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Comparative Roles of the Renal Apical Sodium Transport Systems in Blood Pressure Control

INSERM U367, Paris, France.

Correspondence to Dr. Pierre Meneton, INSERM U367, 17 rue du Fer à Moulin, 75005 Paris, France. Phone: 33-1-45-87-61-13; Fax: 33-1-45-35-66-29; E-mail: pmeneton{at}infobiogen.fr

	Abstract

Top Abstract Introduction Amiloride-Sensitive ENaC Thiazide-Sensitive NCC Loop Diuretic-Sensitive NKCC2 Na+/H+ Exchanger 3 Conclusion References

 
Abstract. Human genetic studies suggest that the genes encoding renal apical Na⁺ transport proteins play an essential role in the control of extracellular fluid volume and BP. Mice with mutations in each of these genes provide the unique opportunity to directly assess their respective involvement in fluid homeostasis and BP control in vivo. Inactivation of either the epithelial Na⁺ channel (ENaC) or the Na⁺-Cl^- cotransporter decreases BP to the same extent in mice fed a low-salt diet, despite a more pronounced perturbation of fluid homeostasis in ENaC-deficient mice. In contrast, inactivation of Na⁺/H⁺ exchanger 3 (NHE3) or the Na⁺-K⁺-2Cl^- contransporter reduces BP with a normal-salt diet and renders mice unable to survive with a low-salt diet. Therefore, the general conception that ENaC in the collecting duct is the main renal controller of Na⁺ balance and extracellular fluid volume should be tempered. For example, NHE3 in the proximal convoluted tubule seems to play a more substantial role in the control of fluid homeostasis. The overall effect of NHE3 inacthvation on BP may also involve absorptive defects in the intestine and colon, where the exchanger normally reabsorbs significant amounts of Na⁺ and water.

	Introduction

Top Abstract Introduction Amiloride-Sensitive ENaC Thiazide-Sensitive NCC Loop Diuretic-Sensitive NKCC2 Na+/H+ Exchanger 3 Conclusion References

 
The regulation of arterial BP is very complex, with many intervening genetic and environmental factors. However, we know that BP is determined by cardiac output, which is influenced by extracellular fluid volume, and that the kidneys play a major role in the long-term control of this volume by matching urinary Na⁺ and water output to dietary intake (1). We also know that the other important parameter that determines BP level is the peripheral vascular resistance, which is continuously regulated by the arterioles to adjust blood flow to the metabolic needs of each tissue (2). Lastly, we know that the functions of the kidneys, heart, and blood vessels are tightly coordinated by multiple regulatory systems acting via endocrine or paracrine pathways (3). From a genetic viewpoint, we are also beginning to gain insights into the identity of the genes that confer to these organs the ability to control BP and insights into the functional gene interactions that determine BP levels. Using linkage studies and positional cloning in human subjects, a dozen genes responsible for monogenic forms of hypertension or hypotension or associated with essential hypertension have been identified to date (4). Remarkably, all of these genes either mediate or are involved in the regulation of renal Na⁺ transport. The analysis of gene-targeting experiments in mice furnishes even more striking evidence for the importance of renal Na⁺ handling in BP control. Among the approximately 2000 genes that have been inactivated to date by homologous recombination, approximately 30 genes (including the genes described as being involved in BP control in human subjects) for which inactivation triggers a chronic BP change in adult mice have been identified (Table 1). Two important observations can be made from this list. First, BP appears to be determined not by a few genes with preponderant actions but rather by a large number of genes, each with a relatively small effect. Second, the vast majority of these genes encode components of hormonal or paracrine systems that are known to participate in the regulation of renal Na⁺ reabsorption (5). Therefore, the currently available genetic data for both human subjects and mice strongly support the concept that regulation of extracellular fluid volume by the kidneys is the major long-term BP control mechanism, and they emphasize the crucial role of tubular Na⁺ transport in this process (1).

