Sirolimus Toxicity and Vascular Endothelial Growth Factor Release From Islet and Renal Cell Lines

Laugharne, Matthew; Cross, Sarah E.; Richards, Sarah; Dawson, Charlotte; Ilchyshyn, Laura; Saleem, Moin A.; Mathieson, Peter W.; Smith, Richard

doi:10.1097/01.tp.0000266555.06635.bf

Cited by 34 publications

(30 citation statements)

References 33 publications

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“…This finding was confirmed by electron microscopy. These data are in line with in vitro data of Laugharne et al, 25 who found podocyte culture cells not to be influenced by rapamycin treatment. In addition, we evaluated the expression of the endothelial cell marker PECAM-1 in kidneys of rapamycin-and vehicle-treated mice and found PECAM-1 to be significantly decreased.…”

Section: Discussionsupporting

confidence: 82%

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Differential Effects of Rapamycin in Anti-GBM Glomerulonephritis

Hochegger

Jansky²,

Soleiman³

et al. 2008

Journal of the American Society of Nephrology

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The immunosuppressive mammalian target of rapamycin inhibitor rapamycin is widely used in solidorgan transplantation, but the effect of rapamycin on kidney disease is controversial. This study evaluated the effect of rapamycin in the autologous phase of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. Disease was induced by preimmunizing the animals with rabbit IgG 5 d before administration of rabbit anti-mouse GBM antiserum. When rapamycin was started on the day of immunization (group 1), mice were protected from glomerulonephritis, suggested by a dramatic decrease in albuminuria, influx of inflammatory cells, and Th1-cytokine expression in the kidneys. Activation of T cells and production of autologous mouse anti-rabbit IgG were also significantly reduced in rapamycin-treated animals. In contrast, when rapamycin was started 14 d after immunization (group 2), mice had a significant increase in albuminuria and renal infiltration of inflammatory cells compared with vehicle-treated animals, and there were no differences in T and B cell responses. A significant decrease in vascular endothelial growth factor-A and an increase in IL-6 were detected in kidneys of these rapamycin-treated mice. In conclusion, rapamycin has the potential to significantly reduce the B and T cell responses and thereby protect from glomerulonephritis when administered early in disease. Once disease is established, however, rapamycin seems to worsen glomerulonephritis by disturbing the endothelial cell/vascular endothelial growth factor system in the kidney.

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Section: Discussionsupporting

confidence: 82%

“…To evaluate whether podocytes or endothelial cells, both potent producers of VEGF, 16,25 are harmed by rapamycin treatment, we performed real-time PCR for the detection of the podocyte marker nephrin and the endothelial cell marker …”

Section: Vegf-a Expression In the Kidney Was Significantly Decreased mentioning

confidence: 99%

Differential Effects of Rapamycin in Anti-GBM Glomerulonephritis

Hochegger

Jansky²,

Soleiman³

et al. 2008

Journal of the American Society of Nephrology

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“…A sirolimus treatment group was chosen as a positive control of drug induced toxicity on β-cell engraftment based on previous reports of this phenomenon. 20,21 The first day following transplant on which recipeints began to maintain non-fasting blood glucose less than 12.0 mM, defined as normoglycemia, was no different between AEB and vehicle treated controls ( Fig. 2A and p = 0.40).…”

Section: Aeb071 (Sotrastaurin) Does Not Exhibit Toxic Effects On Humamentioning

confidence: 99%

“…6,7,[9][10][11]13 Here, we show that it also does not have toxic effects on glucose homeostasis. In clinical pancreatic islet transplant, sirolimus is a commonly used immunosuppressive agent and has been shown to have negative effects on β-cell function and be diabetogenic in some, 4,5,20 but not all, animal models of β-cell function. 27,28 Our findings support continued investigation into AEB as an alternate immunosuppressive agent since it provides clear benefit over current immunosuppressive agents insofar as it has no detectable toxicity on β-cells nor glucose homeostasis.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

AEB071 (sotrastaurin) does not exhibit toxic effects on human islets in vitro nor after transplantation into immunodeficient mice

Merani

McCall

Pawlick

et al. 2011

Islets

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“…The improvement of the immunosuppression protocol accounts for the present success of islet transplantation [57] . Encapsulation can protect allogeneic islets from immunity without using immunosuppressants.…”

Section: Cell Sourcesmentioning

confidence: 99%

Encapsulated islets transplantation: Past, present and future

Sakata

Sumi²,

Yoshimatsu³

et al. 2012

WJGP

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Islet transplantation could become an ideal treatment for severe diabetes to prevent hypoglycemia shock and irreversible diabetic complications, once some of the major and unresolved obstacles are overcome, including limited donor supplies and side effects caused by permanent immunosuppressant use. Approximately 30 years ago, some groups succeeded in improving the blood glucose of diabetic animals by transplanting encapsulated islets with semi-permeable membranes consisting of polymer. A semi-permeable membrane protects both the inner islets from mechanical stress and the recipient's immune system (both cellular and humoral immunities), while allowing bidirectional diffusion of nutrients, oxygen, glucose, hormones and wastes, i.e., immune-isolation. This device, which enables immune-isolation, is called encapsulated islets or bio-artificial pancreas. Encapsulation with a semipermeable membrane can provide some advantages: (1) this device protects transplanted cells from the recipient's immunity even if the xenogeneic islets (from large animals such as pig) or insulin-producing cells are derived from cells that have the potential for differentiation (some kinds of stem cells). In other words, the encapsulation technique can resolve the problem of limited donor supplies; and (2) encapsulation can reduce or prevent chronic administration of immunosuppressants and, therefore, important side effects otherwise induced by immunosuppressants. And now, many novel encapsulated islet systems have been developed and are being prepared for testing in a clinical setting.

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Sirolimus Toxicity and Vascular Endothelial Growth Factor Release From Islet and Renal Cell Lines

Cited by 34 publications

References 33 publications

Differential Effects of Rapamycin in Anti-GBM Glomerulonephritis

Differential Effects of Rapamycin in Anti-GBM Glomerulonephritis

AEB071 (sotrastaurin) does not exhibit toxic effects on human islets in vitro nor after transplantation into immunodeficient mice

Encapsulated islets transplantation: Past, present and future

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