Excretion of metabolites of prostacyclin and thromboxane by rats with nephrotoxic nephritis: effects of interleukin‐1

Abstract

1 To obtain direct evidence of abnormal eicosanoid biosynthesis in rats injected with anti-glomerularbasement-membrane antibodies (a-GBM), products derived from thromboxane A2 (TXA2) and prostacyclin (PGO2) were measured in 24 h urine collections before and after a-GBM. 2 Administration of a-GBM (9.5 mg) caused albuminuria, decreased creatinine clearance, increased numbers of intra-glomerular neutrophils and increased excretion of TXB2, 2,3-dinor-TXB2 (products of TXA2) and 6-oxo-PGF1a and 2,3-dinor-6-oxo-PGF1. (products of PGO2) at 24 h. 3 Interleukin-1 (IL-I,,; 5ug) alone caused an increase in PGO2 metabolite excretion but had no effect on TXA2 metabolites. It had no effect on creatinine clearance but increased numbers of glomerular neutrophils by approximately 4-5 fold compared to a-GBM. 4 Pretreatment of rats with IL-1 before a-GBM synergistically increased albumin excretion but only additively increased eicosanoid excretion. Numbers of intra-glomerular neutrophils and creatinine clearance were unchanged compared to IL-1p alone.5 The cyclo-oxygenase inhibitor, ibuprofen (10mgkg-i.p., twice daily for 4 days) inhibited both serum TXB2 production and urinary prostaglandin excretion. It also caused an almost complete attenuation of albumin excretion. Creatinine clearance and glomerular neutrophils remained unchanged after a-GBM/ IL-1 . 6 We conclude that the 50% inhibition of thromboxane production induced by ibuprofen does not modify the fall in creatinine clearance of accumulation of neutrophils in the glomerulus caused by the a-GBM. This degree of inhibition of eicosanoid production was associated with a striking decrease in proteinuria, but this may reflect a haemodynamic rather than a disease modifying action.

Prostaglandin E3 metabolism and cancer

“…Quantification of urinary PGE metabolites [108] and the major urinary metabolite of PGI [109] can potentially be another biomarker for fatty acid status. In 1988, Kivits et al reported that in rats, an AA diet increased urinary tetranor-prostaglandin E 1 (PGE-M) which is the major urinary metabolite of PGE 2 [110].…”

Passive immunization against tumour necrosis factor-alpha (TNF-α) and IL-lβ protects from LPS enhancing glomerular injury in nephrotoxic nephritis in rats

“…They increase urinary volume and sodium excretion transiently. These changes are independent of changes in glomerular filtration rate, effective renal plasma flow [35] or thromboxane excretion [36]. However, they correlate with increased urinary prostaglandin excretion [35].…”

“…We have shown previously that systemic injection of IL-l/f in this model increased renal synthesis of prostaglandin E; and prostaglandin-1;. and ibuprofen decreased both prostaglandin synthesis and increased albuminuria [36]; there were no changes in Ihromboxanc excretion in these sUidies.…”

Major urinary metabolites of 6-keto-prostaglandin F2α in mice

“…The major urinary metabolites of AA-derived 6-keto-PGF 1 ␣ have been described in both man ( 12,17,18 ) and rats ( 19 ) but not in mice. In contrast, no careful, quantitative analysis of the metabolites of PGI 3 have been performed in any species, although homologs of the major PGI 2 metabolites have been measured in urine of primates following dietary fi sh oil (20)(21)(22).…”