Transport In The Distal Convolution And Collecting Duct

As discussed in Chapter 23 (see Fig. 5 in that chapter), the distal convolution, i.e., the portion of the nephron between the macula densa and the beginning of the cortical collecting duct, consists of the distal convoluted tubule and the connecting tubule. The initial portion of the distal convolution is a very short continuation of the thick ascending limb, which is followed by the abrupt appearance of distal tubule cells (DCT cells), which have highly amplified basolateral membranes, as well as the highest density of mitochondria and Na+,K+-ATPase activity of any nephron segment. Beyond the middle of the distal convolution, connecting tubule cells (CNT cells) appear with increasing frequency as the nephron transitions to become the connecting tubule. Intercalated cells also appear as a minority cell type scattered among the CNT cells, and they appear in increasing frequency along the length of the connecting tubule. The density of intercalated cells rises to ~30% in the cortical collecting duct, but it then diminishes along the medullary collecting duct and falls to zero in the inner medullary collecting duct. The functional properties of the intercalated cells will be discussed in subsequent chapters concerning renal potassium and acid-base balance, whereas this section focuses on the functional properties of the primary cell types in these nephron segments.

Along a short segment at the end of the connecting tubule, principal cells, which are the major cell type in the collecting duct, replace the CNT cells and form the initial collecting tubule. These initial collecting tubules converge, with the confluence of 10-12 forming a cortical collecting duct. Cortical collecting ducts run through the cortex and enter the medulla, where they are referred to as medullary collecting ducts. Within the inner region of the medulla, these collecting ducts come together to eventually form the larger ducts of Bellini that empty into the renal calyces.

It is more convenient to discuss the functions of the distal convolution and collecting duct according to the cell types that populate it rather than by the traditional segmental divisions. In the early to mid-distal convoluted tubule, DCT cells are the majority cell type and they have distinct functional properties. Although the majority cell types in the connecting tubules (CNT cells) and collecting ducts (principal cells) have somewhat different morphology, they appear to be functionally quite similar. As discussed later, CNT and principal cells reabsorb Na+ by an electrogenic channel mechanism in contrast to an electroneutral NaCl cotransporter found in DCT cells. The CNT and principal cells are also unique as the primary sites of action of the hormones aldosterone and vasopressin in the nephron. In this and subsequent chapters of this section, the connecting tubule and the collecting duct, which are populated primarily by CNT and principal cells, will be referred to collectively as the aldosterone-responsive distal nephron (ARDN).

Approximately 10% of the filtered load of water collectively enters the distal convolution and it contains less than 10% of the filtered load of NaCl and KC1 and more than 50% of the filtered urea. Along the distal convolution, Na+ is actively reabsorbed and K+ is secreted. Because the net reabsorption of Na+ is normally greater than the secretion of K+, there is a net loss of solute from the lumen. Thus, the tubular fluid in the early distal convolution would continue to be diluted if the cells in all segments were water impermeable. This is true in the distal convoluted tubule because, just as with the thin and thick ascending limb, the epithelium formed by the DCT and intercalated cells is impermeable to water. However, the water permeability of the luminal membrane of CNT and principal cells in the ARDN is regulated by vasopressin, and it can range from negligible to very high. As will be discussed in detail in Chapter 28, when there is an excess of body water, the water permeability of the luminal membranes of CNT and principal cells is very low. In this condition, the final urine osmolality can be as low as 50 mOsm/kg H2O or less with a urine flow rate as much as 10% of the GFR. In dehydration, the water permeability of the luminal membranes of the CNT and principal cells is high, allowing osmotic equilibration between tubular fluid and the adjacent interstitium. In the cortex, this results in a tubular fluid that becomes isosmotic to plasma. In the medullary regions of collecting duct, where the inter-stitium is hypertonic, the tubular fluid also becomes hypertonic as water is osmotically reabsorbed. In a maximum antidiuretic state, the urine osmolality can rise as high as 1200 mOsm/kg H2O with a urine flow rate down to 0.5 mL/min.

NaCl Reabsorption by DCT Cells in the Distal Convoluted Tubule

An important function of the distal convoluted tubule is the reabsorption of NaCl. Active transport of Na+ occurs by the same fundamental mechanism in other nephron segments. Na+ enters the cell across the luminal membrane down an electrochemical potential gradient that is generated by the Na+,K+-ATPase in the basolateral membrane. This pump uses energy from the hydrolysis of ATP to drive Na+ from the cell in a ratio of three Na+ exiting for two K+ entering the cells.

As shown in Fig. 5, Na+ enters DCT cells across the luminal membrane by a mechanism that cotransports one Na+ and one CP, in contrast to the Na+/K+2Cl" cotransporter in the thick ascending limb. The Cl" that

FIGURE 5 Active NaCl reabsorption by DCT cells in the distal convoluted tubule. The unique transporters in the DCT cells are highlighted in color. NaCl entry across the luminal membrane is mediated by a thiazide-sensitive NaCl cotransporter. As in the thick ascending limb, Cl" leaves the cell primarily by selective channels in the basolateral membrane. There are K+ conductive channels in the luminal and basolateral membrane.