The reabsorption of Na⁺ along the nephron follows a general rule, i.e., Na⁺ entry across the apical membrane is the primary determinant of the intracellular Na⁺ concentration in epithelial cells. In turn, the intracellular Na⁺ concentration directly controls the activity of the Na⁺/K⁺-ATPase responsible for Na⁺ extrusion across the basolateral membrane (6). Therefore, apical Na⁺ entry is limiting for transepithelial Na⁺ and fluid transport, and any change in the quantity and/or activity of the proteins mediating this entry should affect the reabsorption rate. For this reason, fluid transport regulatory systems usually act primarily on these apical Na⁺ transport proteins. Four major apical Na⁺ transport systems are present along the nephron, each being expressed in a specific segment, as shown in Figure 1 (7). Na⁺/H⁺ exchanger 3 (NHE3) mediates bulk reabsorption of filtered Na⁺ in the proximal convoluted tubule. The Na⁺-K⁺-2Cl^- contransporter (NKCC2), located in the thick ascending limb of Henle's loop, reabsorbs much of the remaining luminal Na⁺ and participates in the establishment of the corticopapillary interstitial osmotic gradient necessary for urine concentration. The last few percent of filtered Na⁺ are reabsorbed by the Na⁺-Cl^- cotransporter (NCC) in the distal convoluted tubule and by the epithelial Na⁺ channel (ENaC) in the connecting tubule and collecting duct. The use of gene-targeting techniques has recently resulted in mouse models in which each of the genes encoding these proteins has been separately inactivated in a constitutive manner (8). By comparing the effects of these mutations on fluid homeostasis and BP and by analyzing the compensatory mechanisms, the functional roles of these apical Na⁺ transport systems and their integration into the physiologic processes and development of animals can be investigated. The goal is not to understand how these systems operate in the acute control of Na⁺ balance but rather to assess the effects of permanent perturbations of their function on extracellular fluid volume and BP. Indeed, it is likely that any relevant mutation or polymorphism involved in BP control is constitutive and does not arise from somatic genetic processes, given the low spontaneous mutation rate of DNA in mammals and the slow division rate of renal and cardiovascular cells (9).

View larger version (32K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Main apical Na+ transport proteins expressed along the nephron. The reabsorbed fractions of filtered Na+ and specific inhibitors used as diuretic agents are indicated for each transport system. The drawing (lower left) represents a more realistic view of the nephron surrounded by blood vessels.

	Amiloride-Sensitive ENaC

Top Abstract Introduction Amiloride-Sensitive ENaC Thiazide-Sensitive NCC Loop Diuretic-Sensitive NKCC2 Na+/H+ Exchanger 3 Conclusion References

 
ENaC is the primary target of diuretic agents such as amiloride and its derivatives, which selectively inhibit channel activity in the micromolar range (10). The channel is composed of three different subunits (, , and ), which form a tetrameric pore with a stoichiometry of 2:1:1 (11). and subunit mutations associated with functional defects of the channel have been identified in human subjects with pseudohypoaldosteronism type 1 and Liddle's syndrome (12). Similar inactivating or activating mutations induced in mice by homologous recombination have likewise been shown to reproduce the hypotension or hypertension phenotypes (see the article by Hummler and Beermann in this issue). ENaC also indirectly participates in hypertensive phenotypes (apparent minerlocorticoid excess syndrome and glucocorticoid-remediable aldosteronism) that are linked to mutations that alter the response to aldosterone or the production of mineralocorticoids, as demonstrated in human subjects and mice (13). Disruption of the -subunit gene by homologous recombination results in very low levels of mRNA and protein in the kidneys, lung, and colon of homozygous mutant mice (ENaC^-/-). With normal salt intake, the ENaC^-/- mice exhibit elevated plasma aldosterone levels and compensated metabolic acidosis, compared with wild-type mice, with no change in BP. When fed a low-salt diet, ENaC^-/- mice develop clinical symptoms of acute pseudohypoaldosteronism type 1, with weight loss, salt-wasting in the urine, hyperkalemia, and decreased BP, and are unable to survive more than a few weeks after the dietary switch (14). These data demonstrate that ENaC plays an important role in the control of BP through its ability to control the final urinary Na⁺ excretion rate along the connecting tubule and collecting duct.

	Thiazide-Sensitive NCC

Top Abstract Introduction Amiloride-Sensitive ENaC Thiazide-Sensitive NCC Loop Diuretic-Sensitive NKCC2 Na+/H+ Exchanger 3 Conclusion References

