Related Experiment Video
Updated: Jul 14, 2026
Sustained Administration of β-cell Mitogens to Intact Mouse Islets Ex Vivo Using Biodegradable Poly(lactic-co-glycolic acid) Microspheres
Published on: November 5, 2016
Sirolimus toxicity and vascular endothelial growth factor release from islet and renal cell lines
Matthew Laugharne1, Sarah Cross, Sarah Richards
1Academic Renal Unit, Paul O'Gorman Lifeline Centre, Clinical Science at North Bristol, Southmead Hospital, Westbury-on-Trym, Bristol, UK.
Abstract:
Presently, sirolimus (rapamycin) is used as both induction and maintenance immunosuppression in solid organ transplants, including whole pancreas and kidney, and islet transplantation. Sirolimus has been suggested to have deleterious effects on islet beta-cell and renal function. We investigated the effect of sirolimus on the viability of islets, podocytes, and renal tubular cells. Sirolimus reduced the viability of islets and HK-2 human proximal renal tubular cells in vitro. This toxic effect was associated with a reduction of vascular endothelial growth factor (VEGF) release by islets but not the proximal tubular cells. Sirolimus reduced both viability and VEGF production by murine beta-cells, and blockade of VEGF-164 was associated with a reduction in viability. Transfection of murine islets with adenoviral VEGF-165 improved islet viability. These data are consistent with the hypothesis that sirolimus is toxic to islets and beta-cells by blockade of VEGF-mediated survival pathways.
Insights
Sirolimus (rapamycin) may harm islet and beta-cell function in transplants. This immunosuppressant reduces cell viability by blocking vascular endothelial growth factor (VEGF) survival pathways.
Area of Science:
- Immunology
- Cell Biology
- Transplantation Medicine
Background:
- Sirolimus (rapamycin) is a key immunosuppressant in organ and islet transplantation.
- Concerns exist regarding sirolimus's potential negative impact on islet beta-cell and renal function.
Purpose of the Study:
- To investigate the effects of sirolimus on the viability of islets, podocytes, and renal tubular cells.
- To elucidate the role of vascular endothelial growth factor (VEGF) in sirolimus-induced toxicity.
Main Methods:
- In vitro assessment of sirolimus's impact on islet, podocyte, and renal tubular cell viability.
- Measurement of VEGF release from treated cells.
- Experimental manipulation of VEGF levels in murine islets.
Main Results:
- Sirolimus reduced the viability of islets and human proximal renal tubular cells (HK-2).
- Sirolimus decreased VEGF release from islets and murine beta-cells.
- VEGF blockade correlated with reduced cell viability, while VEGF-165 augmentation improved islet viability.
Conclusions:
- Sirolimus exhibits toxicity towards islets and beta-cells.
- This toxicity is mediated through the blockade of VEGF-dependent survival pathways.
- Findings suggest a mechanism for sirolimus-induced beta-cell dysfunction in transplantation settings.
