Indomethacin reduces proteinuria in passive Heymann nephritis in rats

C. Zoja, A. Benigni, P. Verroust, P. Ronco, T. Bertani, G. Remuzzi

Research output: Contribution to journalArticlepeer-review

Abstract

Indomethacin has been used to lower proteinuria in human glomerular diseases with controversial results. The mechanism of indomethacin beneficial effects has not been established. A possible explanation is that indomethacin reduces proteinuria by inhibiting the synthesis of renal prostaglandins (PGs); however, appropriate studies to address this issue have never been done. The objectives of the present study were: a) to investigate whether indomethacin influences protein excretion in an experimental model of immunological-mediated glomerular disease; b) to establish if the possible favorable effect of indomethacin on proteinuria is related to a reduction in glomerular filtration rate (GFR); c) to establish the possible association between the antiproteinuric effect of indomethacin and its inhibitory effect on arachidonic acid (AA) metabolites of renal or extrarenal origin; and d) to further investigate the relationship between proteinuria and renal thromboxane (Tx) synthesis previously demonstrated in experimental models of nephrotoxic nephritis and adriamycin (ADR) nephrosis. To this purpose we used an experimental immune-complex disease, passive Heymann nephritis (PHN) which was induced in the rat by a single intravenous (i.v.) injection of heterologous serum directed against a bruch border component (gp 330 antigen). Indomethacin at a dose of 6 mg/kg intraperitoneally (i.p.) administered for four consecutive days to PHN animals during the period of heavy proteinuria, effectively reduced urinary protein excretion. The reduction in proteinuria does not appear to be a consequence of a reduction in GFR as documented by inulin clearance. Glomerular synthesis and urinary excretion of vasodilatory prostacyclin (PGI2) and PGE2 were decreased or unchanged in PHN animals in respect to control animals. At variance, isolated glomeruli from rats with PHN studied 16 days after anti-gp 330 serum injection, when animals were heavily proteinuric, generated significantly more TxB2, the stable breakdown product of TxA2, than normal glomeruli. Urinary excretion of TxB2 was also significantly higher in rats with PHN than in normal rats. Indomethacin reduced the urinary TxB2 excretion by 74%. The administration of a selective Tx-synthase inhibitor UK-38,485 at a dose fully inhibiting platelet TxA2 synthesis only partially (around 40%) inhibited urinary excretion of TxB2 and did not reduce urinary protein excretion. These results may provide the experimental basis for the clinical observation that indomethacin has an antiproteinuric effect in humans.

Original languageEnglish
Pages (from-to)1335-1343
Number of pages9
JournalKidney International
Volume31
Issue number6
Publication statusPublished - 1987

ASJC Scopus subject areas

  • Nephrology

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