The sodium-activated sodium channel is expressed in the rat kidney thick ascending limb and collecting duct cells and is upregulated during high salt intake

Na+ is the major cation in extracellular fluid due to the ability of cells to continuously extrude Na+ through the Na+-K+-ATPase. Its functions include maintaining tonicity and concentration of extracellular fluid, acid-base balance (reabsorption of Na+ and secretion of H+), nerve conduction and neuromuscular function, glandular secretion, and water balance. Although the daily NaCl requirement is only 2–4 g, average consumption of salt is much greater, thus placing a major burden on the kidney to excrete the excess Na+ and Cl− to maintain Na balance (4). Augmented extracellular Na+ concentration ([Na+]) activates distinct signaling pathways that prevent large increases in intracellular [Na+] and increase Na+ excretion. These signaling pathways include increases in intracellular Ca2+, activation of salt-inducible kinases, and the regulation of Na+ transporters in the kidney (3, 4). The activation of these cell-signaling pathways in response to chronic increased Na+ intake also elicits oxidative stress, which could contribute to the development and progression of hypertension and kidney injury (2, 14). Although many systems are activated to increase Na+ excretion, it remains unclear how the kidney can specifically sense elevations in [Na+] in tubules or interstitial fluid. A specific sodium-activated sodium channel (Na sensor or Nax) has been recently localized in the brain and has been postulated to control salt intake (11, 17). The Na sensor, also called NaG/SCL11 (in rats), Nav2.3 (in mice), and Nav2.1 (in humans), is present in the brain specifically in the circumventricular area (11). The Na sensor has a 50% homology with voltage-gated Na+ channels but includes differences in the key regions for voltage sensing and inactivation (15). This sensor is a concentration-sensitive Na+ channel with a threshold value of 150 mmol/l for extracellular Na+ concentration in the brain (11). The physiological role of the brain Na sensor has been evaluated in Na sensor knockout mice (Na-sensor-KO) (18). Compared with wild-type mice, Na sensor-KO mice show a marked neuronal activation, estimated by c-Fos immunoreactivity, in the subfornical organ and organum vasculosum of the lamina terminalis after water deprivation. This event has been associated with the observation that Na sensor-deficient mice are not able to suppress overconsumption of NaCl (18). Na sensor expression has been reported in lungs, pregnant uterus, and heart (1, 6, 13). However, its presence in peripheral organs involved in salt regulation, particularly the kidneys, has been demonstrated only in the nonmyelinating Schwann cells of the kidney nerve endings (17). Accordingly, we hypothesized that the Na sensor is present in the kidney tubular epithelial cells and that its expression is increased by high salt intake. This study describes the presence of Na sensor transcript and protein in normal rat kidneys and provides evidence for its localization on the luminal membranes of principal cells of the collecting ducts and in thick ascending limb of Henle's loop (TAL) cells. We also observed the protein expression of the Na sensor in the medullary kidney tissue of Sprague-Dawley rats subjected to a high-salt diet for 7 days.