Tacrolimus Activated BMP Signaling Acts in Synergy with Stress-Activated FOXO1 to Induce Loss of Beta-Cell Function and Identity
1Transplant Center, Leiden University Medical Center, Leiden, Netherlands, 2Molecular Cell Biology, Leiden University Medical Center, Leiden, Netherlands, 3of Nephrology, Leiden University Medical Center, Leiden, Netherlands, 4Nephrology, Leiden University Medical Center, Leiden, Netherlands
Meeting: 2019 American Transplant Congress
Abstract number: C193
Keywords: Indirect pathway, Islets, Pancreas, Post-transplant diabetes
Session Information
Session Name: Poster Session C: Kidney: Cardiovascular and Metabolic
Session Type: Poster Session
Date: Monday, June 3, 2019
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall C & D
*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 November 21, 2024.« Back to 2019 American Transplant Congress