Distal convoluted tubule, transport

Electroneutral NaCl transport in the distal convoluted tubule is inhibited by the class of thiazide diuretics (chlorothiazide, hydrochlorothiazide, metolazone, chlorthalidone, and others). Thiazides interfere with the Cl binding site of NCC, and cause a relatively small... 

Thick ascending limb This limb is also impermeable to water. It contains ion pumps to pump electrolytes actively into the interstitium. The main pump is the Na+/2C1 /K+ co-transporter. Fluid leaving this limb is, therefore, hypotonic and passes into the distal convoluted tubule. 

A nephron, showing the major sites and percentage (in braces) of sodium absorption along with other features of solute transport. The filtered load = GFR (180 L/day) Xplasma Na+ (140 mEq/L) or 25,200 mEq/day. About 1% of this amount is excreted in voided urine. Sites where tubular fluid is isosmotic, hypertonic, or hypotonic relative to plasma are shown. POT, proximal convoluted tubule LH, loop of Henle DOT, distal convoluted tubule CCD, cortical collecting duct TAL, thick ascending loop. 

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. 

The distal convoluted tubule, along with the collecting duct, is an important site of K+ transport. The direc-... 

Na+-Ct cotransport in distal convoluted tubules. This transport protein, shown by the open circle on the apical cell membrane, does not require K+ for its function. It is a different gene product than the Na+-K+-2Chcotransporter. Na+-CI cotransport is limited largely, if not entirely, to the distal convoluted tubules. 

In distal convoluted tubules, calcium is transported by an active transport mechanism through rather than between cells. Moreover, in distal convoluted tubules there is a reciprocal relation between the direction and magnitude of calcium on Na+ transport. As Na+ absorption increases, calcium decreases, and conversely, reductions of Na+ absorption are accompanied by elevated calcium reabsorption. This interaction has important implications for diuretics acting in the distal convoluted tubule. 

Figure 12.4 Mechanism of action of Na+/K+symport inhibitors (thiazides) on the distal convoluted tubule. As in the other parts of the nephron, Na+movement is powered by the energy-requiring sodium pump (P) in the basolateral membrane which exchanges intracellular Na+for K-i-in the extracellular fluid (ECF). The transport of Na-rand Cl- into the cell from the filtrate against the prevailing electrochemical gradient is facilitated by the symporter (S). The Na-Hons are then transported by the pump mechanism described above and the Cl- ions diffuse passively Into the ECF through ion channels in the basolateral membrane. Thiazide diuretics inhibit the symporter by disabling the Cl- binding site with the loss of Na-rand Cl- in the urine.

Thiazides Hydrochlorothiazide Block Na/CI transporter in renal distal convoluted tubule Reduce blood volume plus poorly understood vascular effects Hypertension, mild heart failure ... 

Only about 10% of the filtered NaCI is reabsorbed in the distal convoluted tubule (DCT). Like the TAL of Henle s loop, this segment is relatively impermeable to water and NaCI reabsorption further dilutes the tubular fluid. The mechanism of NaCI transport in the DCT is an electrically neutral thiazide-sensitive Na+ and cotransporter (NCC, Figure 15-4). 

Ion transport pathways across the luminal and basolateral membranes of the distal convoluted tubule cell. As in all tubular cells, Na+/K+ ATPase is present in the basolateral membrane. NCC is the primary sodium and chloride transporter in the luminal membrane. (R, parathyroid hormone [PTH] receptor.)... 

Thiazides inhibit NaCI reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na+/Q transporter (NCC). In contrast to the situation in the TAL, in which loop diuretics inhibit Ca2+ reabsorption, thiazides actually enhance Ca2+ reabsorption. This enhancement has been postulated to result from effects in both the proximal and distal convoluted tubules. In the proximal tubule, thiazide-induced volume depletion leads to enhanced Na+ and passive Ca2+ reabsorption. In the DCT, lowering of intracellular Na+ by thiazide-induced blockade of Na+ entry enhances Na+/Ca2+ exchange in the basolateral membrane (Figure 15-4), and increases overall reabsorption of Ca2+. Although thiazides rarely cause hypercalcemia as the result of this enhanced reabsorption, they can unmask hypercalcemia due to other causes (eg, hyperparathyroidism, carcinoma, sarcoidosis). Thiazides are useful in the treatment of kidney stones caused by hypercalciuria. 

