having reduced 6-keto-PGF1I excretion. The group of SLE patients with active renal lesions differed significantly from the group with inactive lesions for having a lower creatinine clearance and urinary 6-keto-PGFI. and higher urinary TXB2.Higher urinary TXB2 excretion was associated with comparable platelet TXB2 production in whole blood, undetectable TXB2 in peripheral venous blood, and unchanged urinary excretion of 2,3-dinor-TXB2. A significant inverse correlation was found between urinary TXB2 and creatinine clearance rate (Cc,). In contrast, the urinary excretion of 6-keto-PGFI. showed a significant linear correlation with both Cc, and para-aminohippurate clearance rate (CPAH). In four SLE and seven CGD patients, inhibition of renal cyclooxygenase activity by ibuprofen was associated with a significant reduction in urinary 6-keto-PGFIe, and TXB2 and in both Ccr and CPAH. However, the average decrease in both clearances was 50% lower in SLE patients than in CGD patients, when fractionated by the reduction in urinary 6-keto-PGFi, or PGE2 excretion.We conclude that the intrarenal synthesis of PGI2 and TXA2 is specifically altered in SLE. Such biochemical alterations are

Regional Vascular Responses to Thromboxane A2 Analogue and Their Blockade with Vapiprost, a Selective Thromboxane Receptor Blocking Drug, in Anesthetized Dogs

“…4. These present results suggest the pos sibility that blockade of the TP-receptor may exert a ben eficial action, particularly in some renal diseases, since renal vasoconstriction due to intrarenal TXA2 produc tion has been found to participate in cyclosporine nephrotoxicity (29)(30)(31) and lupus nephritis (32,33). Additionally, enhanced renal vascular reactivity to the TXA2 analogue U46619 has recently been shown in Goldblatt hypertensive rats (34,35) and genetically hypertensive rats (36).…”

Effects of KW-3635, a Specific Thromboxane A2-Receptor Antagonist, on the Development of Lupus Nephritis in NZB × NZW F1 Mice

“…These actions include constriction of glomeru lar afferent and efferent arterioles, intraglomerular plate let aggregation, contraction of glomerular mesangial cells and increase of mesangial cell matrix synthesis (1,2). In creased renal TXA2 biosynthesis has been documented in a variety of animal models of renal disease (3 5) and in patients with systemic lupus erythematosus (SLE) (6). These results suggest that TXA2 plays an important role in the progression of renal diseases.…”

“…In the patients with SLE, a significant inverse correlation was found between the urinary TXB2/6-keto-PGFIa ratio and creatinine clear ance (Ccr) (6). Moreover, recent studies have shown that a thromboxane A2-receptor antagonist (TXRA) improves renal function in patients with lupus nephritis (7,8).…”

Eicosanoids, Mesangial Contraction, and Intracellular Signal Transduction.

“…It is released at the site of vascular injury or inflammation, such as in the course of experimental nephritis (Lianos et al 1983), ureteral obstruction (Okegawa et al 1983), renal allograft rejection (Coffman et al 1985), and lupus nephritis in man (Patrono et al 1985).…”

“…This may indicate differences between the mechanism of action of LT and various other contractile stimuli, such as ANG II, AVP and TxA2, which rapidly stimulate phospholipase activity and AA metabolism in these cells (Patrono et al 1985;Mene' and Dunn 1986). …”