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. 1986 Jan;77(1):252–259. doi: 10.1172/JCI112284

Increased renal thromboxane production in murine lupus nephritis.

V E Kelley, S Sneve, S Musinski
PMCID: PMC423334  PMID: 3455932

Abstract

To determine whether the amount of cyclooxygenase metabolites correlates with the development of lupus nephritis, intrarenal eicosanoid production was measured in autoimmune mice. Disease progression was related to the renal biosynthesis of prostaglandin (PGE2), prostacyclin (6 keto PGF1 alpha), and thromboxane (TXB2) using the MRL-lpr and NZB X NZW F1 hybrid mouse strains with predictably progressive forms of renal disease that mimic the human illness. Mice were evaluated for renal disease by measuring urinary protein excretion and renal immunopathological conditions and these features were related to renal eicosanoid production. These studies show that: (a) intrarenal synthesis of TXB2 increased incrementally in MRL-lpr and NZB X NZW F1 hybrid mice as renal function deteriorated and renal pathologic events progressed; (b) there were no consistent increases in the levels of two other cyclooxygenase metabolites, PGE2 or 6 keto PGF1 alpha; (c) increased TXB2 production occurred in the renal medulla, cortex, and within enriched preparations of cortical glomeruli; (d) when renal disease was prevented by pharmacologic doses of PGE2, intrarenal TXB2 did not increase; (e) administration of a dose of ibuprofen (9 mg/kg), a cyclooxygenase inhibitor capable of reducing 90% of platelet TXB2 without affecting intrarenal levels, did not retard the progression of renal damage. Taken together, these data indicate that the intrarenal level of TXB2 rises in relation to the severity of murine lupus nephritis. Furthermore, because of the potential deleterious effects of TXA2, enhanced production of this eicosanoid may be an important mediator of renal injury.

