Acute effects of FK506 and cyclosporine A on cultured human proximal tubular cells

Blaehr, Hanne; Andersen, Claus B.; Ladefoged, J

doi:10.1016/0926-6917(93)90062-u

Cited by 7 publications

(4 citation statements)

References 14 publications

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“…In comparison to cytotoxicity, FK506 seemed to exert its antiproliferative action at lesser concentrations than its cytotoxic effects, whereas CsA did not show such a difference. In agreement with these results Blaehr et al [9]reported that FK506 inhibits cell growth on human proximal tubular cells without influencing cellular viability. Yang and Finn [30]observed that CsA treatment of LLC-PK1 and of MDCK cells leads to a more pronounced effect on cell lysis than on cell proliferation.…”

Section: Discussionsupporting

confidence: 79%

“…One possibility for cyclosporine- and FK506-induced nephrotoxicity is renal vasoconstriction with concomitant hemodynamic changes. There is also some evidence supporting a direct effect on renal cells as a mechanism of nephrotoxicity [8, 9, 10]. Limited information is available on the mechanism mediating tubulointerstitial injury and fibrosis induced by CsA and FK506 [5, 11].…”

Section: Introductionmentioning

confidence: 99%

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Different Effects of Cyclosporine A and FK506 on Potassium Transport Systems in MDCK Cells

Aker

Heering

Kinne-Saffran

et al. 2001

Nephron Exp Nephrol

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Background: Hyperkalemia and metabolic acidosis are common manifestations in patients receiving the immunosuppressive agent cyclosporine A (CsA) and the recently introduced FK506. We compared the acute toxic and antiproliferative effects as well as the effects on the transport activity of Na⁺/K⁺-ATPase and Na⁺/K⁺/2Cl^– cotransporter of CsA and FK506 in an established cell line of distal/collecting tubule origin (MDCK cells). Methods: MDCK cells were exposed to various concentrations of CsA or FK506 and the effects on cell viability (MTT test and neutral red uptake), plasma membrane integrity (lactate dehydrogenase (LDH) release) and cell proliferation (bromodeoxyuridine (BrdU) incorporation) were compared. For transport studies, after confluence, MDCK cells were exposed to CsA or FK506 for 48 h in the presence and absence of aldosterone. Ouabain- and bumetanide-sensitive ⁸⁶Rubidium uptake measurements were used to study the activity of the Na⁺/K⁺-ATPase and Na⁺/K⁺/2Cl^– cotransporter at the surface of intact cells. Results: After 24 h of exposure CsA reduced the number of viable cells to 50% at 30 µM, whereas for FK506 2–3 times higher concentrations had to be employed. Similarly, LDH release was stimulated tenfold by 30 µM CsA but only fourfold by 70 µM FK506. In contrast, DNA synthesis was affected at lower concentrations of FK506 than of CsA. In cells treated for 24 h BrdU incorporation was significantly inhibited by 3 µM FK506, whereas a similar inhibition required 10 µM CsA. The transport activity of Na⁺/K⁺-ATPase and of Na⁺/K⁺/2Cl^– cotransporter were significantly decreased (37 and 63%, respectively) on CsA administration (8 µM). In CsA-treated cells the K⁺ channel blockers barium (1 mM), TEA (10 mM) and quinine (1 mM) did not further inhibit the transport activities suggesting that CsA might also act via inhibition of K⁺ channels. FK506 at 8 µM had no effect on Na⁺/K⁺-ATPase transport activity but stimulated Na⁺/K⁺/2Cl^– cotransporter activity by 59%. The stimulatory effect was abolished by K⁺ channel blockers indicating that recycling of K⁺ might increase by FK506. The simultaneous presence of aldosterone (5 µM) protected the cells from the inhibitory effect of CsA on Na⁺/K⁺-ATPase and Na⁺/K⁺/2Cl^– cotransporter activity. The stimulatory effect of FK506 on the Na⁺/K⁺/2Cl^–cotransporter activity was completely abolished in the presence of aldosterone. Conclusions: Both CsA and FK506 showed acute toxicity in MDCK cells in vitro with the effects of FK506 being less pronounced. CsA and FK506 had different effects on the in vivo transport rates of the Na⁺/K⁺-ATPase and the Na⁺/K⁺/2Cl^– cotransporter; CsA ...

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Different Effects of Cyclosporine A and FK506 on Potassium Transport Systems in MDCK Cells

Aker

Heering

Kinne-Saffran

et al. 2001

Nephron Exp Nephrol

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“…Al igual gue en el caso del hígado, protege también frente a Ja isquemia-reperfusión renal (46). A altas concentraciones (0,1-10 mg/L) impide la proliferación de los cultivos ele células tubulares proximales de distintas especies, incluida la humana (47). A diferencia de la administración aguda, estudios toxicológicos en animales han demostrado que la administración subaguda de Tacrolimus produce lesiones en las arteriolas renales (44), necrosis focal de la media a1teriolar (43), vasculilis renal (48), inflamación intersticial y daño en el epitelio tubular p róxima!…”

Section: Efectos Tóxicos Renalesunclassified

Tacrolimus (FK 506): Alternativa inmunosupresora en el trasplante de órgano sólido (1ª Parte)

