Altered glomerular metabolism of arachidonic acid (AA) has already been demonstrated in experimental nephrotoxic nephritis. The Isolated glomeruli from nephrotic rats studied 14 or 30 d after a single intravenous injection of adriamycin (7.5 mg/kg) when animals were heavily proteinuric generated significantly more TxB2, the stable breakdown product of TxA2, than normal glomeruli. No significant changes were found in the other major AA metabolites formed through cyclooxygenase. Urinary excretion of immunoreactive TxB2 was also significantly higher in nephrotic than in normal animals. Administration of a selective Tx synthetase inhibitor, UK-38,485, from day 14 to day 18 after adriamycin resulted in a significant reduction of proteinuria compared with pretreatment values. Glomerular synthesis and urinary excretion of TxB2 were normal during the UK-38,485 treatment. Additional experiments showed that elevated glomerular synthesis and urinary excretion of TxB2 were not a consequence of increased substrate availability. Maximal stimulation of the renin-angiotensin axis with furosemide increased glomerular TxB2 synthesis in normal rats, which was significantly lower than in nephrotic animals. Finally, experiments using a unilateral model of adriamycin nephrosis indicated that the enhancement of glomerular TxB2This work was presented in part at the American Society of Nephrology Annual Meeting in Washington, DC, 1983. Received for publication 23 January 1984 and in revised form 23 July 1984.synthesis is not simply a consequence of the nephrotic syndrome.We conclude that: there is an abnormality of glomerular AA metabolism in nephrotic syndrome, which leads to increased TxA2 production; the increased Tx generation correlates with protein excretion and might be responsible for altering the glomerular basement membrane permeability to protein; and the alteration found in isolated glomeruli probably reflects a modification in vivo, in that urinary excretion of immunoreactive TxB2 is also consistently increased in adriamycin nephrosis.

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Adriamycin (ADR) induces glomerular damage in rats with persistent proteinuria which develops 13 to 15 days after a single intravenous (i.v.) injection (5 mg/kg). Electron microscopy (EM) shows alterations of glomerular visceral epithelial cells with foot process fusions. The disease resembles minimal change nephropathy in humans. We studied the effect of two isocaloric diets with different protein content on urinary protein excretion, renal function, and glomerular morphology in rats treated with ADR. Six groups of rats were used. Group 1 received a single i.v. injection of ADR and was fed a standard diet containing 20% protein. Group 2 was fed a low-protein diet containing 6% protein starting 7 days before ADR. Group 3 was fed a low-protein diet starting the day after ADR. Group 4 served as control. Two additional groups of rats (5 and 6) were used to study the kidney distribution of ADR. Unlike animals fed the standard diet, animals fed the low-protein diet did not develop proteinuria. The kidney distribution of ADR measured at different intervals after drug injection was not influenced by the diet. Renal function as determined by glomerular filtration rate (GFR) and renal plasma flow (RPF) was not significantly modified in nephrotic rats receiving the standard diet compared to control animals. The low-protein regimen induced a significant elevation in RPF compared to the standard diet, but had no influence on GFR. Light and transmission EM studies showed alterations of glomerular visceral epithelial cells with fusion of foot processes in rats fed the standard diet, whereas no significant abnormalities of glomerular epithelial cells were detectable in animals receiving the low-protein diet.(ABSTRACT TRUNCATED AT 250 WORDS)

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