Calcineurin signalling in the thick ascending limb of the kidney (892.30)

Abstract

The calcineurin inhibitors cyclosporine and tacrolimus are widely used for immunosuppressive therapy but hypertension and electrolyte disorders often complicate their application. Hypertension during treatment with tacrolimus has been attributed to inhibition of calcineurin Aα and resultant hyperphosphorylation and activation of the Na+‐Cl‐‐cotransporter (NCC) of the distal convoluted tubule (DCT). Activity of the Na+‐K+‐2Cl‐‐cotransporter (NKCC2) of the thick ascending limb (TAL) is also modulated by the balance between phosphorylation and dephosphorylation reactions. Here we identify NKCC2 as a substrate of calcineurin Aβ and show that cyclosporine activates NKCC2. To further characterize the molecular pathway involved in NKCC2 dephosphorylation we have evaluated SORLA (sorting‐protein‐related receptor with A‐type repeats) knockout mice with nearly complete absence of phosphorylated NKCC2. We establish SORLA as trafficking factor that reduces the apical abundance of calcineurin in TAL thus facilitating NKCC2 phosphorylation. This study elucidates the molecular basis for calcineurin signalling along the TAL. Our results thus have substantial clinical implications for immunosuppressive therapy using calcineurin inhibitors.