Fk506 Binding Protein 12 Deficiency in Endothelial and Hematopoietic Cells Decreases Regulatory T Cells and Causes Hypertension

Abstract

Patients treated with the immunosuppressive drug tacrolimus (FK506), which binds FK506 Binding Protein 12 (FKBP12) then inhibits the calcium-dependent phosphatase calcineurin, exhibit decreased regulatory T cells, endothelial dysfunction, and hypertension; however the mechanisms and whether altered T cell polarization play a role are unknown. Tacrolimus treatment of mice for 1 week dose-dependently decreased CD4+/FoxP3+ (regulatory T cells) and increased CD4+/IL-17+ (T helper 17) cells in the spleen, and caused endothelial dysfunction and hypertension. To determine the mechanisms, we crossed floxed FKBP12 mice with Tie2-Cre mice to generate offspring lacking FKBP12 in endothelial and hematopoietic cells only (FKBP12EC KO). Given FKBP12’s role in inhibiting TGF-β receptor activation, Tie2-Cre-mediated deletion of FKBP12 increased TGF-β receptor activation and SMAD2/3 signaling. FKBP12EC KO mice exhibited increased vascular expression of genes and proteins related to endothelial cell activation and inflammation. Serum levels of the pro-inflammatory cytokines IL-2, IL-6, IFNγ, IL-17a, IL-21, and IL-23 were increased significantly suggesting a Th17 cell-mediated inflammatory state. Flow cytometry studies confirmed this as splenocyte levels of CD4+/IL-17+ cells were increased significantly while CD4+/FoxP3+ cells were decreased in FKBP12EC KO mice. Furthermore, spleens from FKBP12EC KO mice showed increased STAT3 activation, involved in Th17 cell induction, and decreased STAT5 activation, involved in regulatory T cell induction. FKBP12EC KO mice also exhibited endothelial dysfunction and hypertension. These data suggest that tacrolimus, through its activation of TGF-β receptors in endothelial and hematopoietic cells, may cause endothelial dysfunction and hypertension by activating endothelial cells, reducing Tregs, and increasing Th17 cell polarization and inflammation.

Renal Deletion of 12 kDa FK506-Binding Protein Attenuates Tacrolimus-Induced Hypertension

“…Further, Chiasson et al showed that deleting FKBP12 in endothelial and hematopoietic cells leads to hypertension in vivo. 7 We found that FKBP12 is expressed along the nephron, but its role there is unknown. However, our results show that FKBP12 disruption along the nephron does not increase pNCC or cause hypertension; this provides strong evidence that FKBP12 disruption along the nephron is not involved in the hypertensive response.…”

“…5 Systemic deletion of FKBP12 in mice is embryonic-lethal, 6 and disruption of FKBP12 in the vasculature and hematopoietic cells causes hypertension. 7 Thus, tacrolimus may disrupt FKBP12 functions that are independent of calcineurin. Here, we tested the hypothesis that tacrolimus activates NCC and causes systemic hypertension by inhibiting calcineurin in the DCT.…”

Murine coagulation factor VIII is synthesized in endothelial cells

“…39,40 The absence of F8 mRNA enrichment in peripheral blood of wild-type C57BL/6J mice excludes trapped peripheral blood cells as the source for the FVIII endothelial cell signal, as does the absence of F8 mRNA enrichment in the brain or heart (Figure 4). The lack of F8 mRNA in the blood is consistent with a recent clinical report of allogeneic bone marrow transplantation in a child with severe aplastic anemia and hemophilia A.…”

Hypertension in cardiac transplant recipients

“…В экспериментальных моделях было показано, что такролимус способен вызывать изменения в неко-торых популяциях Т-лимфоцитов, следствием чего является развитие дисфункции эндотелия и АГ [22].…”