Role of p-glycoprotein in chronic cyclosporine nephrotoxicity and its relationship to intrarenal angiotensin ii deposits

Moral, R.G. Del; Olmo, Alberto; Osuna, Antonio; Aguilar, M; Carvia, Rafael E.; Becerra, Pablo; Arrebola, Francisco; Guillén, Marta; Reguero, Maria Eugenia; Asensio, C; O’Valle, Francisco

doi:10.1016/s0041-1345(98)00515-6

Cited by 32 publications

(32 citation statements)

References 15 publications

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“…21,41,46,47,[49][50][51][52] Chronic cyclosporine nephrotoxicity is inversely related to P-gp expression in the renal tubule. 53,54 Conversely, P-gp up-regulation appears to protect proximal renal tubular cells from cadmium-induced apoptosis. 55 Although mTOR inhibitors are well known to act simultaneously like CNIs as substrates, and as inhibitors for P-gp, 46,52,56,57 similar associations between P-gp expression and everolimus nephrotoxicity have not been reported so far.…”

Section: Case Discussion and Review Of The Literaturementioning

confidence: 99%

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2015

Exp Clin Transplant

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Mammalian target of rapamycin inhibitors, such as rapamycin and more recently everolimus, have substituted calcineurin inhibitors in many minimization strategies. Despite their acclaimed renal safety profile, several lines of evidence are emerging on their potential nephrotoxic effect. Predisposing conditions for nephrotoxicity involve a complex interplay between several environmental and genetic factors in the donor-recipient pair. Renal injury may be enhanced by pharmacodynamic interactions when combined with other drugs such as calcineurin inhibitors or nutrients that are predominantly related to an increase in local tissue exposure. These toxic interactions may occur within adequate doses and therapeutic blood levels. This explains the occurrence of nephrotoxicity in some but not all cases. Here, we postulated that activity of a low permeability glycoprotein efflux pump related to low protein expression and/or inhibition enhanced immunosuppressive drug entry in different cells. A rise in intracellular drug concentration increases bioactivity, leading to greater immunosuppression and more immune-related, nonrenal adverse events in the recipient and increased nephrotoxicity in the kidney graft. Under specific isolated or combined environmental and/or genetic conditions in both the recipient and donor affecting the glycoprotein efflux pump and/or the mammalian target of rapamycin pathway, these renal injuries may be aggravated by heightened drug tissue concentrations despite adherence to therapeutic drug and blood levels. Mammalian target of rapamycin inhibitors may induce predominantly a dose-dependent renal epithelial cell injury affecting either the glomerular or the renal tubular epithelial cells, leading to cell death and apoptosis. Epithelial mesenchymal transitionmediated interstitial fibrosis and tubular atrophy observed with these drugs may be the result of a cumulative toxic renal tubular injury induced by the direct insult of the drug itself and/or podocytopathy-associated proteinuria. The resulting glomerular tubular damage will ultimately lead to graft failure and loss, if exposure persists.

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Section: Case Discussion and Review Of The Literaturementioning

confidence: 99%

Untitled

2015

Exp Clin Transplant

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“…P-glycoprotein is expressed at the apical side of tubular epithelial cells and is the main protein responsible for the excretion of the CNIs tacrolimus and cyclosporine (284,285), although the renal excretion of these CNIs is only limited (see above). In 1997, del Moral et al suggested that variability in local P-glycoprotein expression is important for chronic CNI nephrotoxicity by using immunohistochemistry and Western blotting in a rat model of chronic CNI nephrotoxicity (286). Another study in rats showed that exposure of cultured renal tubular cells to cyclosporine induces P-glycoprotein overexpression (287).…”

Section: Local Renal Exposure To Cyclosporine and Tacrolimusmentioning

confidence: 99%

“…Another study in rats showed that exposure of cultured renal tubular cells to cyclosporine induces P-glycoprotein overexpression (287). In addition, del Moral et al demonstrated that the up-regulation of P-glycoprotein was inversely related to the incidence of arteriolar hyalinosis, interstitial fibrosis, and periglomerular fibrosis (286). Human studies confirmed this upregulation of tubular epithelial P-glycoprotein expression with cyclosporine treatment, as well as lower expression of P-glycoprotein in renal allograft biopsies with CNI nephrotoxicity (288,289).…”

