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Calcineurin and sorting-related receptor with A-type repeats interact to regulate the renal Na(+)-K(+)-2Cl(-) cotransporter

Item Type:Article
Title:Calcineurin and sorting-related receptor with A-type repeats interact to regulate the renal Na(+)-K(+)-2Cl(-) cotransporter
Creators Name:Borschewski, A. and Himmerkus, N. and Boldt, C. and Blankenstein, K.I. and McCormick, J.A. and Lazelle, R. and Willnow, T.E. and Jankowski, V. and Plain, A. and Bleich, M. and Ellison, D.H. and Bachmann, S. and Mutig, K.
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 Abeta 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 Abeta 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 Abeta. Cyclosporine administration rapidly normalized the abundance of phospho-NKCC2 in SORLA-deficient mice, and a functional interaction between calcineurin Abeta and SORLA was further corroborated by binding assays in rat kidney extracts. In summary, we have shown that calcineurin Abeta and SORLA are key components in the phosphoregulation of NKCC2. These results may have clinical implications for immunosuppressive therapy using calcineurin inhibitors.
Keywords:Cyclosporine, Epithelial Sodium Transport, Cell Signaling, Animals, Mice, Rats
Source:Journal of the American Society of Nephrology
Publisher:American Society of Nephrology (U.S.A.)
Page Range:107-119
Date:January 2016
Official Publication:https://doi.org/10.1681/ASN.2014070728
PubMed:View item in PubMed

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