INVITED REVIEW
Divalent cation transport by the distal nephron: insights from Bartter's and Gitelman's syndromes

David H. Ellison

Division of Nephrology and Hypertension, University of Colorado School of Medicine and Veterans Affairs Medical Center, Denver, Colorado 80220


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
CALCIUM HOMEOSTASIS
MAGNESIUM HOMEOSTASIS
REFERENCES

Elucidation of the gene defects responsible for many disorders of renal fluid and electrolyte homeostasis has provided new insights into normal and abnormal physiology. Identifying the causes of Gitelman's and Bartter's syndromes has greatly enhanced our understanding of ion transport by thick ascending limb and distal convoluted tubule cells. Despite this information, several phenotypic features of these diseases remain confusing, even in the face of molecular insight. Paramount among these are disorders of divalent cation homeostasis. Bartter's syndrome is caused by dysfunction of thick ascending limb cells. It is associated with calcium wasting, but magnesium wasting is usually mild. Loop diuretics, which inhibit ion transport by thick ascending limb cells, markedly increase urinary excretion of both calcium and magnesium. In contrast, Gitelman's syndrome is caused by dysfunction of the distal convoluted tubule. Hypocalciuria and hypomagnesemia are universal parts of this disorder. Yet although thiazide diuretics, which inhibit ion transport by distal convoluted tubule cells, reduce urinary calcium excretion, they have minimal effects on urinary magnesium excretion, when given acutely. This review proposes mechanisms that may account for the differences between the effects of diuretic drugs and the phenotypic features of Gitelman's and Bartter's syndromes. These mechanisms are based on recent insights from another inherited disease of ion transport, inherited magnesium wasting, and from a review of the chronic effects of diuretic drugs in animals and people.

kidney tubules; distal; loop of Henle; calcium; magnesium; thiazide; thiazide-sensitive sodium-chloride cotransporter; bumetanide-sensitive sodium-potassium-2 chloride cotransporter; diuretics; aldosterone; sodium; chloride; voltage; heart failure


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
CALCIUM HOMEOSTASIS
MAGNESIUM HOMEOSTASIS
REFERENCES

MANY OF THE DOMINANT SOLUTE transport pathways in the mammalian kidney have been identified at the molecular level during the past 10 years. Building on this information, it became possible to investigate specific solute transport proteins as candidate genes for inherited disorders of renal electrolyte homeostasis. Among the most illuminating advances was the demonstration that Bartter's and Gitelman's syndromes result from mutation of specific ion transport proteins expressed by cells of the distal nephron (60, 76, 88, 90-93, 95, 96, 98, 104). Many previously confusing phenotypic features of these disorders can now be understood on the basis of knowledge of the molecular genetics of these syndromes. For example, dysfunction of Na transporters [the thiazide-sensitive Na-Cl cotransporter (NCC, TSC, or NCCT) in Gitelman's syndrome and the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2 or BSC1) in Bartter's syndrome] would be predicted to cause salt wasting and extracellular fluid volume depletion, secondary hyperaldosteronism, and hypokalemia. All of these phenotypic features are observed in these clinical syndromes. Yet, despite a clear understanding of the molecular causes of these disorders, the pathogenesis of other phenotypic features continues to confuse. This review will merge recent insights from molecular genetics and molecular anatomy with insights from more traditional disciplines in an attempt to clarify the physiological basis of Gitelman's and Bartter's syndromes. Because other reviews have described the pathogenesis of extracellular fluid volume depletion and hypokalemia (40, 57, 85, 95), this review will emphasize alterations in divalent ion homeostasis, because this has remained a subject of special confusion.

