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Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat model (本文)

森田, 伸也 慶應義塾大学

2021.03.08

概要

Background: Cyclosporine A (CsA) is an essential immunosuppressant in organ transplantation. However, its chronic nephrotoxicity is an obstacle to long allograft survival that has not been overcome. Nuclear factor-κB (NF- κB) is activated in the renal tissue in CsA nephropathy. In this study, we aimed to investigate the effect of the specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in a rat model of CsA nephrotoxicity.

Methods: We administered CsA (15 mg/kg) daily for 28 days to Sprague-Dawley rats that underwent 5/6 nephrectomy under a low-salt diet. We administered DHMEQ (8 mg/kg) simultaneously with CsA to the treatment group, daily for 28 days and evaluated its effect on CsA nephrotoxicity.

Results: DHMEQ significantly inhibited NF-κB activation and nuclear translocation due to CsA treatment. Elevated serum urea nitrogen and creatinine levels due to repeated CsA administration were significantly decreased by DHMEQ treatment (serum urea nitrogen in CsA + DHMEQ vs CsA vs control, 69 ± 6.4 vs 113.5 ± 8.8 vs 43.1 ± 1.1 mg/ dL, respectively, p < 0.0001; serum creatinine in CsA + DHMEQ vs CsA vs control, 0.75 ± 0.02 vs 0.91 ± 0.02 vs 0.49 ± 0.02 mg/dL, respectively, p < 0.0001), and creatinine clearance was restored in the treatment group (CsA + DHMEQ vs CsA vs control, 2.57 ± 0.09 vs 1.94 ± 0.12 vs 4.61 ± 0.18 ml/min/kg, respectively, p < 0.0001). However, DHMEQ treatment did not alter the inhibitory effect of CsA on urinary protein secretion. The development of renal fibrosis due to chronic CsA nephrotoxicity was significantly inhibited by DHMEQ treatment (CsA + DHMEQ vs CsA vs control, 13.4 ± 7.1 vs 35.6 ± 18.4 vs 9.4 ± 5.4%, respectively, p < 0.0001), and these results reflected the results of renal functional assessment. DHMEQ treatment also had an inhibitory effect on the increased expression of chemokines, monocyte chemoattractant protein-1, and chemokine (c-c motif) ligand 5 due to repeated CsA administration, which inhibited the infiltration of macrophages and neutrophils into the renal tissue.

Conclusions: These findings suggest that DHMEQ treatment in combination therapy with CsA-based immunosuppression is beneficial to prevent the development of CsA-induced nephrotoxicity.

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参考文献

1. Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant. 2004;4(3):378–83.

2. Klintmalm GB, Iwatsuki S, Starzl TE. Nephrotoxicity of cyclosporin a in liver and kidney transplant patients. Lancet. 1981;1(8218):470–1.

3. Morris PJ, French ME, Dunnill MS, Hunnisett AG, Ting A, Thompson JF, et al. A controlled trial of cyclosporine in renal transplantation with conversion to azathioprine and prednisolone after three months. Transplantation. 1983; 36(3):273–7.

4. Bennett WM, Pulliam JP. Cyclosporine nephrotoxicity. Ann Intern Med. 1983; 99(6):851–4.

5. Myers BD, Ross J, Newton L, Luetscher J, Perlroth M. Cyclosporine-associated chronic nephropathy. N Engl J Med. 1984;311(11):699–705.

6. Randhawa PS, Shapiro R, Jordan ML, Starzl TE, Demetris AJ. The histopathological changes associated with allograft rejection and drug toxicity in renal transplant recipients maintained on FK506. Clinical significance and comparison with cyclosporine. Am J Surg Pathol. 1993; 17(1):60–8.

7. Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009;4(2):481–508.

8. Granelli-Piperno A, Nolan P, Inaba K, Steinman RM. The effect of immunosuppressive agents on the induction of nuclear factors that bind to sites on the interleukin 2 promoter. J Exp Med. 1990;172(6):1869–72.

9. Nishiyama S, Manabe N, Kubota Y, Ohnishi H, Kitanaka A, Tokuda M, et al. Cyclosporin a inhibits the early phase of NF-kappaB/RelA activation induced by CD28 costimulatory signaling to reduce the IL-2 expression in human peripheral T cells. Int Immunopharmacol. 2005;5(4):699–710.

10. Tamada S, Nakatani T, Asai T, Tashiro K, Komiya T, Sumi T, et al. Inhibition of nuclear factor-kappaB activation by pyrrolidine dithiocarbamate prevents chronic FK506 nephropathy. Kidney Int. 2003;63(1):306–14.

11. Asai T, Nakatani T, Tamada S, Kuwabara N, Yamanaka S, Tashiro K, et al. Activation of transcription factors AP-1 and NF-kappaB in chronic cyclosporine a nephrotoxicity: role in beneficial effects of magnesium supplementation. Transplantation. 2003;75(7):1040–4.

