Renal deletion of 12 kDa FK506-binding protein attenuates tacrolimus-induced hypertension

Rebecca A. Lazelle, Belinda H. McCully, Andrew S. Terker, Nina Himmerkus, Katharina I. Blankenstein, Kerim Mutig, Markus Bleich, Sebastian Bachmann, Chao Ling Yang, David H. Ellison

Research output: Contribution to journalArticle

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1456-1464
Number of pages9
JournalJournal of the American Society of Nephrology
Volume27
Issue number5
DOIs
StatePublished - May 2016

ASJC Scopus subject areas

  • Nephrology

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