Abstract
The administration of FK506 or cyclosporin A (CyA) to animals and humans induces a decrease in glomerular filtration rate and renal plasma flow and an increase in renal vascular resistance. Endothelins (ET-1), very powerful renal vasoconstrictors, are involved in CyA-related alteration in renal haemodynamics. In this study we sought to determine whether FK506 and CyA had a stimulatory effect on endothelin secretion by cultured kidney cells (tubular and mesangial cells) and whether this stimulatory effect coincided with an increase in ET-1 serum level in FK506- and CyA-treated rats. FK506 concentrations of 1,0.1,0.01 and 0.001 μM significantly stimulated ET-1 secretion by cultured tubular and mesangial cells. CyA at 10,1,0.1 and 0.01 μM also exerted an enhancing effect on ET-1 secretion in cultured tubular cells whereas CyA only at 10 and 1 μM had a stimulatory effect on ET-1 secretion by human mesangial cells. We observed that the concentrations of CyA that induced the most substantial enhancing effect were 10 or 100 times higher than those required for FK506 to produce the same effect. The concentrations of FK506 or CyA which induced ET-1 secretion by tubular cells and kidney cells were not cytolytic as assessed by N-acetyl-β-D-glucos-aminidase (NAG) release and lactic dehydrogenase (LDH) release. FK506 or CyA treatment at toxic doses induced an increase in serum level of ET-1 in treated rats. We conclude that FK506 and CyA induced an increase in the synthesis of endothelin in the kidney which may explain the increase in circulating ET-1. This stimulatory effect may contribute to the genesis of haemodynamic preturbations associated with FK506 and CyA.
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References
Barros EJG, Boim MA, Ajzen H, Ramos OL, Schor N (1987) Glomerular hemodynamics and hormonal participation in cy-closporine nephrotoxicity. Kidney Int 3:219–225
Hull RN, Cherry WR, Weaver GW (1976) The origin of a pig kidney cell strain. In Vitro 12:670–674
Ishibashi M (for the Japanese study group) (1991) Japanese study of FK506 in kidney transplantation: Results of early phase II study. Transplant Proc (in press)
Jain AB, Fung J, Todo S, Alessiani M, Takaya S, Abu-Elmagd K, Tzakis A, Starzl TE (1991) Incidence and treatment of episodes of rejection in primary orthotopic liver transplantation under FK506. Transplant Proc 23: 928–930
Kon V, Suguira M, Inagami T, Bradley RH, Ichikawa I, Hoover RL (1990) Role of endothelin in cyclosporin-induced glomerular dysfunction. Kidney Int 37:1487–1491
Kon V, Yoshioka T, Fogo A (1989) Glomerular actions of endothelin in vivo. Clin Invest 83:1762–1767
Kumano K, Wang G, Endo T, Kuwao S (1991) FK506-induced nephrotoxicity in rats. Transplant Proc 23:512–515
Murray BM, Paller MS, Ferris TF (1985) Effect of cyclosporin administration on renal hemodynamics in conscious rats. Kidney Int 28:767–774
Nambi P, Pullen M, Contino LC, Brooks DP (1990) Upregulation of renal endothelin secretion in rats with cyclosporine A-induced nephrotoxicity. Eur J Pharmacol 187:113–116
Ohta K, Hirata Y, Imai T, Kanno K, Emori T, Shichiri M, Maru-mo F (1990) Cytokine-induced release of endothelin-1 from porcine renal epithelial cell line. Biochem Biophys Res Commun 169:578–584
Perico N, Begnini A, Delaini F, Remuzzi G (1986) Functional significance of exaggerated renal thromboxane A2 synthesis induced by cyclosporine A. Am J Physiol 251: F581-F587
Perico N, Dadan J, Remuzzi G (1990) Endothelin mediates the renal vasoconstriction induced by cyclosporine in rat. JASN 1: 76–83
Shapiro R, Jordan M, Fung J, Johnston J, Iwaki Y, Tzakis A, Ha-kala T, Todo S, Starzl TE (1991) Kidney transplantation under FK506. Transplant Proc 23: 920–923
Shichiri M, Hirata Y, Emori T, Ohta K, Nakajima T, Sato K, Sato A, Marumo F (1989) Secretion of endothelin and related peptides from renal epithelial cell lines. FEBS Lett 253:203–206
Sugiura M, Inagami T, Kon V (1989) Endotoxin stimulates endothelin release in vivo and in vitro as determined by radioimmunoassay. Biomed Biophys Res Comun 161:1220–1227
Suzuki N, Matsumoto H, Kitada C, Masaki T, Fujino M (1989) A sensitive sandwich-enzyme immunoassay for human endothelin. J Immunol Methods 188:245–250
Tanaka T, Fujiware Y, Orita Y, Sasaki E, Kitamura H, Abe H (1984) The functional characteristics of cultured rat mesangial cells. Jpn Circ J 48:1017–1029
Thomson AW (1989) FK506 how much potential. Immunology Today 10:6–10
Textor S, Wilson D, Weisner R, Porayko M, Dickson E, Krom R (1991) Differences in renal and systemic vasoconstriction during, administration of FK506 and cyclosporine. Transplant Proc (in press)
Yanigisawa M, Kurihara H, Kimura S, Kobayashi M, Mitsui Y, Yazaki K, Goto Y, Masaki T (1988) A novel vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415
Zoja C, Orisio S, Perico N, Begnini A, Morigi M, Benatti L, Ram-baldi A, Remuzzi G (1991) Constitutive expression of endothelin gene in cultured human mesangial cells and its modulation by transforming growth factor βthrombin, and a thromboxane A2 analogue. Lab Invest 64:16–20
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© 1992 Springer-Verlag Berlin Heidelberg
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Moutabarrik, A. et al. (1992). FK506 mechanism of nephrotoxicity: stimulatory effect on endothelin secretion by cultured kidney cells. In: Kootstra, G., Opelz, G., Buurman, W.A., van Hooff, J.P., MacMaster, P., Wallwork, J. (eds) Transplant International Official Journal of the European Society for Organ Transplantation. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-77423-2_30
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DOI: https://doi.org/10.1007/978-3-642-77423-2_30
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