Calcineurin Inhibitor Cyclosporine A Activates Renal Na-(K)-Cl Cotransporters via Local and Systemic Mechanisms.

Calcineurin Inhibitor Cyclosporine A Activates Renal Na-(K)-Cl Cotransporters via Local and Systemic Mechanisms. Am J Physiol Renal Physiol. 2016 Dec 21;:ajprenal.00575.2016 Authors: Blankenstein KI, Borschewski A, Labes R, Paliege A, Boldt C, McCormick JA, Ellison DH, Bader M, Bachmann S, Mutig K Abstract Calcineurin dephosphorylates NFAT transcription factors, thereby facilitating T-cell mediated immune responses. Calcineurin inhibitors are instrumental for immunosuppression after organ transplantation, but may cause side effects including hypertension and electrolyte disorders. Kidneys were recently shown to display activation of the furosemide-sensitive Na-K-2Cl cotransporter (NKCC2) of the thick ascending limb and the thiazide-sensitive Na-Cl cotransporter (NCC) of the distal convoluted tubule upon calcineurin inhibition using cyclosporin A (CsA). An involvement of major hormones like angiotensin II or arginine vasopressin (AVP) has been proposed. To resolve this issue, the effects of CsA treatment in normal Wistar and AVP-deficient Brattleboro rats, and cultured renal epithelial cells endogenously expressing either NKCC2 or NCC, were studied. Acute administration of CsA to Wistar rats rapidly augmented phosphorylation levels of NKCC2, NCC, and their activating kinases (WNK and SPAK/OSR1), suggesting intraepithelial activating effects. Chronic CsA administration caused salt retention and hypertension, along with stimulation of r...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research