Patients with both Bartter's and Gitelman's syndromes typically present with hypokalemic metabolic alkalosis and a normal to low blood pressure (94). For many years, this common phenotype led to confusion about the discrete nature of these distinct disorders. Several investigators suggested that distinct phenotypes of Bartter's syndrome could be discerned (78, 102). Bettinelli (3) clarified the nature of the two distinct syndromes. One is now called Bartter's syndrome and includes hypokalemic alkalosis and normal to low blood pressure. These patients often present at a young age and may have polyuria. Many have hypercalciuria, which can cause nephrocalcinosis. The other phenotype is now called Gitelman's syndrome. It also includes hypokalemic alkalosis with normal to low blood pressure, but these patients tend to present at an older age and the disease is often milder. The phenotypic signature of Gitelman's syndrome, however, is hypocalciuria and hypomagnesemia. Bartter's syndrome has been linked to mutations in three ion transport proteins, but all of the recognized causes affect a final common pathway that participates in ion transport by thick ascending limb cells (88, 90-92, 96, 104). The first genetic cause to be identified involved mutation in the apical form of NKCC2 (90). Later, mutations in a K channel (ROMK) (91) and in a basolateral Cl channel (CCLNKB) (88) were shown to be linked to the disease in some patients. On the basis of our understanding of mechanisms of NaCl transport by thick ascending limb cells, dysfunction of any of these proteins would be predicted to impair transepithelial NaCl transport, leading to salt wasting and extracellular fluid volume contraction. Several other phenotypic features can now be explained on the basis of knowledge of the molecular pathogenesis. First, it is clear that macula densa cells, cells that control renin secretion (7, 49, 110), express the transport proteins that are mutated in patients with Bartter's syndrome (70). Inasmuch as entry of Na and Cl into macula densa cells inhibits renin secretion (99), the genetic absence of Na and Cl transport pathways in macula densa cells probably accounts for the extreme elevations in plasma renin activity that occur in this disorder and for the juxtaglomerular hypertrophy with which this disease is associated (37). Second, the hypokalemia that occurs in patients with Bartter's syndrome probably results from both a decrease in K reabsorption along the thick ascending limb and an increase in K secretion by cells of the late distal tubule and collecting duct, owing to the combination of high serum aldosterone and high distal flow rate (109).

To date, Gitelman's syndrome appears to be molecularly homogeneous. The only identified cause of this disorder involves mutation in the NCC (59, 66, 98, 103). We have shown that many of the mutations that cause Gitelman's syndrome generate proteins that are functionally inactive when expressed in Xenopus laevis oocytes (55). Most of the mutant proteins are processed (or folded) abnormally, probably activating the "quality control" system of the endoplasmic reticulum. These misprocessed proteins appear to be degraded without reaching the plasma membrane. Dysfunction of this transport protein would be expected to lead to salt wasting, depletion of the extracellular fluid volume, and stimulation of the renin-angiotensin-aldosterone system. This would be predicted to cause hypokalemia by stimulating K secretion along the distal tubule and collecting duct. As would be expected on the basis of the comparative transport capacities of the loop of Henle and distal tubule, Bartter's syndrome is a more severe disorder than is Gitelman's syndrome. Bartter's syndrome typically presents at a younger age, often as failure to thrive, whereas Gitelman's syndrome is often only mildly symptomatic (4, 5 98). Yet, hypokalemia may be severe in patients with Gitelman's syndrome. Although increases in circulating aldosterone, induced by extracellular fluid volume contraction, contribute to the K wasting, the elevation of aldosterone is usually milder than in Bartter's syndrome and other factors may contribute. First, hypomagnesemia predisposes to hypokalemia; correction of hypomagnesemia was shown to reduce or correct renal potassium wasting in patients with Gitelman's syndrome (48). Second, the low luminal calcium concentration along the distal convoluted tubule (DCT) that occurs in Gitelman's syndrome may predispose patients to potassium wasting, because luminal calcium blocks Na channels and inhibits K secretion by the distal tubule (47, 71).


