Dataset Information

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

ABSTRACT: Tacrolimus is a widely used immunosuppressive drug that inhibits the phosphatase calcineurin when bound to the 12 kDa FK506-binding protein (FKBP12). When this binding occurs in T cells, it leads to immunosuppression. Tacrolimus also causes side effects, however, such as hypertension and hyperkalemia. Previously, we reported that tacrolimus stimulates the renal thiazide-sensitive sodium chloride cotransporter (NCC), which is necessary for the development of hypertension. However, it was unclear if tacrolimus-induced hypertension resulted from tacrolimus effects in renal epithelial cells directly or in extrarenal tissues, and whether inhibition of calcineurin was required. To address these questions, we developed a mouse model in which FKBP12 could be deleted along the nephron. FKBP12 disruption alone did not cause phenotypic effects. When treated with tacrolimus, however, BP and the renal abundance of phosphorylated NCC were lower in mice lacking FKBP12 along the nephron than in control mice. Mice lacking FKBP12 along the nephron also maintained a normal relationship between plasma potassium levels and the abundance of phosphorylated NCC with tacrolimus treatment. In cultured cells, tacrolimus inhibited dephosphorylation of NCC. Together, these results suggest that tacrolimus causes hypertension predominantly by inhibiting calcineurin directly in cells expressing NCC, indicating thiazide diuretics may be particularly effective for lowering BP in tacrolimus-treated patients with hypertension.

SUBMITTER: Lazelle RA

PROVIDER: S-EPMC4849833 | biostudies-other | 2016 May

REPOSITORIES: biostudies-other

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

Lazelle Rebecca A RA McCully Belinda H BH Terker Andrew S AS Himmerkus Nina N Blankenstein Katharina I KI Mutig Kerim K Bleich Markus M Bachmann Sebastian S Yang Chao-Ling CL Ellison David H DH

Journal of the American Society of Nephrology : JASN 20151002 5

Tacrolimus is a widely used immunosuppressive drug that inhibits the phosphatase calcineurin when bound to the 12 kDa FK506-binding protein (FKBP12). When this binding occurs in T cells, it leads to immunosuppression. Tacrolimus also causes side effects, however, such as hypertension and hyperkalemia. Previously, we reported that tacrolimus stimulates the renal thiazide-sensitive sodium chloride cotransporter (NCC), which is necessary for the development of hypertension. However, it was unclear ...[more]

PMID: 26432904

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Project description:Patients treated with the immunosuppressive drug tacrolimus (FK506), which binds FK506 binding protein 12 (FKBP12) and 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 splenic CD4(+)/FoxP3(+) (regulatory T cells), increased splenic CD4(+)/IL-17(+) (T-helper 17) cells, 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 knockout [KO]). Given the role of FKBP12 in inhibiting transforming growth factor-? receptor activation, Tie2-Cre-mediated deletion of FKBP12 increased transforming growth factor-? 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 proinflammatory cytokines IL-2, IL-6, interferon-?, IL-17a, IL-21, and IL-23 were increased significantly, suggesting a T-helper 17 cell-mediated inflammatory state. Flow cytometry studies confirmed this, because splenic levels of CD4(+)/IL-17(+) cells were increased significantly, whereas CD4(+)/FoxP3(+) cells were decreased in FKBP12EC KO mice. Furthermore, spleens from FKBP12EC KO mice showed increased signal transducer and activator of transcription 3 activation, involved in T-helper 17 cell induction, and decreased signal transducer and activator of transcription 5 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 transforming growth factor-? receptors in endothelial and hematopoietic cells, may cause endothelial dysfunction and hypertension by activating endothelial cells, reducing regulatory T cells, and increasing T-helper 17 cell polarization and inflammation.

Project description:The pivotal issue of transplant rejection diagnosis and management is design, conduct, and analysis of clinical trials. The historical experience with clinical trials of major immunosuppressive drugs (cyclosporine and especially tacrolimus) is examined in this article. Cyclosporine was a turning point in transplantation, providing an extraordinary improvement over previous therapies. Additionally, early investigational experience with tacrolimus was shown to be important in rescue from cyclosporine failure. Experience with tacrolimus in liver recipients for primary therapy led to understanding that the side effect profile was similar to cyclosporine and that the important side effects of tacrolimus (toxicity and diabetes) could be lessened by altering the drug dose. Early dosing regimens were determined by attempts to balance the toxicities (representing a dose ceiling) against rejection (for minimum dosing). Drug levels became understandable and trough levels could be used to guide therapy. However, when the multicenter liver trial was implemented, high starting doses were included in the protocol design, ignoring information obtained with drug level monitoring. Disregard for this information led to a distortion of the potential value of tacrolimus. Historical controls from the Pittsburgh experience suggested that tacrolimus was a critical immunosuppressant, and the randomized trial against cyclosporine confirmed the drug's ability to compete. The multicenter liver trial, however, was not balanced across treatment arms for other immunosuppressive agents (ie, higher doses of prednisone from center to center, additional induction protocols at various centers). Additionally, analysis of study results differed across continents, and the role of tacrolimus in cyclosporine rescue was not examined thoroughly. When tacrolimus was proposed for use in extrahepatic organ transplantation, again the Pittsburgh experience, as well as experience from other single centers, was determined inadequate evidence of efficacy, and randomized trials were required by the FDA. The fact that multicenter trials in transplantation have historically been poorly designed or analyzed weighed against the dramatic improvements shown from historically controlled studies or single-center trials should lead to question of the regulatory requirement for multicenter randomized trials for all organ types.

Dataset Information

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

Publications

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

Similar Datasets

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