 
Mutations associated with putative loss of function have been found in the gene encoding NCC in patients with Gitelman's syndrome, an inherited hypokalemic alkalosis characterized by hypomagnesemia and hypocalciuria with normal or low BP and some evidence of salt-wasting or hypovolemia (12). NCC is selectively inhibited by thiazides, which are the most widely used diuretic agents for the treatment of essential hypertension (10). Mice lacking NCC (NCC^-/-) grow normally with a normal-salt diet and are indistinguishable from wild-type littermates with respect to urinary Na⁺ excretion and BP. However, these mutant mice demonstrate hypomagnesemia and hypocalciuria, compared with wild-type mice (15). The increased renal Ca²⁺ reabsorption that explains the low urinary Ca²⁺ level cannot occur in the first part of the distal convoluted tubule, which is almost completely absent in NCC^-/- mice. Because NCC normally reabsorbs approximately 7 to 10% of the filtered Na⁺ along the distal convoluted tubule, the loss of function of the transporter induces increased Na⁺ delivery to the connecting tubule and collecting duct. As an expected compensatory phenomenon, the amount of ENaC is upregulated in the apical membrane of principal cells along the connecting tubule (J. Loffing et al., manuscript in preparation). This adaptation is not observed in the collecting duct, suggesting that the upregulation of ENaC-mediated Na⁺ reabsorption in the connecting tubule is sufficient to compensate for NCC inactivation when mice are fed a normal-salt diet. Accordingly, plasma aldosterone levels are not chronically increased in NCC^-/- mice, although the renal renin mRNA level is elevated almost twofold. Another tubular adaptation seems to occur upstream of the distal convoluted tubule in the thick ascending limb of Henle's loop, where the amount of apical NKCC2 is increased approximately twofold. This upregulation of NKCC2 may reflect a more global adaptation of the thick ascending limb to increase Na⁺ as well as Ca²⁺ reabsorption. The compensatory phenomena that occur down-stream of the distal convoluted tubule may explain why NCC^-/- mice can thrive indefinitely on a low-salt diet, in contrast to ENaC^-/- mice. Nevertheless, with such a low-salt diet, NCC^-/- mice exhibit slightly decreased BP and elevated plasma aldosterone levels, compared with wild-type mice (15).

	Loop Diuretic-Sensitive NKCC2

Top Abstract Introduction Amiloride-Sensitive ENaC Thiazide-Sensitive NCC Loop Diuretic-Sensitive NKCC2 Na+/H+ Exchanger 3 Conclusion References

 
NKCC2 reabsorbs approximately 30% of the filtered Na⁺ load in the thick ascending limb of Henle's loop and is selectively inhibited by diuretic agents such as bumetanide and furosemide (10). Mutations in the gene encoding NKCC2 in human subjects have been shown to cause Bartter's syndrome, presumably by inducing a loss of function of the transporter (12). Patients with Bartter's syndrome exhibit, at an early age, severe urinary Na⁺ - and water-wasting associated with extracellular fluid volume depletion, hypokalemic metabolic alkalosis, and increased urinary Ca²⁺ excretion. Accordingly, NKCC2-deficient mice (NKCC2^-/-) exhibit signs of extracellular fluid volume depletion, such as increased hematocrit values, as early as 1 d after birth. At 7 d, NKCC2^-/- mice exhibit plasma renin activity 40 times higher than that of wild-type mice and develop profound renal disorganization, characterized by severe hydronephrosis, before dying approximately 1 wk later (16). For adult NKCC2^-/- mice that have been rescued by subcutaneous injection of indomethacin, 24-h urine volumes are increased almost 10-fold and urine osmolality is reduced 6-fold, compared with wild-type mice, indicating greatly impaired urine-concentrating ability. Urinary excretion of Ca²⁺ is also increased in NKCC2^-/- mice, as a result of the Na⁺ reabsorption defect in the thick ascending limb. As expected, considering the important Na⁺ - and water-wasting in urine, rescued NKCC2^-/- mice exhibit low BP when fed a normal-salt diet and are unable to survive with a low-salt diet (N. Takahashi et al., personal communication).

	Na+/H+ Exchanger 3

Top Abstract Introduction Amiloride-Sensitive ENaC Thiazide-Sensitive NCC Loop Diuretic-Sensitive NKCC2 Na+/H+ Exchanger 3 Conclusion References

