Cellular Effects of Everolimus and Sirolimus on Podocytes

Müller-Krebs, Sandra; Weber, Lena; Tsobaneli, Julia; Kihm, Lars; Reiser, Jochen; Zeier, Martin; Schwenger, Vedat

doi:10.1371/journal.pone.0080340

Cited by 24 publications

(15 citation statements)

References 41 publications

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“…The effects of everolimus and sirolimus on human podocyte cultures were compared [57]. While there was some overlap, there were also differences such as a greater reduction in synaptopodin, podocin and nephrin expression, less NFκB activation, and more apoptosis when podocyte cultures were exposed to sirolimus than when exposed to everolimus.…”

Section: Toxicodynamic Effects On Renal Metabolism and Functionmentioning

confidence: 99%

Everolimus and sirolimus in transplantation-related but different

Klawitter

Nashan

Christians

2015

Expert Opinion on Drug Safety

150

109

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Introduction The inhibitors of the mammalian target of rapamycin (mTOR) sirolimus and everolimus are used as immunosuppressants after organ transplantation in combination with calcineurin inhibitors, but also as proliferation signal inhibitors coated on drug eluting stents and in cancer therapy. Notwithstanding their related chemical structures both have distinct pharmacokinetic, pharmacodynamic and toxicodynamic properties. Areas covered The additional hydroxyethyl group at the C(40) of the everolimus molecule results in different tissue and subcellular distribution, different affinities to active drug transporters and drug metabolizing enzymes as well as differences in drug-target protein interactions including a much higher potency in terms of interacting with the mTOR complex 2 (mTORC2) than sirolimus. Said mechanistic differences as well as differences found in clinical trials in transplant patients are reviewed. Expert opinion In comparison to sirolimus, everolimus has higher bioavailability, a shorter terminal half-life, different blood metabolite patterns, the potential to antagonize the negative effects of calcineurin inhibitors on neuronal and kidney cell metabolism (which sirolimus enhances), the ability to stimulate mitochondrial oxidation (which sirolimus inhibits), and to reduce vascular inflammation to a greater extent. A head-to-head, randomized trial comparing the safety and tolerability of these two mTOR inhibitors in solid organ transplant recipients is merited.

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Section: Toxicodynamic Effects On Renal Metabolism and Functionmentioning

confidence: 99%

Everolimus and sirolimus in transplantation-related but different

Klawitter

Nashan

Christians

2015

Expert Opinion on Drug Safety

150

109

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“…Positive (diabetes) [55]/ negative (other glomerular disease) [56,57] Actin cytoskeleton, VEGF [53,61], synaptopodin, podocin, nephrin, apoptosis [60] Glitazones (PPARγ agonists) Positive SUMOs [75], mitochondrial function [73] Glucocorticoids Positive Glucocorticoid receptor, gene expression, actin rearrangement [34][35][36] RAAS blockade (ACE inhibitor, AT1-R blocker) Positive AT1-R, actin cytoskeleton [23,24], ZO-1 [28] Rituximab (CD20 antibody)…”

Section: Calcineurin Inhibitorsmentioning

confidence: 99%

“…In a knock-out model Raptor deletion induced proteinuria and glomerular lesions in mice, and concomitant Rictor deletion exacerbated this phenotype [52,58,59]. Sirolimus has also been shown to reduce the expression of synaptopodin, podocin and nephrin and in addition to increase podocyte apoptosis [60]. VEGF expression was reduced in the glomeruli of patients with sirolimus-induced thrombotic microangiopathy [61].…”

Section: Mammalian Target Of Rapamycin Inhibitorsmentioning

confidence: 99%

Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

Müller-Deile

Schiffer

2015

Pediatr Nephrol

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Several of the drugs currently used for the treatment of glomerular diseases are prescribed for their immunotherapeutic or anti-inflammatory properties, based on the current understanding that glomerular diseases are mediated by immune responses. In recent years our understanding of podocytic signalling pathways and the crucial role of genetic predispositions in the pathology of glomerular diseases has broadened. Delineation of those signalling pathways supports the hypothesis that several of the medications and immunosuppressive agents used to treat glomerular diseases directly target glomerular podocytes. Several central downstream signalling pathways merge into regulatory pathways of the podocytic actin cytoskeleton and its connection to the slit diaphragm. The slit diaphragm and the cytoskeleton of the foot process represent a functional unit. A breakdown of the cytoskeletal backbone of the foot processes leads to internalization of slit diaphragm molecules, and internalization of slit diaphragm components in turn negatively affects cytoskeletal signalling pathways. Podocytes display a remarkable ability to recover from complete effacement and to re-form interdigitating foot processes and intact slit diaphragms after pharmacological intervention. This ability indicates an active insideout signalling machinery which stabilizes integrin complex formations and triggers the recycling of slit diaphragm molecules from intracellular compartments to the cell surface. In this review we summarize current evidence from patient studies and model organisms on the direct impact of immunosuppressive and supportive drugs on podocyte signalling pathways. We highlight new therapeutic targets that may open novel opportunities to enhance and stabilize inside-out pathways in podocytes.

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“…Pathologic evaluation revealed FSGS-NOS with immunohistochemical evidence of podocyte dysregulation. In cell culture, podocytes exposed to sirolimus exhibit reduced synaptopodin, nephrin, and podocin expression, increased apoptosis, and actin cytoskeletal reorganization, forming a potential basis for this toxicity (28). Ironically, sirolimus has been used with limited success as a treatment for FSGS in the native kidney (29).…”

Section: Additional Therapeutics Agents Associated With Fsgsmentioning

confidence: 99%

Drug-Induced Glomerular Disease

Markowitz¹,

Bomback

Perazella

2015

Clinical Journal of the American Society of Nephrology

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The potential of medications to cause kidney injury is well known. Although nephrotoxicity is most commonly associated with injury in the tubulointerstitial compartment as either acute tubular necrosis or acute interstitial nephritis, a growing body of literature has also highlighted the potential for drug-induced glomerular lesions. This review surveys the three primary patterns of drug-induced glomerular diseases stratified by the cell type at which the glomerular lesion is focused: visceral epithelial cell (or podoctye) injury, endothelial cell injury, and mesangial cell injury. A number of commonly prescribed medications, including IFNs, bisphosphonates, nonsteroidal antiinflammatory drugs, antiplatelet agents, and antiangiogenesis drugs, that are both prescribed and available over the counter, have been implicated in these iatrogenic forms of glomerular disease. Recognition of these druginduced etiologies of glomerular disease and rapid discontinuation of the offending agent are critical to maximizing the likelihood of renal function recovery.

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Cellular Effects of Everolimus and Sirolimus on Podocytes

Cited by 24 publications

References 41 publications

Everolimus and sirolimus in transplantation-related but different

Everolimus and sirolimus in transplantation-related but different

Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

Drug-Induced Glomerular Disease

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