NKCC1 and NKCC2: The pathogenetic role of cation-chloride cotransporters in hypertension

Abstract

This review summarizes the data on the functional significance of ubiquitous (NKCC1) and renal-specific (NKCC2) isoforms of electroneutral sodium, potassium and chloride cotransporters. These carriers contribute to the pathogenesis of hypertension via regulation of intracellular chloride concentration in vascular smooth muscle and neuronal cells and via sensing chloride concentration in the renal tubular fluid, respectively. Both NKCC1 and NKCC2 are inhibited by furosemide and other high-ceiling diuretics widely used for attenuation of extracellular fluid volume. However, the chronic usage of these compounds for the treatment of hypertension and other volume-expanded disorders may have diverse side-effects due to suppression of myogenic response in microcirculatory beds.

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…This long unanswered question seems to have been solved recently. Na-K-Cl cotransporter 1 (NKCC1) mediates intracellular Cl Ϫ accumulation, leading to membrane depolarization and activation of voltage-dependent Ca 2ϩ channels (779). WNKs phosphorylate and activate oxidative stressresponsive kinase 1 (OSR1) and SPAK, leading to downstream phosphorylation and activation of NKCC and Na-Cl cotransporter (NCC) (215).…”

An Appraisal of Methods Recently Recommended for Testing Salt Sensitivity of Blood Pressure

“…In the inpatient acute protocol, it should be kept in mind that the effects of changes in oral salt intake on mechanisms regulating BP are susceptible to potential confounding by effects of furosemide and intravenous salt loading. For example, furosemide itself not only has effects on Na + , K + , 2Cl − cotransporters in the renal tubule, but it also has effects on Na + , K + , 2Cl − cotransporters in the vasculature . In addition, administration of salt by the intravenous route may have different biological effects than administration of salt by the more physiological oral route.…”

“…For example, furosemide itself not only has effects on Na + , K + , 2Cl À cotransporters in the renal tubule, but it also has effects on Na + , K + , 2Cl À cotransporters in the vasculature. 39,40 In addition, administration of salt by the intravenous route may have different biological effects than administration of salt by the more physiological oral route.…”

Molecular basis for regulation of human potassium chloride cotransporters

“…CCCs mediate the electroneutral across cell membrane transport of sodium and/or potassium cations and chloride anion. Two major classes of CCCs exist in mammals, the sodiumindependent co-transporters consisting of KCC1-4 and the sodium-dependent co-transporters including NKCC1-2 and NCC (1)(2)(3). Phosphorylation regulates the transporter activity along with a series of kinases, e.g.…”