Laboratory Investigation

Kidney International (1986) 30, 524–531; doi:10.1038/ki.1986.217

Leukotriene C4 and D4 contract rat glomerular mesangial cells

Michael S Simonson1 and Michael J Dunn1

1Department of Medicine, Case Western Reserve University, Division of Nephrology, University Hospitals of Cleveland, Cleveland, Ohio, USA

Correspondence: Dr Michael J Dunn, Division of Nephrology, University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.

Received 23 July 1985; Revised 17 January 1986.

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Abstract

Leukotriene C4 and D4 contract rat glomerular mesangial cells. The sulfidopeptide leukotrienes, LTC4 and LTD4, have vasoconstrictor effects in the kidney, reducing both renal blood flow and the glomerular filtration rate. As one mechanism regulating the glomerular filtration rate, mesangial cell contraction may reduce the capillary surface area, thereby lowering the ultrafiltration coefficient. Using image analysis microscopy to quantify changes in cell morphology, we found that LTC4 and LTD4 (1times10 -12M to 1times10 -6M) reduced the cross–sectional area of cultured mesangial cells from rat glomeruli. The response to LTC4 and LTD4 (10-6M), as measured by the percentage of responding cells (30 to 35%), the maximum decrease in cross–sectional area (25 to 32%), and the time course was identical to that for angiotensin II (10-6M). The contraction induced by LTD4 was attenuated by an LTD4 receptor antagonist (4R,5S,6Z-nor-LTD1). Also, preincubation with colchicine prevented LTC4-induced contraction. Leukotriene B4, a non-sulfidopeptide leukotriene that stimulates chemotaxis and chemo-kinesis, had negligible agonist activity. Mesangial cells cultured on less adhesive teflon membranes were more responsive to LTD4 (62% of cells responded) than cells cultured on glass or polystyrene (35% of cells responded). Mesangial cell contraction was not merely a shape–change as a result of cell damage, since cellular injury was not documented by lactate dehydrogenase release and proliferation of mesangial cells was not retarded by LTC4. Furthermore, the contraction was independent of cell size. Because leukotrienes stimulate cyclooxygenase products in other cells, we examined the ability of the sulfidopeptide leukotrienes to stimulate prostaglandin and thromboxane synthesis. LTC4 and LTD4 did not stimulate PGE2 formation, the major cyclooxygenase product of rat mesangial cells. Although LTC4, but not LTD4, stimulated a small amount of thromboxane synthesis, a thromboxane synthetase inhibitor (UK-38485) and a receptor antagonist (EP-092) did not alter leukotriene-mediated contraction. The contraction of mesangial cells exposed to LTC4 and LTD4 may contribute to the reduction in the ultrafiltration coefficient seen in some types of glomerular injury.

Abbreviations:

LT, leukotriene(s); LTB4, LTC4, LTD4, leukotriene B4, C4, D4; ANG II, angiotensin II; CSA, cross-sectional area; KHH, Krebs–Henseleit HEPES; GFR, glomerular filtration rate; Kf, ultrafiltration coefficient; PGE2, prostaglandin E2; TxA2, thromboxane A2; LDH, lactate dehydrogenase.

