Na+/K+/2C1 cotransporter

NKCC is a heavily glycosylated protein with 12 putative membrane-spanning regions. Thirty percent of the sodium that is filtered by renal glomeruli is reabsorbed by Na-K-2C1 cotransport in the ascending limb of Henle in the nephron. Na-K-2C1 cotransport is a target of all loop diuretics. 

The thick ascending limb is a major site of salt absorption and a principal locus of action of an important group of diuretics. Approximately 25% of the filtered sodium is reabsorbed by the thick ascending limb of Henle s loop. Sodium transport in this nephron segment is mediated by Na+-K+-2C1 cotransport (Fig. 21.3). This transporter is present only on the apical, or urine, side of the tubule cells. Although K+ is taken up by the transporter, little net K+ reabsorption occurs in the thick ascending limb because much of the absorbed K+... 

Sodium reabsorption continues in the distal convoluted tubule, which accounts for some 6 to 8% of the transport of sodium. The entry of Na+ across the apical cell membrane is mediated by Na+-Cl cotransport (Fig. 21.4). This protein is a distinct gene product that differs from the Na -K+-2C1 cotransporter in thick ascending limbs. 

These agents bind to Cl binding site of Na -K -2C1" cotransporter glycoprotein and inhibit its transport function in ascending limb of loop of Henle. 

Cerebral tissue acidosis following ischemia or flaumatic brain injury contributes to cytotoxic brain edema formation. In vitro lactacidosis induces swelling of glial cells by intracellular Na" - and Cl accumulation by the Na" /H+-antiporter, Cr/HCOs antiporters, and the Na -K -2C1 cotransport (Staub et al., 1990 Ringel et al., 2006a). 

Aoki, Y, Albrecht, F., Bergman, K. R., and Jose, P. (1996). Stimulation of Na+-K+-2C1 cotransport in rat medullary thick ascending limb by dopamine. Am. J. Physiol 271, R1561-R1567. 

Flatman PW. 2005. Activation of ferret erythrocyte Na -K -2C1 cotransport by deoxygenation. J Physiol (Lond) 563 421-431. 

Ethacrynic add and furosemide are weak acids that are both filtered and secreted, so they achieve high levels in the tubular lumen. Loop diuretics inhibit the Na+/K+/2C1" cotransporter on the luminal membrane of the thick ascending loop (TAL). 

Inhibition of the Na/K/2C1 cotransporter decreases intracellular K+ levels —>4-back-diffusion of K+ ->4- positive potential ->4- reabsorption of Ca2+ and Mg2+. Thus, loop diuretics increase urinary levels of Na+, K+, Ca2+, Mg2-1-, and Cl . 

Loop diuretics cause potassium loss by the initial inhibition of the Na+/K+/2C1 cotransporter. In addition, the abrupt loss in plasma volume, due to the efficacy of these drugs, results in the stimulation of aldosterone secretion, which promotes an additional loss of potassium. 

It is well known that 20-HETE has opposing effects depending on its site of action. It plays an antihypertensive role in renal tubules, where it promotes water and Na excretion. In proximal tubules, 20-HETE induces phosphorylation of the Na /K -ATPase alpha subunit via protein kinase C (PKC) to inhibit Na /K -ATPase activity [67]. In the medullary thick ascending limb, it inhibits the large-conductance 70 pS K+ channel and the Na -K+-2C1 cotransporter to prevent efflux... 

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