The collecting duct consists of a series of subsegments. Following the connecting tubule, there is the initial cortical collecting tubule (segment prior to the confluence of multiple tubules), followed by the cortical collecting duct, the outer medullary collecting duct (divided into outer stripe and inner stripe segments), and the inner medullary or papillary collecting duct. In general, these segments are similar, but significant differences exist. Below we describe some of the general mechanisms responsible for transport of NaCl, and H +/HC03~. Where relevant we note differences between segments.
As shown in Fig. 9, NaCl absorption is mediated by electrogenic transcel-lular Na+ absorption with passive paracellular CI ~ diffusion. The basolateral membrane Na/K ATPase maintains low cell Na + concentrations which, along with the negative cell voltage, provides a favorable driving force for Na+ to enter the cell through apical Na+ channels. K+, which enters the cell on the Na/K ATPase recycles across the basolateral membrane. In the cortical collecting duct, a significant fraction of the K+ which enters the cell on the Na/K ATPase may also exit through an apical membrane K + channel (K + secretion; see below). Electrogenic Na+ absorption generates a lumen-negative voltage which provides an important and essential driving force for passive paracellular
Voltage -10 mV
FIGURE 9. Na+ transport in the principal cell of the cortical collecting duct. Electrogenic Na + absorption is mediated by an apical membrane Na+ channel. Na+ which enters the cell across the apical membrane channel exits the cell on the basolateral membrane Na/K ATPase. K + which enters the cell on the Na/K ATPase, exits on a basolateral or apical membrane K + channel. Electrogenic Na + absorption establishes a lumen negative voltage which drives a paracellular CI" absorptive current. Active transport mechanism; o, passive transporter; =, channel.
CI" absorption. In the cortical collecting duct and outer stripe of the outer medullary collecting duct, such electrogenic NaCl reabsorption is mediated by the principal cell. In the inner stripe of the outer medullary collecting duct, transcellular Na + transport rates are very low but increase again in the inner medullary collecting duct. In all of the above segments, the apical Na + channel is inhibited by low, micromolar concentrations of amiloride.
The nature of the apical membrane epithelial Na + channel has been studied using patch clamp techniques. Three types of epithelial Na+ channels have been found in the apical membrane of collecting duct cells. The first of these, found most frequently in patches from the cortical collecting duct apical membrane, has a single channel conductance of 4-5 pS, an open probability of 0.4, is highly Na+ selective with a PNa:PK > 10, has slow voltage-independent kinetics (long open and closed times), and is inhibited by amiloride. This highly Na + selective channel is the likely candidate for the major collecting duct Na + channel. The open probability of the channel is increased by cell hyperpolari-zation and by cell alkalinization.
Utilizing expression cloning in Xenopus oocytes, cDNAs encoding three sub-
units of this Na + channel have been identified. The first clone, referred to as arENaC (a subunit of rat epithelial Na+ channel) generates a small Na+ current when expressed in Xenopus oocytes. The characteristics of this current are identical to those described above for the epithelial Na + channel, with a conductance of 4.9 pS, long open and closed times, and high Na+ selectivity (PNa: PK > 20). Subsequently identified cDNAs, ySrENaC and -yrENaC, generate only minimal Na + currents when expressed alone or in combination. However, expression of ¡3 or y subunits with the a subunit increases the magnitude of the Na+ current. Finally, expression of a, ft, and y subunits together leads to expression of much larger Na + currents, a, (3, and -yrENaC are encoded by related genes which share approximately 35% amino acid identity. They also share a common structure with two membrane spanning domains and a large central extracellular domain that is heavily glycosylated and contains a cysteine rich sequence. Liddle's syndrome, a familial disease due to increased activity of the epithelial Na+ channel, has been shown to be associated with an activating mutation in /3rENaC or yrENaC. In addition, changes in dietary NaCl regulate the number of open rENaC channels.
In addition to the above channel, an 8-pS channel has been found with a PNa:PK of 5 (moderately Na+ selective) and a 28-pS channel with a PNa:PK of 1 (nonselective). This latter channel has been identified in patches from the apical membrane of inner medullary collecting duct cells. This 28-pS channel is inhibited by cyclic GMP and likely represents the ANP inhibitable channel of the inner medullary collecting duct. All three of the above channels are inhibited by amiloride.
In addition to electrogenic Na+ transport, some investigators have found thiazide-sensitive electroneutral NaCl absorption in the cortical collecting duct. The mechanisms responsible appear to be similar to those described above for the distal convoluted tubule and connecting tubule.
The cortical collecting duct is an important site for regulation of Na + transport (Table 3). Mineralocorticoid hormones increase the rate of Na+ transport significantly. This effect is mediated by several effects including stimulation of apical membrane Na+ channels, stimulation of the NaK ATPase, and stimulation of metabolic enzymes such as citrate synthase. It has been noted that increased activity of the apical membrane Na + conductance precedes the rise in Na/K ATPase activity. Spironolactone is a diuretic that inhibits Na + transport in
TABLE 3 Regulation of Collecting Duct Na + Absorption
Mineralocorticoid Vasopressin PGE-2 Bradykinin this segment by blocking mineralocorticoid receptors. Vasopressin has also been demonstrated to increase Na + transport and to activate apical membrane Na+ conductance, whereas both PGE-2 and bradykinin inhibit Na+ transport. Atrial natriuretic peptide inhibits Na + transport in the inner medullary collecting duct and in the rat cortical collecting duct. As described above, this effect is likely mediated by inhibition of the cyclic GMP regulated Na + channel. Amiloride and triamterene inhibit Na + absorption by blocking the apical membrane Na + channel.
In addition to NaCl absorption, the collecting duct is also an important site of urinary acidification. H "/HCO . transport in the initial cortical collecting tubule and cortical collecting duct is mediated by intercalated cells. These cells consist of two types. The type A intercalated cell, shown in Fig. 10, mediates H + secretion into the tubular fluid.
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