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References

  1. Samuelsson B: Leukotrienes: Mediators of immediate hypersensitivity reactions and inflammation. Science 220:568–575, 1983 | Article | PubMed | ISI | ChemPort |
  2. Lewis RA, Austen KF: The biologically active leukotrienes. J Clin Invest 73:889–897, 1984
  3. Hedqvist P, Dahlen SE, Gustafsson L, Hammarstrom S, Samuelsson B: Biological profile of leukotrienes C4 and D4. Acta Physiol Scand 110:331–333, 1980 | PubMed | ISI | ChemPort |
  4. Sirois P, Roy S, Tetrault JP, Borgeat P, Picard S, Corey EJ: Pharmacological activity of leukotrienes A4, B4, C4 and D4 on selected guinea-pig, rat, rabbit, and human smooth muscles. Prostaglandins Med 7:327–340, 1981 | Article | ChemPort |
  5. Feurerstein N, Foegh, Ramwell P: Leukotrienes C4 and D4 induce prostaglandin and thromboxane release from rat peritoneal macrophages. Br J Pharmacol 72:389–391, 1981
  6. Folco G, Hansson G, Granstrom E: Leukotriene C4 stimulates TxA2 formation in isolated sensititized guinea pig lungs. Biochem Pharmacol 30:2491–2493, 1981
  7. Cramer EB, Pologe L, Pawlowski NA, Cohn ZA, Scott WA: Leukotriene C promotes prostacyclin synthesis by human endothelial cells. Proc Natl Acad Sci 80:4109–4113, 1983
  8. Badr K, Baylis C, Pfeffer J, Pfeffer M, Soberman RJ, Lewis RA, Austen KF, Corey EJ, Brenner B: Renal and systemic hemodynamic responses to intravenous infusion of leukotriene C4 in the rat. Circ Res 54:492–499, 1984 | PubMed | ISI | ChemPort |
  9. Rosenthal A, Pace-Asciak CR: Potent vasoconstriction of the isolated perfused rat kidney by leukotrienes C4 and D4. Can J Phys Pharmacol 61:325–328, 1983
  10. Piper PJ, Stanton A, McLeod L: The actions of leukotrienes C4 and D4 in the porcine renal vascular bed. Prostaglandins 29:61–73, 1985 | Article | PubMed | ChemPort |
  11. Ballermann BJ, Lewis RA, Corey EJ, Austen KF, Brenner BM: Identification and characterization of leukotriene C4 receptors in isolated rat renal glomeruli. Circ Res 56:324–330, 1985
  12. Ausiello DA, Kreisberg JJ, Roy C, Karnovsky MJ: Contraction of cultured rat glomerular cells after stimulation with angiotensin II and arginine vasopressin. J Clin Invest 65:754–760, 1980 | PubMed | ISI | ChemPort |
  13. Brenner BM: Control of glomerular function by intrinsic contractile elements. Fed Proc 42:3045–3079, 1983
  14. Dworkin LD, Ichikawa I, Brenner B: Hormonal modulation of glomerular function. Am J Physiol 244:F95–F104, 1983 | PubMed | ISI | ChemPort |
  15. Levine L, Morgan R, Lewis R, Austen K, Clark D, Marfat A, Corey E: Radioimmunoassay of the leukotrienes of slow reacting substance of anaphylaxis. Proc Natl Acad Sci 78:7692–7696, 1981
  16. Armstrong RA, Jones RL, Peesapati V, Will SG, Wilson NH: Competitive antagonism at thromboxane receptors in human platelets. Br J Pharmacol 84:595–607, 1985
  17. Jones RL, Peesapati V, Wilson NH: Antagonism of the thromboxane-sensitive contractile systems of the rabbit aorta, dog saphenous vein and guinea-pig trachea. Br J Pharmacol 76:423–438, 1982 | PubMed | ChemPort |
  18. Striker GE, Killen PO, Farrin FM: Human glomerular cells in vitro: Isolation and characterization. Transplant Proc 12(suppl l):88–99, 1980 | PubMed | ISI | ChemPort |
  19. Lovett D, Sterzel RB, Kashgarian M, Ryan JL: Neutral proteinase activity produced in vitro by cells of the glomerular mesangium. Kidney Int 23:342–349, 1983 | PubMed | ISI | ChemPort |
  20. Kreisberg J, Karnovsky MJ: Glomerular cells in culture. Kidney Int 23:439–447, 1983 | PubMed | ISI | ChemPort |
  21. Gabridge MG: The chamber/dish: An improved vessel for cell and expiant culture. In vitro 17:91–97, 1981
  22. Bradbury S: Microscopical image analysis: Problems and approaches. Microsc 115:137–150, 1978
  23. Bradbury S: Quantitative image analysis, in Analytical and Quantitative Methods in Microscopy, edited by Meek GA, Elder HY, Cambridge, Cambridge University Press, 1977, pp. 91–116
  24. Huang HK: Biomedical image processing. CRC Crit Rev Bioengineering 5:185–271, 1981
  25. Markwell MK, Haas SM, Bieber LL, Tolbert NE: A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples. Anal Biochem 87:206–210, 1978 | Article | PubMed | ISI | ChemPort |
