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. 1996 Aug;118(7):1621–1626. doi: 10.1111/j.1476-5381.1996.tb15583.x

Inhibition by tetranactin of interleukin 1 beta- and cyclic AMP-induced nitric oxide synthase expression in rat renal mesangial cells.

D Kunz 1, G Walker 1, I Wiesenberg 1, J Pfeilschifter 1
PMCID: PMC1909823  PMID: 8842423

Abstract

1. We have investigated whether tetranactin, a cyclic antibiotic produced by Streptomyces aureus with a molecular structure related to cyclosporin A, influences inducible nitric oxide synthase (iNOS; EC 1.14.13.39) induction in rat glomerular mesangial cells. 2. Previously we have shown that iNOS is expressed in renal mesangial cells in response to two principal classes of activating signals comprising inflammatory cytokines such as interleukin 1 (IL-1) or tumour necrosis factor alpha and agents that elevate cellular levels of cyclic AMP. Treatment of mesangial cells with IL-1 beta or the membrane-permeable cyclic AMP analogue, N6, 0-2'-dibutyryladenosine 3',5'-phosphate (Bt2 cyclic AMP) for 24 h induces iNOS activity measured as nitrite levels in cell culture supernatants by 44 fold or 33 fold, respectively. Incubation of mesangial cells with tetranactin inhibits IL-1 beta- and cyclic AMP-dependent production of nitrite in a dose-dependent fashion with IC50 values of 50 nM and 10 nM, respectively. 3. Western-blot analyses of mesangial cell extracts reveal that the inhibition of nitrite synthesis by tetranactin is due to a suppression of iNOS protein levels. This effect is preceded by a reduction of iNOS mRNA steady state levels as demonstrated by Northern blot analyses of total cellular RNA isolated from stimulated mesangial cells. 4. Thus, tetranactin is a potent inhibitor of iNOS expression in cytokine- and cyclic AMP-stimulated mesangial cells and represents a new class of iNOS inhibitors with IC50s in the low nanomolar range. This compound may be useful in the therapy of diseases associated with pathological NO overproduction due to iNOS expression.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anggård E. Nitric oxide: mediator, murderer, and medicine. Lancet. 1994 May 14;343(8907):1199–1206. doi: 10.1016/s0140-6736(94)92405-8. [DOI] [PubMed] [Google Scholar]
  2. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  3. Callewaert D. M., Radcliff G., Tanouchi Y., Shichi H. Tetranactin, a macrotetrolide antibiotic, suppresses in vitro proliferation of human lymphocytes and generation of cytotoxicity. Immunopharmacology. 1988 Jul-Aug;16(1):25–32. doi: 10.1016/0162-3109(88)90047-1. [DOI] [PubMed] [Google Scholar]
  4. Cattell V., Cook T. The nitric oxide pathway in glomerulonephritis. Curr Opin Nephrol Hypertens. 1995 Jul;4(4):359–364. doi: 10.1097/00041552-199507000-00013. [DOI] [PubMed] [Google Scholar]
  5. Corbett J. A., Tilton R. G., Chang K., Hasan K. S., Ido Y., Wang J. L., Sweetland M. A., Lancaster J. R., Jr, Williamson J. R., McDaniel M. L. Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction. Diabetes. 1992 Apr;41(4):552–556. doi: 10.2337/diab.41.4.552. [DOI] [PubMed] [Google Scholar]
  6. Garvey E. P., Oplinger J. A., Tanoury G. J., Sherman P. A., Fowler M., Marshall S., Harmon M. F., Paith J. E., Furfine E. S. Potent and selective inhibition of human nitric oxide synthases. Inhibition by non-amino acid isothioureas. J Biol Chem. 1994 Oct 28;269(43):26669–26676. [PubMed] [Google Scholar]
