Date: Monday, June 3, 2019
Session Name: Poster Session C: Kidney: Cardiovascular and Metabolic
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall C & D
- Tacrolimus (Tac), Rather Than Cyclosporine (CsA), Interacts with Insulin Resistance (IR) to Alter Key Transcription Factors for β-Cell Identity & Function without Altering NFAT Localization.
- Rapamycin-Resistant mTORC1 Regulates Dendritic Cell B7-H1 Expression That Acts in Synergy with IL-1β To Promote Regulatory T Cell Induction
*Purpose: Tacrolimus, the most widely used immunosuppressive drug, is known to be highly diabetogenic. It is thought to trigger β-cell death through inhibition of the calcineurin/NFAT pathway. This paradigm however is challenged by recent clinical1 and pre-clinical2,3 data. FKBP12, tacrolimus’ immunophilin, inhibits BMP-receptors, whose modulation has been associated with β-cell failure. Here, we hypothesised that tacrolimus activates the BMP/SMAD signaling pathway, which then acts in synergy with a metabolic stress-activated pathway, thereby inducing loss of β-cell function and identity.
*Methods: Primary human islets were treated for 72h with 2ng/mL tacrolimus together with 200µM palmitate and 11mM glucose to induce a mild metabolic stress. We evaluated nuclear localization of pSMAD1/5/9, FOXO1, NKX6.1, PDX1, MAFA by immunostaining (n=7 donors). We measured gene expression of canonical BMP targets (n=4). β-cell function was assessed by glucose stimulated insulin secretion test. Intervention experiments were performed using a BMP inhibitor (120nM LDN1931893). Protocol pancreas allograft biopsies were used to validate findings in vivo.
*Results: An increased frequency of nuclear pSMAD1/5/9 was found in β-cells upon tacrolimus treatment (74.0%±13.1 vs. 16.5%±8.5). Gene expression of canonical BMP targets, ID1 and ID3, was increased by 2.4±0.3 and 1.6±0.5 times, respectively. Metabolic stress induced an increased expression of nuclear FOXO1 in β-cells (75.9%±4.8 vs. 13.3%±4.6), and only under these circumstances did tacrolimus induce a 52% loss of nuclear MAFA and complete abolition of the insulin secretory response. Importantly, all effects were prevented upon BMP inhibition: levels of pSMAD1/5/9, ID1, ID3, MAFA and insulin secretion were similar to controls, but not affecting FOXO1. Protocol pancreas biopsies confirmed nuclear localisation of pSMAD1/5/9 compared to cyclosporin, but normal localisation of FOXO1 and MAFA in absence of obesity.
*Conclusions: We identified, in primary human islets, a novel mechanism of action of tacrolimus through activation of the BMP pathway and synergistic interaction with the FOXO1-stress response, causing loss of β-cell function and identity. This insight may lead to the development of novel strategies for protection of β-cell identity and function after transplantation.1Porrini E et al. NDT 2008
2Rodriguez AE et al. AJT 2013
3Triñanes J et al. AJT 2017
To cite this abstract in AMA style:Trinañes J, Dijke Pten, Rabelink TJ, Koning EJde, Carlotti F, Vries APde. Tacrolimus Activated BMP Signaling Acts in Synergy with Stress-Activated FOXO1 to Induce Loss of Beta-Cell Function and Identity [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/tacrolimus-activated-bmp-signaling-acts-in-synergy-with-stress-activated-foxo1-to-induce-loss-of-beta-cell-function-and-identity/. Accessed September 25, 2020.
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