Background: Fibroblast growth factor 23 (FGF-23), which binds to FGF receptor, has been associated with allograft rejection, CKD progression, and poor graft survival in pediatric and adult renal transplant recipients. Ligation of HLA class I antibodies to the endothelium up-regulates the expression of FGF receptors on the endothelial cell (EC) surface. Therefore, we aimed to determine whether HLA Class I antibody could augment FGF-23 induced endothelial cell (EC) signal transduction and proliferation, contributing to transplant vasculopathy.
Methods: Primary human aortic EC, passages 2-8, were treated with varying concentrations of FGF-23 (1-100 ng/ml) and basic fibroblast growth factor (bFGF, 1-100 ng/ml). Phosphorylation of S6 Ribosomal Protein (S6RP) Ser235/236, Akt Ser473, and ERK Thr202/Tyr204 was measured by Western blot. EC were stimulated with either FGF-23 or bFGF alone or in combination with the murine anti-Class I HLA mAb W6/32 (1ug/ml) directed against a monomorphic epitope on all HLA class I molecules. EC proliferation was assessed by flow cytometry using CSFE labeling.
Results: FGF-23, similar to bFGF, stimulated a 60% increase in Akt Ser473 phosphorylation, an essential regulator of survival proteins Bcl-2 and Bcl-xL (p<0.05),a 35% increase in ERK phosphorylation, a known mediator of cell proliferation (p<0.05), and 20% increase in S6RP phosphorylation, which are downstream targets of mTOR responsible for EC proliferation (p<0.05), which was significantly augmented by the addition of HLA class I Ab (p<0.05). Additionally FGF-23 induced a 30% increase in EC proliferation compared to untreated EC (p<0.05) which was significantly augmented to 80% by the addition of HLA class I Ab (p<0.05).
Conclusions: Anti-Class I antibody augmentation of FGF-23 induction of PI3K/Akt, mTOR and MAPK/ERK pathways may play an important and novel role in EC proliferation.Thus, together they can be synergistic in promoting antibody-mediated rejection and development of transplant vasculopathy, leading to poor transplant outcomes.
To cite this abstract in AMA style:Tsai E, Jin Y, Wesseling-Perry K, Salusky I, Ettenger R, Reed E. HLA Class I Antibody Augments FGF-23 Induced Transplant Vasculopathy and Chronic Antibody Mediated Rejection [abstract]. Am J Transplant. 2013; 13 (suppl 5). http://atcmeetingabstracts.com/abstract/hla-class-i-antibody-augments-fgf-23-induced-transplant-vasculopathy-and-chronic-antibody-mediated-rejection/. Accessed September 24, 2017.
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