12. Tamada S, Asai T, Kuwabara N, Iwai T, Uchida J, Teramoto K, et al. Molecular mechanisms and therapeutic strategies of chronic renal injury: the role of nuclear factor kappaB activation in the development of renal fibrosis. J Pharmacol Sci. 2006;100(1):17–21.

13. Gonzalez-Guerrero C, Ocana-Salceda C, Berzal S, Carrasco S, Fernandez- Fernandez B, Cannata-Ortiz P, et al. Calcineurin inhibitors recruit protein kinases JAK2 and JNK, TLR signaling and the UPR to activate NF-kappaB- mediated inflammatory responses in kidney tubular cells. Toxicol Appl Pharmacol. 2013;272(3):825–41.

14. Miyajima A, Kosaka T, Seta K, Asano T, Umezawa K, Hayakawa M. Novel nuclear factor kappa B activation inhibitor prevents inflammatory injury in unilateral ureteral obstruction. J Urol. 2003;169(4):1559–63.

15. Shinoda K, Nakagawa K, Kosaka T, Tanaka N, Maeda T, Kono H, et al. Regulation of human dendritic cells by a novel specific nuclear factor- kappaB inhibitor, dehydroxymethylepoxyquinomicin. Hum Immunol. 2010; 71(8):763–70.

16. Kono H, Nakagawa K, Morita S, Shinoda K, Mizuno R, Kikuchi E, et al. Effect of a novel nuclear factor-kappaB activation inhibitor on renal ischemia- reperfusion injury. Transplantation. 2013;96(10):863–70.

17. Umezawa K, Chaicharoenpong C. Molecular design and biological activities of NF-kappaB inhibitors. Mol Cells. 2002;14(2):163–7.

18. Yamamoto M, Horie R, Takeiri M, Kozawa I, Umezawa K. Inactivation of NF- kappaB components by covalent binding of (−)-dehydroxymethylepoxyquinomicin to specific cysteine residues. J Med Chem. 2008;51(18):5780–8.

19. Takeiri M, Horie K, Takahashi D, Watanabe M, Horie R, Simizu S, et al. Involvement of DNA binding domain in the cellular stability and importin affinity of NF-kappaB component RelB. Org Biomol Chem. 2012;10(15):3053– 9.

20. Ariga A, Namekawa J, Matsumoto N, Inoue J, Umezawa K. Inhibition of tumor necrosis factor-alpha -induced nuclear translocation and activation of NF-kappa B by dehydroxymethylepoxyquinomicin. J Biol Chem. 2002; 277(27):24625–30.

21. Horie K, Ma J, Umezawa K. Inhibition of canonical NF-kappaB nuclear localization by (−)-DHMEQ via impairment of DNA binding. Oncol Res. 2015; 22(2):105–15.

22. Suzuki E, Umezawa K. Inhibition of macrophage activation and phagocytosis by a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin. Biomed Pharmacother. 2006;60(9):578–86.

23. Carlos CP, Mendes GE, Miquelin AR, Luz MA, da Silva CG, van Rooijen N, et al. Macrophage depletion attenuates chronic cyclosporine a nephrotoxicity. Transplantation. 2010;89(11):1362–70.

24. Rosen S, Greenfeld Z, Brezis M. Chronic cyclosporine-induced nephropathy in the rat. A medullary ray and inner stripe injury. Transplantation. 1990; 49(4):445–52.

25. Yang CW, Ahn HJ, Kim WY, Shin MJ, Kim SK, Park JH, et al. Influence of the renin-angiotensin system on epidermal growth factor expression in normal and cyclosporine-treated rat kidney. Kidney Int. 2001;60(3):847–57.

26. Yoon HE, Ghee JY, Piao S, Song JH, Han DH, Kim S, et al. Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy. Nephrol Dial Transplant. 2011;26(3):800–13.

27. Cantarovich D, Karam G, Giral-Classe M, Hourmant M, Dantal J, Blancho G, et al. Randomized comparison of triple therapy and antithymocyte globulin induction treatment after simultaneous pancreas-kidney transplantation. Kidney Int. 1998;54(4):1351–6.

28. Suzuki K, Sugiyama C, Ohno O, Umezawa K. Preparation and biological activities of optically active dehydroxymethylepoxyquinomicin, a novel NF- κB inhibitor. Tetrahedron. 2004;60(33):7061–6.

29. Yoshida T, Yamashita M, Horimai C, Hayashi M. Smooth muscle-selective inhibition of nuclear factor-kappaB attenuates smooth muscle phenotypic switching and neointima formation following vascular injury. J Am Heart Assoc. 2013;2(3):e000230.

30. Sanz AB, Sanchez-Nino MD, Ramos AM, Moreno JA, Santamaria B, Ruiz- Ortega M, et al. NF-kappaB in renal inflammation. J Am Soc Nephrol. 2010; 21(8):1254–62.

31. Zhong Z, Arteel GE, Connor HD, Yin M, Frankenberg MV, Stachlewitz RF, et al. Cyclosporin a increases hypoxia and free radical production in rat kidneys: prevention by dietary glycine. Am J Phys. 1998;275(4):F595–604.