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Selected References

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  1. Barcelli U., Rademacher R., Ooi Y. M., Ooi B. S. Modification of glomerular immune complex deposition in mice by activation of the reticuloendothelial system. J Clin Invest. 1981 Jan;67(1):20–27. doi: 10.1172/JCI110013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beck T. R., Hassid A., Dunn M. J. The effect of arginine vasopressin and its analogs on the synthesis of prostaglandin E2 by rat renal medullary interstitial cells in culture. J Pharmacol Exp Ther. 1980 Oct;215(1):15–19. [PubMed] [Google Scholar]
  3. Burch R. M., Knapp D. R., Halushka P. V. Vasopressin stimulates thromboxane synthesis in the toad urinary bladder: effects of imidazole. J Pharmacol Exp Ther. 1979 Sep;210(3):344–348. [PubMed] [Google Scholar]
  4. Donadio J. V., Jr, Anderson C. F., Mitchell J. C., 3rd, Holley K. E., Ilstrup D. M., Fuster V., Chesebro J. H. Membranoproliferative glomerulonephritis. A prospective clinical trial of platelet-inhibitor therapy. N Engl J Med. 1984 May 31;310(22):1421–1426. doi: 10.1056/NEJM198405313102203. [DOI] [PubMed] [Google Scholar]
  5. Foegh M. L., Winchester J. F., Zmudka M., Helfrich G. B., Cooley C., Ramwell P. W., Schreiner G. E. Urine i-TXB2 in renal allograft rejection. Lancet. 1981 Aug 29;2(8244):431–434. doi: 10.1016/s0140-6736(81)90772-8. [DOI] [PubMed] [Google Scholar]
  6. Hassid A., Konieczkowski M., Dunn M. J. Prostaglandin synthesis in isolated rat kidney glomeruli. Proc Natl Acad Sci U S A. 1979 Mar;76(3):1155–1159. doi: 10.1073/pnas.76.3.1155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Holdsworth S. R., Thomson N. M., Glasgow E. F., Dowling J. P., Atkins R. C. Tissue culture of isolated glomeruli in experimental crescentic glomerulonephritis. J Exp Med. 1978 Jan 1;147(1):98–109. doi: 10.1084/jem.147.1.98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hunsicker L. G., Shearer T. P., Plattner S. B., Weisenburger D. The role of monocytes in serum sickness nephritis. J Exp Med. 1979 Sep 19;150(3):413–425. doi: 10.1084/jem.150.3.413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hurd E. R., Johnston J. M., Okita J. R., MacDonald P. C., Ziff M., Gilliam J. W. Prevention of glomerulonephritis and prolonged survival in New Zealand Black/New Zealand White F1 hybrid mice fed an essential fatty acid-deficient diet. J Clin Invest. 1981 Feb;67(2):476–485. doi: 10.1172/JCI110056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kelley V. E., Ferretti A., Izui S., Strom T. B. A fish oil diet rich in eicosapentaenoic acid reduces cyclooxygenase metabolites, and suppresses lupus in MRL-lpr mice. J Immunol. 1985 Mar;134(3):1914–1919. [PubMed] [Google Scholar]
  11. Kelley V. E., Izui S., Halushka P. V. Effect of ibuprofen, a fatty acid cyclooxygenase inhibitor, on murine lupus. Clin Immunol Immunopathol. 1982 Nov;25(2):223–231. doi: 10.1016/0090-1229(82)90185-4. [DOI] [PubMed] [Google Scholar]
  12. Kelley V. E., Winkelstein A., Izui S., Dixon F. J. Prostaglandin E1 inhibits T-cell proliferation and renal disease in MRL/1 mice. Clin Immunol Immunopathol. 1981 Nov;21(2):190–203. doi: 10.1016/0090-1229(81)90208-7. [DOI] [PubMed] [Google Scholar]
  13. Kelley V. E., Winkelstein A., Izui S. Effect of prostaglandin E on immune complex nephritis in NZB/W mice. Lab Invest. 1979 Dec;41(6):531–537. [PubMed] [Google Scholar]
  14. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  15. Lewis G. P. Immunoregulatory activity of metabolites of arachidonic acid and their role in inflammation. Br Med Bull. 1983 Jul;39(3):243–248. doi: 10.1093/oxfordjournals.bmb.a071827. [DOI] [PubMed] [Google Scholar]
  16. Lianos E. A., Andres G. A., Dunn M. J. Glomerular prostaglandin and thromboxane synthesis in rat nephrotoxic serum nephritis. Effects on renal hemodynamics. J Clin Invest. 1983 Oct;72(4):1439–1448. doi: 10.1172/JCI111100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Okegawa T., Jonas P. E., DeSchryver K., Kawasaki A., Needleman P. Metabolic and cellular alterations underlying the exaggerated renal prostaglandin and thromboxane synthesis in ureter obstruction in rabbits. Inflammatory response involving fibroblasts and mononuclear cells. J Clin Invest. 1983 Jan;71(1):81–90. doi: 10.1172/JCI110754. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Petrulis A. S., Aikawa M., Dunn M. J. Prostaglandin and thromboxane synthesis by rat glomerular epithelial cells. Kidney Int. 1981 Oct;20(4):469–474. doi: 10.1038/ki.1981.163. [DOI] [PubMed] [Google Scholar]
  19. Prescott S. M. The effect of eicosapentaenoic acid on leukotriene B production by human neutrophils. J Biol Chem. 1984 Jun 25;259(12):7615–7621. [PubMed] [Google Scholar]
  20. Prickett J. D., Robinson D. R., Steinberg A. D. Dietary enrichment with the polyunsaturated fatty acid eicosapentaenoic acid prevents proteinuria and prolongs survival in NZB x NZW F1 mice. J Clin Invest. 1981 Aug;68(2):556–559. doi: 10.1172/JCI110288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Prickett J. D., Robinson D. R., Steinberg A. D. Effects of dietary enrichment with eicosapentaenoic acid upon autoimmune nephritis in female NZB X NZW/F1 mice. Arthritis Rheum. 1983 Feb;26(2):133–139. doi: 10.1002/art.1780260203. [DOI] [PubMed] [Google Scholar]
  22. Purkerson M. L., Joist J. H., Yates J., Valdes A., Morrison A., Klahr S. Inhibition of thromboxane synthesis ameliorates the progressive kidney disease of rats with subtotal renal ablation. Proc Natl Acad Sci U S A. 1985 Jan;82(1):193–197. doi: 10.1073/pnas.82.1.193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Remuzzi G., Imberti L., Rossini M., Morelli C., Carminati C., Cattaneo G. M., Bertani T. Increased glomerular thromboxane synthesis as a possible cause of proteinuria in experimental nephrosis. J Clin Invest. 1985 Jan;75(1):94–101. doi: 10.1172/JCI111703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Scharschmidt L. A., Dunn M. J. Prostaglandin synthesis by rat glomerular mesangial cells in culture. Effects of angiotensin II and arginine vasopressin. J Clin Invest. 1983 Jun;71(6):1756–1764. doi: 10.1172/JCI110931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Schreiner G. F., Kiely J. M., Cotran R. S., Unanue E. R. Characterization of resident glomerular cells in the rat expressing Ia determinants and manifesting genetically restricted interactions with lymphocytes. J Clin Invest. 1981 Oct;68(4):920–931. doi: 10.1172/JCI110347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Steinberg A. D., Huston D. P., Taurog J. D., Cowdery J. S., Ravecheé E. S. The cellular and genetic basis of murine lupus. Immunol Rev. 1981;55:121–154. doi: 10.1111/j.1600-065x.1981.tb00341.x. [DOI] [PubMed] [Google Scholar]
  27. Striker G. E., Mannik M., Tung M. Y. Role of marrow-derived monocytes and mesangial cells in removal of immune complexes from renal glomeruli. J Exp Med. 1979 Jan 1;149(1):127–136. doi: 10.1084/jem.149.1.127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Theofilopoulos A. N., Dixon F. J. Etiopathogenesis of murine SLE. Immunol Rev. 1981;55:179–216. doi: 10.1111/j.1600-065x.1981.tb00343.x. [DOI] [PubMed] [Google Scholar]
  29. Zenser T. V., Davis B. B. Effects of calcium on prostaglandin E2 synthesis by rat inner medullary slices. Am J Physiol. 1978 Sep;235(3):F213–F218. doi: 10.1152/ajprenal.1978.235.3.F213. [DOI] [PubMed] [Google Scholar]

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