FIGURE 5 Active NaCl reabsorption by DCT cells in the distal convoluted tubule. The unique transporters in the DCT cells are highlighted in color. NaCl entry across the luminal membrane is mediated by a thiazide-sensitive NaCl cotransporter. As in the thick ascending limb, Cl" leaves the cell primarily by selective channels in the basolateral membrane. There are K+ conductive channels in the luminal and basolateral membrane.

enters the cell by this route exits the cell primarily by Cl"-selective channels in the basolateral membrane. The NaCl cotransporter has been cloned and sequenced, and it is different from the Na+/K+/2Cl" cotransporter in the thick ascending limb. This difference is also reflected by the fact that different diuretics selectively inhibit the two transporters. Whereas the Na+/K+/2Cl" cotransporter is inhibited by furosemide and other loop diuretics (see earlier discussion), the NaCl cotransporter is inhibited by thiazide diuretics such as hydrochlorothiazide. Because the thick ascending limb reabsorbs much more Na+ than the early distal convoluted tubule, the loop diuretics are more effective than the thiazide diuretics.

Because the luminal entry of Na+ in DCT cells is electroneutral, it does not depolarize the luminal membrane and, thus, the transepithelial voltage in the distal convoluted tubule is nearly zero. However, the voltage becomes progressively more lumen-negative as the transition to the connecting tubule is made. The luminal membrane of DCT cells also contains K+ channels of the type found in the thick ascending limb and in CNT and principal cells. These channels can mediate K+ secretion but probably only in the very late distal convoluted tubule where a rising lumen-negative transepithelial voltage provides the necessary driving force.

Ion Transport in the Aldosterone-Responsive Distal Nephron

The mechanisms involved in NaCl reabsorption and K+ secretion in CNT cells and principal cells, in the connecting tubule and collecting duct, are shown in Fig. 6. Na+ enters the cells via a Na+-selective channel (ENaC) in the luminal membrane and is pumped out of the cell by the Na+,K+-ATPase. The ENaC-mediated Na+ conductance of the luminal membrane causes it to be depolarized relative to the basolateral membrane and, thus, it gives rise to a lumen-negative transepithelial voltage. As discussed in the previous section, this lumen-negative transepithelial voltage is small at the end of the distal convoluted tubule but it can be as high as -50 mV in the connecting tubule and collecting duct.

The epithelial Na+ channel is highly selective to Na+ compared with K+, although it can also transport Li+. These channels can also be selectively blocked by the diuretics amiloride and triamterene. Because the ARDN reabsorbs less than 2% of the filtered load of Na+,

FIGURE 6 Na+ reabsorption and K+ secretion by CNT cells and principal cells. These cells are the majority cell type in, respectively, the connecting tubule and the collecting duct. Na+ enters both types of cells by ENaC. This channel can be selectively blocked by the diuretics amiloride and triamterene. The luminal membrane also contains K+ channels, but the predominance of Na+ channels depolarizes the luminal membrane and gives rise to the lumen-negative transepithelial voltage. The depolarization of the luminal membrane is a significant driving force for the preferential efflux of intracellular K+ across this membrane into the lumen. Thus K+ secretion results from K+ accumulation in the cell produced by the Na+,K+-ATPase and the favorable electrochemical potential gradient for movement from the cell to the lumen.

FIGURE 6 Na+ reabsorption and K+ secretion by CNT cells and principal cells. These cells are the majority cell type in, respectively, the connecting tubule and the collecting duct. Na+ enters both types of cells by ENaC. This channel can be selectively blocked by the diuretics amiloride and triamterene. The luminal membrane also contains K+ channels, but the predominance of Na+ channels depolarizes the luminal membrane and gives rise to the lumen-negative transepithelial voltage. The depolarization of the luminal membrane is a significant driving force for the preferential efflux of intracellular K+ across this membrane into the lumen. Thus K+ secretion results from K+ accumulation in the cell produced by the Na+,K+-ATPase and the favorable electrochemical potential gradient for movement from the cell to the lumen.

amiloride and triamterene are not nearly as potent in producing natriuresis (increased Na+ excretion) as the loop or thiazide diuretics. However, they are often used in combination with the latter diuretics because, as discussed later, they counteract the tendency of those diuretics to produce hypokalemia.

The high K+ concentration in CNT and principal cells favors the movement of K+ from the cells into the lumen. This movement occurs through another type of channel that is specific for K+ ions. The membrane potential opposes the movement of K+ out of the cell, because the cell is negative with respect to the lumen. However, because of the depolarization produced by Na+ channels in the luminal membrane, this voltage is lower than across most cell membranes. Thus, there is a net electrochemical driving force for the movement of K+ into the lumen. This results in secretion of K+ so that the tubular fluid K+ concentration can become much higher than in the plasma.

Two important factors favor increased secretion of K+. First, whenever fluid flow to the connecting tubule and collecting duct is increased, the secretion of K+ causes less of a rise in the luminal concentration because that secretion occurs into a larger volume flow. Thus, the amount of K+ secreted and finally excreted can be markedly increased by an increased flow out of the loop of Henle. Again, this is an illustration of the principle of mass flow: although the luminal K+ concentration is lower, its mass flow (the product of the tubular fluid K+ concentration and the volume flow rate) is greater. Second, the secretion of K+ is also increased when the delivery of Na+ to the connecting tubule and collecting duct is increased, because Na+ entry into the cell depolarizes the luminal membrane and makes the lumen more negative. Thus, when Na+ reabsorption is augmented, the more lumen-negative transepithelial voltage favors increased potassium secretion and excretion. These are important principles in considering the effects of diuretics on K+ balance (see Clinical Note).

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