  26. Scharschmidt LA, Dunn MJ: Prostaglandin synthesis by rat glomerular mesangial cells in culture. J Clin Invest 71:1756–1764, 1983 | PubMed | ISI | ChemPort |
  27. Bergmeyer HU, Bernt E: Lactate dehydrogenase, in Methods of Enzymatic Analysis, edited by Bergmeyer HU, Deerfield Beach, Verlag Chemie Int., 1974, pp. 574–579
  28. Gleason JG, Ku TW, McCarthy ME, Weichman BM, Holden D, Osborn RR, Zabko-Potapovich B, Berkowitz B, Wasserman MA: 2-nor-leukotriene analogs: Antagonists of the airway and vascular smooth muscle effects of leukotriene C4, D4, and E4. Biochem Biophys Res Comm 117:732–739, 1983
  29. Weichman BM, Wasserman MA, Holden DA, Osborn RR, Woodward DF, Ku TW, Gleason JG: Antagonism of the pulmonary effects of the peptide leukotrienes by a leukotriene D4 analog. J Pharmacol Exp Ther 227:700–705, 1983
  30. Simonson MS: Image analysis microscopy: Principles and applications. Biotechniques 3:484–493, 1985
  31. Mahieu PR, Foidart JB, DuBois CH, Dechenne CA, Deheneffe J: Tissue culture of normal rat glomeruli: Contractile activity of the cultured mesangial cells. Invest Cell Pathol 3:121–128, 1980
  32. Foidart J, Sraer J, DeLarue F, Mahieu P, Ardaillou R: Evidence for mesangial glomerular receptors for angiotensin II linked to mesangial cell contractility. FEBS Lett 121:333–339, 1980 | Article | PubMed | ChemPort |
  33. Tanaka T, Fujiwara Y, Orita A, Sasaki E, Kitamura H, Abe H: The functional characteristics of cultured rat mesangial cell. Jpn Circ 7 48:1017–1029, 1984
  34. Penit J, Faure M, Jard S: Vasopressin and angiotensin II receptors in rat aortic smooth muscle cells in culture. Am J Physiol 244:E72–E82, 1983 | PubMed | ChemPort |
  35. Ives HE, Schultz GS, Galardy RE, Jamieson JD: Preparation of functional smooth muscle cells from the rabbit aorta. J Exp Med 148:1400–1413, 1978 | Article | PubMed | ChemPort |
  36. Drazen JM, Austen KF, Lewis RA, Clark DA, Goto G, Marfat A, Corey EJ: Comparative airway and vascular activities of leukotrienes C-l and D in vivo and in vitro. Proc Natl Acad Sci USA 77:4354–4358, 1980 | Article | PubMed | ChemPort |
  37. Clark MA, Cook M, Mong S, Hogaboom G, Shorr R, Stadel J, Crooke S: Leukotriene C4 ([3H]-LTC4) binding to membrane isolated from a hamster smooth muscle cell line (DDT1MF2). Life Sci 35:441–448, 1984
  38. Krilis S, Lewis RA, Corey EJ, Austen KF: Specific receptors for leukotriene C4 on a smooth muscle cell line. J Clin Invest 72:1516–1519, 1983
  39. Krilis S, Lewis RA, Corey EJ, Austen KF: Specific binding of leukotriene C4 to ileal segments and subcellular fractions of ileal smooth muscle cells. Proc Natl Acad Sci 81:4529–4533, 1984
  40. Pace-Asciak CR, Smith WL: Enzymes in the biosynthesis and catabolism of the eicosanoids: Prostaglandinds, thromboxanes, leukotrienes, and hydroxy fatty acids, in The Enzymes, Vol. 16, edited by Boyer PD, New York, Academic Press, 1983, p. 544–603
  41. Meister AS, Tate S, Griffith OW: gamma-glutamyl transpeptidase, in Methods in Enzymology, vol. 77, edited by Jakoby WB, New York, Academic Press, 1981, p. 237–253
  42. Austen KF, Corey EJ, Drazen JM, Leitch AG: The effect of indomethacin on the contractile response of the guinea-pig parenchymal strip to leukotrienes B4, C4, D4, and E4. Br J Pharmacol 80:47–53, 1983 | PubMed | ChemPort |
  43. Creese BR, Bach MK, Fitzpatrick FA, Bothwell WM: Leukotriene-induced contraction and thromboxane production in guinea-pig lung parenchymal strips. Eur J Pharm 102:197–204, 1984
  44. Baylis C, Brenner BM: Modulation by prostaglandin synthesis inhibitors of the action of exogenous angiotensin II on glomerular ultrafiltration in the rat. Circ Res 43:889–898, 1978
  45. Scharschmidt LA, Lianos E, Dunn MJ: Arachidonate metabolites and the control of glomerular function. Fed Proc 42:3058–3063, 1983 | PubMed | ISI | ChemPort |
  46. Tucker BJ, Gushwa LC, Wilson CB, Blantz RC: Effect of leukocyte depletion on glomerular dynamics during acute glomerular immune injury. Kidney Int 28:28–35, 1985

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