Hydrochlorothiazide Inhibition of the Na/CI transporter in the distal convoluted tubule Modest increase in NaCI excretion some wasting hypokalemic metabolic alkalosis t decreased urine Ca Hypertension, mild heart failure, nephrolithiasis, nephrogenic diabetes insipidus Oral duration 8-12 h Toxicity Hypokalemic metabolic alkalosis, hyperuricemia, hyperglycemia, hyponatremia... 

Because K+ does not recycle across the apical membrane of the distal convoluted tubule as it does in the loop of Henle, there is no lumen-positive potential in this segment, and Ca2+ and Mg2+ are not driven out of the tubular lumen by electrical forces. However, Ca2+ is actively reabsorbed by the distal convoluted tubule epithelial cell via an apical Ca2+ channel and basolateral Na+/Ca2+ exchanger (Figure 15-5). This process is regulated by parathyroid hormone. As will be seen below, the differences in the mechanism of Ca2+ transport in the distal convoluted tubule and in the loop of Henle have important implications for the effects of various diuretics on Ca2+ transport. 

The thiazide diuretics emerged from efforts to synthesize more potent carbonic anhydrase inhibitors. It subsequently became clear that the thiazides inhibit NaCl transport predominantly in the distal convoluted tubule. However, some members of this group retain significant carbonic anhydrase inhibitory activity. The prototypical thiazide is hydrochlorothiazide. 

The cells of the distal convoluted tubule are also impermeable to water. About 10% of the filtered sodium chloride is reabsorbed via a Na7CI" transporter, which is sensitive to thiazide diuretics. Additionally, Ca++ excretion is regulated by parathyroid hormone in this portion of the tubule. 

Figure 10.1 Sites and mechanisms of action of diuretics. The location of each cell type along the nephron is indicated by the shading patterns. Spironoiactone (not shown) is a competitive aldosterone antagonist and acts primarily in the collecting duct. PT, proximal tubule LH, loop of Henie TAL, thick ascending limb DT, distal tubule DCT, distal convoluted tubule CD, collecting duct PC, principal cell CA, carbonic anhydrase CAI, carbonic anhydrase inhibitors , primary active transport. (Adapted with permission from Ellison D H 1991 The physiologic basis of diuretic synergism its role in treating diuretic resistance. Annals of Internal Medicine 114 886-894.)...

Figure 18-5 Site 3 The Na transport systems responsible for the reabsorption of Na and Cl" in the water-impermeable distal convoluted tubule. Inhibitors of the luminal membrane-bound Na /CI cotransport system include the thiazide and thiazide-like diuretics.

The answer is c. (Murray, pp 505—626. Scriver, pp 4029—4240. Sack, pp 121-138. Wilson, pp 287-320.) Vasopressin, which is also called antidiuretic hormone, increases the permeability of the collecting ducts and distal convoluted tubules of the kidney and thus allows passage of water. Like the mineralocorticoid aldosterone, vasopressin results in an expansion of blood volume. However, the mode of action of aldosterone is different it causes sodium reabsorption, not water reabsorption. Sodium reabsorption indirectly leads to increased plasma osmolality and thus water retention in the blood. Cortisol is a glucocorticoid that potentiates catabolic metabolism chronically. Epinephrine stimulates catabolic metabolism acutely. Insulin acutely favors anabolic metabolism, in large part by allowing glucose and amino acid transport into cells. 

The ascending thick limb or the pars recta of the distal tubule leads into the distal convoluted tubules or the pars convoluta of the distal tubule. The macula densa is a specialized region corresponding to the initial portion of the pars convoluta of the distal tubule. The two segments of the distal tubule (the pars recta and pars convoluta) are similar morphologically and functionally in terms of active chloride transport and permeability to water. 

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