32. Djamali A. Oxidative stress as a common pathway to chronic tubulointerstitial injury in kidney allografts. Am J Physiol Renal Physiol. 2007; 293(2):F445–55.

33. Longoni B, Boschi E, Demontis GC, Ratto GM, Mosca F. Apoptosis and adaptive responses to oxidative stress in human endothelial cells exposed to cyclosporin a correlate with BCL-2 expression levels. FASEB J. 2001;15(3): 731–40.

34. Galletti P, Di Gennaro CI, Migliardi V, Indaco S, Della Ragione F, Manna C, et al. Diverse effects of natural antioxidants on cyclosporin cytotoxicity in rat renal tubular cells. Nephrol Dial Transplant. 2005;20(8):1551–8.

35. Wolf G, Killen PD, Neilson EG. Cyclosporin a stimulates transcription and procollagen secretion in tubulointerstitial fibroblasts and proximal tubular cells. J Am Soc Nephrol. 1990;1(6):918–22.

36. Johnson DW, Saunders HJ, Johnson FJ, Huq SO, Field MJ, Pollock CA. Cyclosporin exerts a direct fibrogenic effect on human tubulointerstitial cells: roles of insulin-like growth factor I, transforming growth factor beta1, and platelet-derived growth factor. J Pharmacol Exp Ther. 1999;289(1):535– 42.

37. Thomas SE, Andoh TF, Pichler RH, Shankland SJ, Couser WG, Bennett WM, et al. Accelerated apoptosis characterizes cyclosporine-associated interstitial fibrosis. Kidney Int. 1998;53(4):897–908.

38. Shihab FS, Andoh TF, Tanner AM, Yi H, Bennett WM. Expression of apoptosis regulatory genes in chronic cyclosporine nephrotoxicity favors apoptosis. Kidney Int. 1999;56(6):2147–59.

39. Servais H, Ortiz A, Devuyst O, Denamur S, Tulkens PM, Mingeot-Leclercq MP. Renal cell apoptosis induced by nephrotoxic drugs: cellular and molecular mechanisms and potential approaches to modulation. Apoptosis. 2008; 13(1):11–32.

40. Yamashita M, Yoshida T, Suzuki S, Homma K, Hayashi M. Podocyte-specific NF-kappaB inhibition ameliorates proteinuria in adriamycin-induced nephropathy in mice. Clin Exp Nephrol. 2017;21(1):16–26.

41. Calne RY, Rolles K, White DJ, Thiru S, Evans DB, McMaster P, et al. Cyclosporin a initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet. 1979; 2(8151):1033–6.

42. Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine a. Nat Med. 2008;14(9):931–8.

43. Young BA, Burdmann EA, Johnson RJ, Alpers CE, Giachelli CM, Eng E, et al. Cellular proliferation and macrophage influx precede interstitial fibrosis in cyclosporine nephrotoxicity. Kidney Int. 1995;48(2):439–48.

44. Yoshimura T, Takeya M, Takahashi K. Molecular cloning of rat monocyte chemoattractant protein-1 (MCP-1) and its expression in rat spleen cells and tumor cell lines. Biochem Biophys Res Commun. 1991;174(2):504–9.

45. Gonzalez-Guerrero C, Cannata-Ortiz P, Guerri C, Egido J, Ortiz A, Ramos AM. TLR4-mediated inflammation is a key pathogenic event leading to kidney damage and fibrosis in cyclosporine nephrotoxicity. Arch Toxicol. 2017;91(4): 1925–39.

46. Jin M, Lv P, Chen G, Wang P, Zuo Z, Ren L, et al. Klotho ameliorates cyclosporine A-induced nephropathy via PDLIM2/NF-kB p65 signaling pathway. Biochem Biophys Res Commun. 2017;486(2):451–7.

47. Nakahama H. Stimulatory effect of cyclosporine a on endothelin secretion by a cultured renal epithelial cell line, LLC-PK1 cells. Eur J Pharmacol. 1990; 180(1):191–2.

48. Kurtz A, Della Bruna R, Kuhn K. Cyclosporine a enhances renin secretion and production in isolated juxtaglomerular cells. Kidney Int. 1988;33(5):947–53.

49. Bobadilla NA, Gamba G. New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone. Am J Physiol Renal Physiol. 2007;293(1):F2–9.

50. Roullet JB, Xue H, McCarron DA, Holcomb S, Bennett WM. Vascular mechanisms of cyclosporin-induced hypertension in the rat. J Clin Invest. 1994;93(5):2244–50.

51. Park HS, Kim EN, Kim MY, Lim JH, Kim HW, Park CW, et al. The protective effect of neutralizing high-mobility group box 1 against chronic cyclosporine nephrotoxicity in mice. Transpl Immunol. 2016;34:42–9.

52. Neria F, Castilla MA, Sanchez RF, Gonzalez Pacheco FR, Deudero JJ, Calabia O, et al. Inhibition of JAK2 protects renal endothelial and epithelial cells from oxidative stress and cyclosporin a toxicity. Kidney Int. 2009;75(2):227– 34.

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