Calcineurin and Sorting-Related Receptor with A-Type Repeats Interact to Regulate the Renal Na+-K+-2Cl(-) Cotransporter

Borschewski, A., Himmerkus, N., Boldt, C., Blankenstein, K. I., McCormick, J. A., Laze, R., Willnow, T. E., Jankowski, V., Plain, A., Bleich, Markus, Ellison, D. H., Bachmann, S. and Mutig, K. (2016) Calcineurin and Sorting-Related Receptor with A-Type Repeats Interact to Regulate the Renal Na+-K+-2Cl(-) Cotransporter Journal of the American Society of Nephrology, 27 (1). pp. 107-119. DOI 10.1681/ASN.2014070728.

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Abstract

The furosemide-sensitive Na+-K+-2Cl(-)-cotransporter (NKCC2) is crucial for NaCl reabsorption in kidney thick ascending limb (TAL) and drives the urine concentrating mechanism. NKCC2 activity is modulated by N-terminal phosphorylation and dephosphorylation. Serine-threonine kinases that activate NKCC2 have been identified, but less is known about phosphatases that deactivate NKCC2. Inhibition of calcineurin phosphatase has been shown to stimulate transport in the TAL and the distal convoluted tubule. Here, we identified NKCC2 as a target of the calcineurin A beta isoform. Short-term cyclosporine administration in mice augmented the abundance of phospho-NKCC2, and treatment of isolated TAL with cyclosporine increased the chloride affinity and transport activity of NKCC2. Because sorting-related receptor with A-type repeats (SORLA) may affect NKCC2 phosphoregulation, we used SORLA-knockout mice to test whether SORLA is involved in calcineurin-dependent modulation of NKCC2. SORLA-deficient mice showed more calcineurin A beta in the apical region of TAL cells and less NKCC2 phosphorylation and activity compared with littermate controls. In contrast, overexpression of SORLA in cultured cells reduced the abundance of endogenous calcineurin A beta. Cyclosporine administration rapidly normalized the abundance of phospho-NKCC2 in SORLA-deficient mice, and a functional interaction between calcineurin A beta and SORLA was further corroborated by binding assays in rat kidney extracts. In summary, we have shown that calcineurin A beta and SORLA are key components in the phosphoregulation of NKCC2. These results may have clinical implications for imnnunosuppressive therapy using calcineurin inhibitors.

Document Type: Article
Additional Information: Times Cited: 7 Borschewski, Aljona Himmerkus, Nina Boldt, Christin Blankenstein, Katharina I. McCormick, James A. Laze, Rebecca Willnow, Thomas E. Jankowski, Vera Plain, Allein Bleich, Markus Ellison, David H. Bachmann, Sebastian Mutig, Kerim
Research affiliation: Kiel University
Refereed: Yes
DOI etc.: 10.1681/ASN.2014070728
ISSN: 1046-6673
Date Deposited: 25 Feb 2017 06:51
Last Modified: 08 Mar 2017 09:45
URI: http://eprints.uni-kiel.de/id/eprint/36022

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