title: 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.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, and.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Lazelle
authors.affiliation: Division of Trauma, Critical Care and Acute Care Surgery, Department of Surgery, Oregon Health and Science University, Portland, Oregon;
authors.forename: Belinda H
authors.initials: BH
authors.lastname: McCully
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, and.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Terker
authors.affiliation: Institute of Physiology, Christian-Albrechts-University Kiel, Kiel, Germany;
authors.forename: Nina
authors.initials: N
authors.lastname: Himmerkus
authors.affiliation: Institute of Vegetative Anatomy, Charité, Universitätsmedizin Berlin, Campus Charité-Mitte, Berlin, Germany; and.
authors.forename: Katharina I
authors.initials: KI
authors.lastname: Blankenstein
authors.affiliation: Institute of Vegetative Anatomy, Charité, Universitätsmedizin Berlin, Campus Charité-Mitte, Berlin, Germany; and.
authors.forename: Kerim
authors.initials: K
authors.lastname: Mutig
authors.affiliation: Institute of Physiology, Christian-Albrechts-University Kiel, Kiel, Germany;
authors.forename: Markus
authors.initials: M
authors.lastname: Bleich
authors.affiliation: Institute of Vegetative Anatomy, Charité, Universitätsmedizin Berlin, Campus Charité-Mitte, Berlin, Germany; and.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bachmann
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, and Renal Section, VA Portland Health Care System, Portland, Oregon.
authors.forename: Chao-Ling
authors.initials: CL
authors.lastname: Yang
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, and Institute of Vegetative Anatomy, Charité, Universitätsmedizin Berlin, Campus Charité-Mitte, Berlin, Germany; and Renal Section, VA Portland Health Care System, Portland, Oregon Ellisond@ohsu.edu.
authors.forename: David H
authors.initials: DH
authors.lastname: Ellison
mesh_terms: D000818:Animals; D017353:Gene Deletion; D006973:Hypertension / Q000139:chemically induced* / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007668:Kidney; D008297:Male; D051379:Mice; D016559:Tacrolimus / Q000009:adverse effects*; D022061:Tacrolimus Binding Protein 1A / Q000235:genetics / Q000502:physiology*
chemical_list: D007166:Immunosuppressive Agents; D022061:Tacrolimus Binding Protein 1A; D016559:Tacrolimus
keywords: K channels; hypertension; immunosuppression; ion transport; kidney tubule; tacrolimus