  7. Green L. C., Wagner D. A., Glogowski J., Skipper P. L., Wishnok J. S., Tannenbaum S. R. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem. 1982 Oct;126(1):131–138. doi: 10.1016/0003-2697(82)90118-x. [DOI] [PubMed] [Google Scholar]
  8. Griffiths M. J., Messent M., MacAllister R. J., Evans T. W. Aminoguanidine selectively inhibits inducible nitric oxide synthase. Br J Pharmacol. 1993 Nov;110(3):963–968. doi: 10.1111/j.1476-5381.1993.tb13907.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Klemm P., Hecker M., Stockhausen H., Wu C. C., Thiemermann C. Inhibition by N-acetyl-5-hydroxytryptamine of nitric oxide synthase expression in cultured cells and in the anaesthetized rat. Br J Pharmacol. 1995 Aug;115(7):1175–1181. doi: 10.1111/j.1476-5381.1995.tb15021.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Knowles R. G., Moncada S. Nitric oxide synthases in mammals. Biochem J. 1994 Mar 1;298(Pt 2):249–258. doi: 10.1042/bj2980249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kunz D., Mühl H., Walker G., Pfeilschifter J. Two distinct signaling pathways trigger the expression of inducible nitric oxide synthase in rat renal mesangial cells. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5387–5391. doi: 10.1073/pnas.91.12.5387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kunz D., Walker G., Eberhardt W., Nitsch D., Pfeilschifter J. Interleukin 1 beta-induced expression of nitric oxide synthase in rat renal mesangial cells is suppressed by cyclosporin A. Biochem Biophys Res Commun. 1995 Nov 13;216(2):438–446. doi: 10.1006/bbrc.1995.2642. [DOI] [PubMed] [Google Scholar]
  13. Kunz D., Walker G., Eberhardt W., Pfeilschifter J. Molecular mechanisms of dexamethasone inhibition of nitric oxide synthase expression in interleukin 1 beta-stimulated mesangial cells: evidence for the involvement of transcriptional and posttranscriptional regulation. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):255–259. doi: 10.1073/pnas.93.1.255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kunz D., Walker G., Pfeilschifter J. Dexamethasone differentially affects interleukin 1 beta- and cyclic AMP-induced nitric oxide synthase mRNA expression in renal mesangial cells. Biochem J. 1994 Dec 1;304(Pt 2):337–340. doi: 10.1042/bj3040337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Marsden P. A., Ballermann B. J. Tumor necrosis factor alpha activates soluble guanylate cyclase in bovine glomerular mesangial cells via an L-arginine-dependent mechanism. J Exp Med. 1990 Dec 1;172(6):1843–1852. doi: 10.1084/jem.172.6.1843. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Mason J. Pharmacology of cyclosporine (sandimmune). VII. Pathophysiology and toxicology of cyclosporine in humans and animals. Pharmacol Rev. 1990 Sep;41(3):423–434. [PubMed] [Google Scholar]
  17. Misko T. P., Moore W. M., Kasten T. P., Nickols G. A., Corbett J. A., Tilton R. G., McDaniel M. L., Williamson J. R., Currie M. G. Selective inhibition of the inducible nitric oxide synthase by aminoguanidine. Eur J Pharmacol. 1993 Mar 16;233(1):119–125. doi: 10.1016/0014-2999(93)90357-n. [DOI] [PubMed] [Google Scholar]
  18. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  19. Mühl H., Kunz D., Pfeilschifter J. Expression of nitric oxide synthase in rat glomerular mesangial cells mediated by cyclic AMP. Br J Pharmacol. 1994 May;112(1):1–8. doi: 10.1111/j.1476-5381.1994.tb13019.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mühl H., Kunz D., Rob P., Pfeilschifter J. Cyclosporin derivatives inhibit interleukin 1 beta induction of nitric oxide synthase in renal mesangial cells. Eur J Pharmacol. 1993 Nov 2;249(1):95–100. doi: 10.1016/0014-2999(93)90666-6. [DOI] [PubMed] [Google Scholar]