Díaz

Azanza

Sádaba

et al. 2017

revista-de-medicina

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IntroducciónLa eclosión de los trasplantes de órganos facilitada por los buenos resultados obtenidos ha sido posible por la disponibilidad de fármacos inmunosupresores.La Ciclosporina A fue con toda probabilidad el primero de los inmunos upresores que presentaba un perfil de eficacia y tolerancia aceptable, pero prácticamente el único disponible. Por ello resultaba necesario disponer de otras opciones que pudiesen utilizarse en las situaciones en las que este fá rmaco no podía ser utilizado o resultaba ineficaz. Fruto de este interés en desarrollar nuevos inmusosupresores se ha investigado el FK 506 o Tacrolimus, macrólido aislado del hongo Streptomyces tsukubaensis con un potente y selectivo efecto antilinfodto T, fármaco de gran interés y que será el protagonista de este a1tículo que pretende revisar s us aspectos más relevantes. Propiedades Farmacodinámicas Mecanismo de acciónAl igual que Cidosporina A, Tacrolimus tiene efectos inmunosupresores sobre la inmunidad humoral y celular, si bien su potencia de acción llega a ser entre 10 y 100 veces mayor. A través de Ja interacción con una inmunofilina citoplasmática, Tacrolimus inhibe las vías metabólicas de pendientes del calcio en las células T, impidiendo la transcripción de un grupo de genes codificadores de li nfoquinas. Se ha com probado que Tacrolimus se une a una inmu nofilina predominante 28

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“…As with the liver, tacrolimus pretreatment reduces TNF production and acute renal injury associated with renal ischaemia and reperfusion in the rat (Sakr et al 1992b;Van Thiel et al 1992). At supratherapeutic concentrations (0.1 to 10 mg/ L) tacrolimus exerts a direct cytotoxic effect on cultured porcine tubular epithelial LLC-PKI cells (Moutabarrik et al 1992) and inhibits porcine and human (Blaehr et al 1993) proximal tubular cell proliferation. Toxicological studies in the rodent, dog, and baboon have indicated that, on subacute administration, tacrolimus produces renal vascular changes, including arteriolar vascular lesions (Veda et al 1991;Yamada et al 1991), focal medial arteriolar necrosis (Kumano et al 1991;Ochiai et al 1989b;Todo et al 1988), renal vasculitis (Collier et al 1987, interstitial inflammation (Ohara et al 1990) and epithelial damage to the proximal tubule (Veda et al 1991;Yamada et al 1991).…”

Section: Renal Effects Of Tacrolimusmentioning

confidence: 99%

Tacrolimus

Peters¹,

Fitton²,

Plosker³

et al. 1993

Drugs

325

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Tacrolimus (FK 506) is a macrolide immunosuppressant which possesses similar but more potent immunosuppressant properties compared with cyclosporin, inhibiting cell-mediated and humoral immune responses. Like cyclosporin, tacrolimus demonstrates considerable interindividual variation in its pharmacokinetic profile. This has caused difficulty in defining the optimum dosage regimen and has highlighted the usefulness of therapeutic drug monitoring. Most clinical studies with tacrolimus have neither been published in their entirety nor subjected to extensive peer review; there is also a paucity of published randomised investigations of tacrolimus versus cyclosporin, particularly in renal transplantation. Despite these drawbacks, tacrolimus has shown notable efficacy as a rescue or primary immunosuppressant therapy when combined with corticosteroids in adult and paediatric recipients following liver or kidney transplantation. Indeed, graft salvage rates in patients experiencing rejection or drug-related toxicity were > or = 50%, although data in renal transplantation are limited. Compared with cyclosporin as a primary immunosuppressant, tacrolimus showed comparable or greater patient/graft survival rates in liver allograft recipients (where cost savings associated with reduced hospitalisation costs were evident in one study), and comparable patient/graft survival in patients following kidney transplantation. Worthy of note was the efficacy of tacrolimus as a primary immunosuppressant in patients who received en bloc kidney allografts. The incidence of rejection was largely reduced following rescue therapy with tacrolimus and was generally lower (notably for refractory rejection) than that observed for cyclosporin, at least in liver allograft recipients. This was reflected in less need for adjunct immunotherapy including antilymphocyte preparations for the treatment of rejection episodes. The potential for reduction or withdrawal of corticosteroid therapy with tacrolimus appears to be a distinct advantage compared with cyclosporin, and this may be enhanced by the reduced incidence of infectious complications and of hypertension and hypercholesterolaemia reported by some investigators. In other respects, however, the tolerability profile of tacrolimus appears to be broadly similar to that of cyclosporin. Against this background, preliminary data indicate that tacrolimus provides a valuable therapeutic alternative to retransplantation in patients experiencing liver or kidney graft rejection or drug-related toxicity. Pending confirmation of initial randomised studies and preliminary results from large randomised investigations, tacrolimus may well be considered as an alternative primary immunosuppressant to cyclosporin in hepatic (particularly) and renal transplantation. Furthermore, the steroid-sparing effects of tacrolimus, although of benefit to all patient groups, may prove to be of particular worth in children and in en bloc kidney recipients. In these patients tacrolimus may well emerge as the drug of choice.(ABSTRA...

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Acute effects of FK506 and cyclosporine A on cultured human proximal tubular cells

Cited by 7 publications

References 14 publications

Different Effects of Cyclosporine A and FK506 on Potassium Transport Systems in MDCK Cells

Different Effects of Cyclosporine A and FK506 on Potassium Transport Systems in MDCK Cells

Tacrolimus (FK 506): Alternativa inmunosupresora en el trasplante de órgano sólido (1ª Parte)

Tacrolimus

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