Lazelle, R. A., McCully, B. H., Terker, A. S., Himmerkus, N., Blankenstein, K. I., Mutig, K., Bleich, Markus, Bachmann, S., Yang, C. L. and Ellison, D. H. (2016) Renal Deletion of 12 kDa FK506-Binding Protein Attenuates Tacrolimus-Induced Hypertension. Journal of the American Society of Nephrology, 27 (5). pp. 1456-1464. DOI 10.1681/ASN.2015040466.

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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.

Document Type:	Article
Additional Information:	Times Cited: 4 Lazelle, Rebecca A. McCully, Belinda H. Terker, Andrew S. Himmerkus, Nina Blankenstein, Katharina I. Mutig, Kerim Bleich, Markus Bachmann, Sebastian Yang, Chao-Ling Ellison, David H.
Keywords:	hypertensionimmunosuppressionion transportK channelskidney tubuletacrolimus
Research affiliation:	Kiel University > Kiel Marine Science OceanRep > The Future Ocean - Cluster of Excellence Kiel University
Refereed:	Yes
Open Access Journal?:	No
Publisher:	American Society of Nephrology
Projects:	Future Ocean
Date Deposited:	16 Mar 2017 07:43
Last Modified:	27 May 2019 14:41
URI:	https://oceanrep.geomar.de/id/eprint/36188

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