  21. Mühl H., Pfeilschifter J. Possible role of protein kinase C-epsilon isoenzyme in inhibition of interleukin 1 beta induction of nitric oxide synthase in rat renal mesangial cells. Biochem J. 1994 Oct 15;303(Pt 2):607–612. doi: 10.1042/bj3030607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 Sep;6(12):3051–3064. [PubMed] [Google Scholar]
  23. Nathan C., Xie Q. W. Regulation of biosynthesis of nitric oxide. J Biol Chem. 1994 May 13;269(19):13725–13728. [PubMed] [Google Scholar]
  24. Pfeilschifter J. Anti-inflammatory steroids inhibit cytokine induction of nitric oxide synthase in rat renal mesangial cells. Eur J Pharmacol. 1991 Mar 19;195(1):179–180. doi: 10.1016/0014-2999(91)90399-b. [DOI] [PubMed] [Google Scholar]
  25. Pfeilschifter J. Cross-talk between transmembrane signalling systems: a prerequisite for the delicate regulation of glomerular haemodynamics by mesangial cells. Eur J Clin Invest. 1989 Aug;19(4):347–361. doi: 10.1111/j.1365-2362.1989.tb00241.x. [DOI] [PubMed] [Google Scholar]
  26. Pfeilschifter J. Does nitric oxide, an inflammatory mediator of glomerular mesangial cells, have a role in diabetic nephropathy? Kidney Int Suppl. 1995 Sep;51:S50–S60. [PubMed] [Google Scholar]
  27. Pfeilschifter J., Rob P., Mülsch A., Fandrey J., Vosbeck K., Busse R. Interleukin 1 beta and tumour necrosis factor alpha induce a macrophage-type of nitric oxide synthase in rat renal mesangial cells. Eur J Biochem. 1992 Jan 15;203(1-2):251–255. doi: 10.1111/j.1432-1033.1992.tb19854.x. [DOI] [PubMed] [Google Scholar]
  28. Pfeilschifter J., Schwarzenbach H. Interleukin 1 and tumor necrosis factor stimulate cGMP formation in rat renal mesangial cells. FEBS Lett. 1990 Oct 29;273(1-2):185–187. doi: 10.1016/0014-5793(90)81080-8. [DOI] [PubMed] [Google Scholar]
  29. Schreiber S. L., Crabtree G. R. The mechanism of action of cyclosporin A and FK506. Immunol Today. 1992 Apr;13(4):136–142. doi: 10.1016/0167-5699(92)90111-J. [DOI] [PubMed] [Google Scholar]
  30. Szabó C., Southan G. J., Thiemermann C. Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiourea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12472–12476. doi: 10.1073/pnas.91.26.12472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tanouchi Y., Shichi H. Immunosuppressive and anti-proliferative effects of a macrotetrolide antibiotic, tetranactin. Immunology. 1988 Mar;63(3):471–475. [PMC free article] [PubMed] [Google Scholar]
  32. Teunissen M. B., Pistoor F. H., Rongen H. A., Kapsenberg M. L., Bos J. D. A comparison of the inhibitory effects of immunosuppressive agents cyclosporine, tetranactin, and didemnin B on human T cell responses in vitro. Transplantation. 1992 Apr;53(4):875–881. doi: 10.1097/00007890-199204000-00031. [DOI] [PubMed] [Google Scholar]
  33. Tschaikowsky K., Meisner M., Schönhuber F., Rügheimer E. Induction of nitric oxide synthase activity in phagocytic cells inhibited by tricyclodecan-9-yl-xanthogenate (D609). Br J Pharmacol. 1994 Nov;113(3):664–668. doi: 10.1111/j.1476-5381.1994.tb17043.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wu C. C., Thiemermann C., Vane J. R. Glibenclamide-induced inhibition of the expression of inducible nitric oxide synthase in cultured macrophages and in the anaesthetized rat. Br J Pharmacol. 1995 Mar;114(6):1273–1281. doi: 10.1111/j.1476-5381.1995.tb13343.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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