Sodium and chloride are both predominantly extracellular ions. In plasma, the sodium concentration is maintained between 135 to 145 mmol/L, whereas the chloride concentration is maintained between 98 to 108 mmol/L.
Both sodium and chloride are freely ﬁltered at the glomerulus and almost completely (approximately 99%) reabsorbed. 60% of the ﬁltered load is reabsorbed in the proximal tubule; 30% is reabsorbed in the thick ascending limb; 7% is reabsorbed in the distal convoluted tubule; and 2% to 3% is reabsorbed in the connecting tubule and collecting duct.
Mechanisms Of Transport
In all portions of the nephron, basolateral Na+/K+ ATPases pump sodium from the tubular epithelial cells into the interstitium. As a result, intracellular sodium concentrations remain low, establishing a gradient for transcellular reabsorption.
Proximal Tubule. Throughout the proximal tubule, sodium crosses the apical membranes of tubular epithelial cells on Na+/H+ exchangers (NHE-3), causing proton secretion by secondary active transport. To a lesser extent, sodium crosses apical membranes on symporters that transport one or more sodium ions in combination with various substances, including glucose, amino acids, phosphate, lactate, and citrate. The reabsorption of sodium, irrespective of the mechanism, transiently establishes an osmotic transepithelial gradient that promotes the passive, isotonic reabsorption of water (see Plate 3-15).
As sodium and water are reabsorbed, chloride becomes increasingly concentrated in proximal tubular ﬂuid. In addition, the initial segment of the proximal tubular lumen has a negative charge. Thus there are chemical and electrical gradients favoring chloride reabsorption, which occurs along a paracellular pathway. In later parts of the proximal tubule, the negative charge in the lumen dissipates, owing to extensive para- cellular reabsorption of chloride. Instead, there is a positive charge, which creates an electrical gradient for the paracellular reabsorption of sodium. Despite this reversal, paracellular chloride reabsorption continues because of the strong chemical gradient in its favor.
Some chloride also undergoes transcellular reabsorption via apical Cl- anion antiporters, which are coupled with basolateral Cl- channels and K+/Cl- cotransporters (KCC-3 and -4).
Thin Limb. The descending thin limb is impermeable to solutes but permits reabsorption of water, as discussed on Plate 3-15. Tubular ﬂuid thus becomes concentrated in this segment, which establishes a chemical gradient favoring the reabsorption of some sodium and chloride from the ascending thin limb. Sodium undergoes paracellular reabsorption, whereas chloride undergoes transcellular reabsorption through apical and basolateral CLC-NKA channels.
Thick Ascending Limb. In this segment, sodium, chloride, and potassium undergo transcellular reabsorption together on an apical cotransporter (NKCC2). Two chloride ions are transported for each sodium and potassium ion. The basolateral Na+/H+ pumps establish a chemical gradient for sodium that drives this process. Once in the cell, chloride crosses the basolateral membrane via channels (CLC-NKB) and K+/Cl- transporters (KCC-4). Potassium, in contrast, is recycled back into the lumen through apical ROM-K channels. The net result is a positive charge in the tubular lumen, which promotes the paracellular reabsorption of sodium and other cations.
Although the NHE-3 Na+/H+ exchanger is present in this segment, it makes only a minor contribution to overall sodium reabsorption and is more important for bicarbonate reabsorption (see Plate 3-21).
Distal Convoluted Tubule. In this segment, sodium and chloride undergo transcellular reabsorption together on an apical Na+/Cl- symporter (NCC). The basolateral Na+/K+ pumps establish a chemical gradient for sodium that drives this process. Once in the cell, chloride crosses the basolateral membrane via the CLC-NKB channel.
Connecting Tubule and Collecting Duct. In these segments, sodium undergoes transcellular reabsorption through apical channels (ENaC) located on principal cells. The reabsorption of sodium generates a negative charge in the tubular lumen, which creates a gradient for the paracellular reabsorption of chloride. Although not shown in the illustration, chloride also undergoes transcellular reabsorption across type B intercalated cells through an apical HCO3-/Cl- exchanger (pendrin) and a basolateral channel (CLC-NKB).
Regulation Of Sodium Handling
Sodium is the principle osmole of extracellular ﬂuid, and its plasma concentration is modulated by the systems that control the retention or excretion of free water. Thus an increase in sodium concentration results in the retention of free water, whereas a decrease in sodium concentration results in the excretion of free water. This mechanism is controlled by central osmoreceptors, which sense increases in osmolality and respond by promoting feelings of thirst, water-seeking behavior, and the release of antidiuretic hormone (ADH, or vasopressin). Through water consumption and the actions of ADH, which promotes water reabsorption from collecting ducts (see Plate 3-17), free water is added to the extracellular ﬂuid (ECF) until normal osmolality is restored. At this point, osmoreceptor activation ceases.
Because of this system, an increase or decrease in total body sodium will lead, by necessity, to expansion or contraction of the ECF volume. Free water intake, in contrast, does not affect ECF volume. First, free water distributes into both the intracellular and extracellular ﬂuids. Second, dilution of the ECF after ﬂuid intake suppresses ADH release, causing dilute urine to be produced until normal plasma osmolality is restored. Because total body sodium is thus the primary determinant of ECF volume, the mechanisms that control ECF volume directly modulate the rate of sodium excretion in urine.
In the setting of ECF depletion, for example, several mechanisms increase the renal retention of sodium. Activation of baroreceptors in the aortic arch and carotid bodies, for example, causes an increase in sympathetic tone. Norepinephrine constricts afferent and efferent arterioles, which reduces the glomerular ﬁltration rate, and it also stimulates NHE-3 transporters and Na+/K+ ATPases in the proximal tubule, which promotes sodium reabsorption. Meanwhile, renin release occurs secondary to multiple factors, including sympathetic input, decreased stretching of afferent arterioles, and decreased tubular ﬂow rates. Renin catalyzes the synthesis of angiotensin II (AII), which has many effects that promote sodium retention. First, AII stimulates apical NHE-3 transporters and basolateral Na+/K+ ATPases in the proximal tubule. Second, AII promotes the release of aldosterone, which increases sodium reabsorption from the distal nephron by upregulating ENaC and NCC transporters. Third, AII promotes the release of ADH, which up-regulates sodium and water reabsorption from the collecting duct (by up-regulating ENaC and aquaporin channels) and the thick ascending limb (by upregulating NKCC2 transporters). Finally, AII constricts the efferent arteriole, which lowers hydrostatic pressure in the peritubular capillaries and, moreover, increases the ﬁltration fraction, raising osmotic pressure in the peritubular capillaries. These altered forces both favor reabsorption from the proximal tubules.
In the setting of ECF overload, these various mechanisms are inactivated, promoting renal excretion of sodium. The effect is ampliﬁed by the release of atrial natriuretic peptide (ANP), which occurs in response to stretching of the cardiac atria. ANP dilates the afferent arteriole and constricts the efferent arteriole, which raises the glomerular ﬁltration rate. In addition, it blocks sodium reabsorption from the proximal and distal tubules, as well as water reabsorption from the collecting duct. Finally, it suppresses the release of renin, aldosterone, and ADH.
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