Section: Local Renal Exposure To Cyclosporine and Tacrolimusmentioning

confidence: 99%

Calcineurin Inhibitor Nephrotoxicity

Naesens

Kuypers²,

Sarwal³

2009

Clinical Journal of the American Society of Nephrology

1,207

965

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The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question-whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway-remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-␤ and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.Clin J Am Soc Nephrol 4: 481-508, 2009. doi: 10.2215/CJN.04800908 T he introduction of the calcineurin inhibitor (CNI) cyclosporine in human kidney transplantation in the late 1970s revolutionized transplantation medicine, and made transplantation a preferable therapeutic intervention for end-stage renal diseases (1,2). In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered, and tacrolimus was used successfully in human liver, kidney, and heart allograft recipients (3,4). Currently, 94% of kidney transplant recipients are discharged after transplantation with a CNI-based immunosuppressive regimen (5).The immunosuppressive properties of cyclosporine and tacrolimus result from inhibition of calcineurin, a calcium-and calmodulin-dependent phosphatase (protein phosphatase 3 [PPP3C], formerly PP2B). Intracellularly, these completely different molecules bind to cyclophylin and FKBP12 for cyclosporine and tacrolimus, respectively (6 -9). The competitive binding of cyclosporine-cyclophylin and tacrolimus-FKBP12 complexes to calcineurin inhibits phosphatase activity of calcineurin. This inhibition then suppresses the transcription of IL-2 via inhibition of the dephosphorylation and impaired translocation of the nucl...

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“…Group 1 received normal saline s.c daily, group 2 received Cremophor EL and ethanol (CsA vehicle) s.c daily, group 3 received CsA 25 mg/kg/day s.c once daily (Lee et al, 1999;del Moral et al, 1997) and group 4 received telmisartan 3 mg/kg/day orally in addition to CsA (Takahashi et al, 2007).…”

Section: Experimental Groupsmentioning

confidence: 99%

Amelioration of chronic cyclosporine A-induced nephrotoxicity by telmisartan in rats

Al-Amran

Hadi²,

Kamoona³

et al. 2011

Afr. J. Pharm. Pharmacol.

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Nephrotoxicity is a major problem of Cyclosporine A (CsA) treatment, despite its beneficial role in organ transplantation and in a variety of immunologic disorders. This study was undertaken to investigate the potential renoprotective role of telmisartan in amelioration of chronic CsA induced nephrotoxicity. The rats were randomized into 4 equal groups. Group 1 received normal saline (control), group 2 received Cremophor EL and ethanol (CsA vehicle), group 3 received CsA 25 mg/kg/day s.c and group 4 received telmisartan 3 mg/kg/day orally in addition to CsA. The rats were pair fed with a standard chow diet throughout the experiment period (8 weeks). CsA nephrotoxicity was assessed in terms of increased S.Cr (from 0.52± 0.16 to 1.29 ± 0.20 mg/ml), blood urea (from 24.69 ± 1.89 to 75.88± 2.33 mg/ml) and serum K (from 3.43 ± 0.18 to 5.23 ± 0.43 meq/l). CsA also caused significant increase (p<0.01) in MDA (from 0.74 ± 0.13 to 2.96 ± 0.43 nmol/mg protein) and significant decrease (p<0.01) in GSH and catalase in renal tissue. Telmisartan failed to restore the altered renal functions. On the other hand, it causes a significant improvement in the histological changes including the tubulointerstitial fibrosis and arteriolopathy (p<0.01). It also caused significant reduction (p<0.01) in CsA-induced oxidative stress. These findings suggested that telmisartan has a promising renoprotective effect against chronic CsA induced nephrotoxicity.

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Role of p-glycoprotein in chronic cyclosporine nephrotoxicity and its relationship to intrarenal angiotensin ii deposits

Cited by 32 publications

References 15 publications

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Calcineurin Inhibitor Nephrotoxicity

Amelioration of chronic cyclosporine A-induced nephrotoxicity by telmisartan in rats

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