LAUSR

In the current issue of Acta Physiologica, Gao et al. explore the possible role of the inward rectifying potassium channel (Kir) 4.1 in cyclosporin Ainduced hyperkalemic hypertension.1 Calcineurin inhibitors, such as cyclosporin A and tacrolimus, are immunosuppressive drugs, which are widely used to prevent transplant rejection and treat autoimmune diseases. Side effects of calcineurin inhibitors include hypertension, hyperkalemia, hypercalciuria, and acidosis.2 These effects of calcineurin inhibitors resemble familial hyperkalemic hypertension, a genetic disease characterized by overactivity of the thiazidesensitive sodium chloride cotransporter (NCC) expressed in the renal distal convoluted tubule.2 Previous work has established the involvement of NCC underlying the hypertensive effect of calcineurin inhibitors. In fact, in contrast to the effects in wildtype mice, calcineurin inhibition does not cause hypertension, hypercalciuria, acidosis, or increased potassium levels in NCCdeficient mice.2 Furthermore, thiazidedependent inhibition of NCC reverses the hypertensive effect observed with calcineurin inhibition, whereas an exaggerated hypertensive response was seen in mice overexpressing NCC.2 In agreement with this, treatment with calcineurin inhibitors has been shown to increase NCC phosphorylation, an indirect measure of NCC activity, in murine kidney, tubule suspensions, and cell models.2,3 Studies of kidney biopsies or urinary extracellular vesicles of kidney transplant recipients treated with calcineurin inhibitors showed higher total and phosphorylated levels of NCC compared to controls. Furthermore, these patients had a greater fractional chloride excretion in response to NCC blockade, indicative of an increased NCC activity.2,3 So overall, the effect of calcineurin inhibitors on NCC is well established. However, the mechanism linking calcineurin inhibition to altered NCC activity is unclear. A potential candidate linking calcineurin with NCC is the Kir4.1/Kir5.1 channel. In the kidney, Kir4.1 interacts with Kir5.1 to form a basolateral potassium channel in the late cortical thick ascending limb, distal convoluted tubule, connecting tubule, and cortical collecting duct. Kir4.1 confers permeability to potassium, whereas Kir5.1 is thought to serve as a regulatory subunit.4 The Kir4.1/ Kir5.1 channel determines the basolateral potassium conductance in the distal convoluted tubule and plays a key role in setting the membrane potential. Interestingly, in this issue of Acta Physiologica, Gao et al. show by patchclamp measurements that cyclosporin A stimulates Kir4.1/ Kir5.1 activity in the distal convoluted tubule and makes the basolateral membrane potential more negative.1 Studies in recent years have demonstrated the importance of the Kir4.1/Kir5.1 channel in the regulation of NCC. Lossoffunction mutations of KCNJ10, encoding the human Kir4.1 gene, cause EAST syndrome, which symptoms include sodium wasting and hypokalemic alkalosis, symptoms mirroring calcineurin inhibition.4 Deletion of Kcnj10 in the mouse kidney leads to depolarization of the membrane potential and a reduced NCC expression and activity in the distal convoluted tubule, along with a reduced blood pressure, sodium and potassium wasting.4 In addition, changes in Kir4.1/Kir5.1 activity have been shown to be indispensable for the regulation of NCC by dietary changes in sodium and potassium, bradykinin, activation of the type 2 angiotensin II receptor, and the βadrenergic receptor.4 Collectively, this shows the central role of Kir4.1/5.1 in the regulation of NCC. The mechanism linking Kir4.1/Kir5.1 channels to NCC is not completely understood but is thought to depend on modulation of the with no lysine (WNK) kinases by intracellular chloride (Figure 1). Increased activity of the Kir4.1/Kir5.1 channel hyperpolarizes the membrane thereby increasing the driving force for chloride exit. In vitro studies in HEK cells have delineated that transfection with lossoffunction mutants of Kir4.1 results in an increased intracellular chloride concentration and reduced phosphorylated NCC levels. Conversely, low extracellular potassium, known to increase Kir4.1/Kir5.1 activity,