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Acute inhibition of calcineurin using cyclosporine activates renal salt transporters (892.31)
Author(s) -
Blankenstein Katharina,
Borschewski Aljona,
Ellison David,
Bachmann Sebastian,
Mutig Kerim
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.892.31
Subject(s) - calcineurin , phosphorylation , endocrinology , medicine , cotransporter , chemistry , homeostasis , reabsorption , phosphatase , in vivo , kidney , pharmacology , biology , biochemistry , transplantation , sodium , microbiology and biotechnology , organic chemistry
Renal tubular transport processes are essential for systemic water and salt homeostasis and blood pressure control. The renal distal cation‐chloride cotransporters NKCC2 and NCC play a pivotal role in volume regulation. Increased activity of these transporters may cause salt retention and hypertension. Both NKCC2 and NCC are activated by N‐terminal phosphorylation. We recently showed that chronic administration of a calcineurin inhibitor tacrolimus was associated with increased NCC phosphorylation suggesting a role of the phosphatase in deactivation of the distal transporters. In this study we test acute effects of another calcineurin inhibitor, cyclosporine A (CsA) on NKCC2 and NCC in vivo and in cultured cells. The expression of cyclophilins, interacting with CsA during calcineurin inhibition, has been localized to the distal nephron using in situ hybridization and immunohistochemistry. Administration of CsA (25 mg/kg) to normal rats for 4 h led to marked increases of phosphorylated NKCC2 (3 fold) and NCC (6 fold). The concomitant analysis of total NKCC2 or NCC abundance revealed no significant changes. To exclude potential systemic influences, cultured rat TAL cells were treated with CsA for 4 h, which led to a substantial increase of NKCC2 phosphorylation. Our data suggest that phosphorylation of NKCC2 and NCC is acutely regulated by CsA at posttranscriptional level. Considering the broad clinical application of CsA and its renal side effects such as hypertension and electrolyte disorders, understanding of mechanisms of its side effects has clinical implications. Grant Funding Source : DFG 88126042