 
Most of the filtered Na⁺ is reabsorbed in the proximal convoluted tubule, and NHE3 has been shown to be responsible for up to 60% of the Na⁺ reabsorption in this segment (17). Therefore, NHE3 would be predicted to exert major effects on the overall fluid and electrolyte balances and BP. In the absence of specific inhibitors or described mutations inducing a loss of function, the only available model for studying the role of NHE3 in vivo is NHE3-deficient mice generated by homologous recombination (18). Homozygous mutant mice (NHE3^-/-) grow similarly to wild-type mice with a normal-salt diet but exhibit marked perturbations of electrolyte and acid-base balances. The sharp reduction in fluid reabsorption in the proximal convoluted tubule overloads downstream segments of the nephron, which develop compensatory responses to limit Na⁺ - and water-wasting in the urine. Thus, ENaC activity in NHE3^-/- mice is upregulated in the connecting tubule and collecting duct, because of greatly increased plasma aldosterone levels. Increased sodium reabsorption, presumably mediated by NKCC2, can be also demonstrated in Henle's loop of NHE3^+/- mice (19). However, the main renal compensatory mechanism observed in NHE3^-/- mice is the decrease in the single-nephron GFR mediated in part by activation of the tubuloglomerular feedback loop, such that distal delivery of fluid to the distal nephron is not different between NHE3^-/- mice and wild-type mice (19). By adapting their single-nephron GFR, NHE3^-/- mice excrete even less Na⁺ and water daily in the urine, compared with wild-type mice. Despite these adaptations, which also include upregulation of renin mRNA levels, NHE3^-/- mice exhibit decreased BP when fed a normal-salt diet and are unable to survive with a low-salt diet. In addition to the renal consequences of NHE3 inactivation, some absorptive defects can be observed in the intestine of NHE3^-/- mice, where the exchanger normally mediates Na⁺ and water reabsorption in cooperation with the apical Cl^-/HCO₃ exchanger. NHE3^-/- mice exhibit diarrhea and marked increases (two-to fivefold) in the volume of the contents of all intestinal segments, despite a number of compensatory mechanisms that occur in the distal colon to limit fluid-wasting in the feces. For example, mRNA forms encoding ENaC and subunits are upregulated and transepithelial amiloride-sensitive Na⁺ current is sharply increased, as expected with the very high plasma aldosterone levels. The massive induction of colonic H⁺/K⁺-ATPase mRNA seems to be related to the recovery of K⁺, which is abnormally secreted into the lumen because of the increased electrogenic Na⁺ reabsorption (18). These data demonstrate that adult NHE3^-/- mice at steady state lose Na⁺ and water in the feces rather than in the urine, in comparison with wild-type mice.

	Conclusion

Top Abstract Introduction Amiloride-Sensitive ENaC Thiazide-Sensitive NCC Loop Diuretic-Sensitive NKCC2 Na+/H+ Exchanger 3 Conclusion References

 
With the development of gene-targeting techniques in mice (8), it has become possible to directly assess in vivo the roles of apical Na⁺ transport proteins expressed along the nephron in the control of extracellular fluid volume and BP. By comparison of the effects of individual inactivation of the four main apical Na⁺ transport systems, insight into how these different transport systems are functionally integrated in renal and whole-body physiologic processes can be gained. Analysis of the mutant phenotypes has already provided several interesting observations. The current conception among renal physiologists that long-term regulation of urinary Na⁺ output occurs primarily in the collecting duct should apparently be tempered, at least in the mouse (20). Indeed, a primary Na⁺ reabsorption defect in the collecting duct does not have a more significant effect on fluid homeostasis and BP than does a reabsorption defect in the thick ascending limb of Henle's loop or the proximal convoluted tubule. Clearly, the most detrimental mutation is the inactivation of NKCC2, which directly affects the countercurrent urine-concentrating mechanism and triggers profound disorganization of the renal tissue. Inactivation of NHE3 demonstrates that the proximal convoluted tubule also has a crucial role in the control of fluid homeostasis and BP. It is likely that the role of the proximal convoluted tubule in controlling urinary Na⁺ output has been largely underestimated, in favor of the role of the collecting duct, despite the fact that the proximal convoluted tubule has been shown to be a target of numerous endocrine and paracrine regulatory factors (21). Part of the overall effect of NHE3 inactivation may be also related to absorptive defects in the intestine, where the exchanger normally mediates Na⁺ reabsorption (22). Given the relatively small intestinal contribution to the Na⁺ balance, compared with the renal contribution, the kidneys should be able to easily correct any intestinal reabsorption defect, to maintain fluid homeostasis. However, the mutation alters both renal and intestinal function in NHE3^-/- mice, and it is possible that the kidneys, which must compensate for their own dysfunction, cannot properly handle the intestinal defects. The same phenomenon may occur to a lesser extent in ENaC^-/- mice, because the channel is expressed in the colon.

Further investigations of the role of apical Na⁺ transport systems should include interbreeding of mutant mouse strains to assess additive or synergistic relationships among the segments of the nephron, with respect to their abilities to affect the Na⁺ balance and BP. Tissue-specific gene inactivation should allow clarification of the role of fecal Na⁺ - and water-wasting in overall fluid homeostasis in cases where the genes are expressed in both the intestine and the kidneys. Finally, similar comparisons of the roles of apical sodium transport systems should be undertaken, using activating mutations to study their potential involvement in hypertension (23).

	Acknowledgments

 
I thank Gary E. Shull, François Alhenc-Gelas, and Brigitte Kaissling for the work conducted in their laboratories. Part of the work presented was supported by National Institues of Health Grants DK50594, HL41496, DK39626, and DK48816 and by INSERM.

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Top Abstract Introduction Amiloride-Sensitive ENaC Thiazide-Sensitive NCC Loop Diuretic-Sensitive NKCC2 Na+/H+ Exchanger 3 Conclusion References

 

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