    CALCIUM HOMEOSTASIS
TOP
ABSTRACT
INTRODUCTION
CALCIUM HOMEOSTASIS
MAGNESIUM HOMEOSTASIS
REFERENCES

A major phenotypic difference between Bartter's and Gitelman's syndromes involves urinary calcium excretion. The hypercalciuria of Bartter's syndrome is believed to result largely from dysfunction of thick ascending limb cells. Figure 1 summarizes sites of calcium, magnesium, and sodium reabsorption along the nephron in normal individuals. As shown in Fig. 2, calcium absorption along the loop of Henle is largely passive, paracellular, and driven by the lumen-positive transepithelial voltage that is generated by Na-K-2Cl cotransport and luminal K recycling (38, 39). When Na-K-2Cl cotransport is reduced or blocked by loop diuretics or genetic abnormality, the lumen-positive voltage declines or approaches zero (10). For this reason, calcium reabsorption declines (11). Although this mechanism undoubtedly contributes to calcium wasting, another cause may also contribute. As will be discussed in more detail below, rates of Na and calcium transport by distal tubules tend to correlate inversely (16-19, 33). Because dysfunction of the thick ascending limb increases distal NaCl delivery (32, 46), and because distal NaCl transport is load dependent (31, 50), NaCl transport by DCT cells will be increased in patients with Bartter's syndrome (see Fig. 2). This situation resembles that observed during chronic loop diuretic administration (32, 100). Increased cellular Na and Cl entry raises the intracellular Cl activity of DCT cells, which would be predicted to deplolarize them,1 inhibiting the apical calcium channel (36, 43). This would be predicted to impair distal calcium reabsorption, providing a distal contribution to calcium wasting and nephrolithiasis.


View larger version (23K):
[in this window]
[in a new window]
 
Fig. 1.   Summary of segmental magnesium, calcium, and sodium reabsorption along the nephron. From Quamme, GA. Renal magnesium handling: new insights in understanding old problems. Kidney Int 52: 1180-1195, 1997. Used with permission.



View larger version (92K):
[in this window]
[in a new window]
 
Fig. 2.   Pathogenesis of Bartter's syndrome. A: a normal thick ascending limb (TAL) and distal convoluted tubule (DCT). A representative cell is shown in each segment. Note that the luminal voltage of the TAL is positive and the DCT voltage is near to 0 mV. In the figure, calcium and magnesium are shown traversing the same paracellular pathway. In patients with Bartter's syndrome (B) or during loop diuretic treatment, NaCl transport is inhibited along the TAL. This reduces the transepithelial voltage to near 0, reducing magnesium and calcium absorption, secondarily. It also increases distal delivery of Na, K, Cl, Ca, and Mg. This leads to hypertrophy of the DCT and increases in NaCl transport. This reduces Ca absorption, according to mechanisms described in the text.

In contrast to patients with Bartter's syndrome, patients with Gitelman's syndrome invariably demonstrate hypocalciuria (89).The hypocalciuria resembles the clinically useful effect of DCT diuretics (thiazides and others) to reduce urinary calcium excretion (35). The mechanisms of hypocalciuria in Gitelman's syndrome are now reasonably well established (see Fig. 3). First, mild contraction of the extracellular fluid volume will increase calcium reabsorption along the proximal tubule (18). Second, the reduction in NaCl entry into DCT cells stimulates transepithelial calcium transport. When apical Na and Cl entry into DCT cells is inhibited, because of either diuretic treatment or genetic disease, the intracellular Cl concentration declines. As noted above, a lower intracellular Cl activity hyperpolarizes the cell. Friedman and colleagues (36) showed that hyperpolarization activates a distinctive calcium channel that is expressed by DCT cells. Thus hyperpolarization increases apical calcium entry. Proteins cloned by Bindels and colleagues (42) (ECaC) and Peng and colleagues (72a) (CaT2) may be apical calcium channels of the distal nephron (43). Direct measurements of calcium current through these channels, however, have not been reported, and it is not known whether their open probability is affected by membrane voltage. In contrast, a distal tubule calcium channel studied by Matsunaga and colleagues (67) does demonstrate increased open probability during membrane hyperpolarization. Another difference between the cloned channels and the channels studied by Matsunaga and colleagues involves sensitivity to dihydropiridines. Dihydropiridines have little effect on ECaC and CaT2 (42), whereas they are strongly inhibitory of the distal tubule channels described by Matsunaga and colleagues (67).


View larger version (99K):
[in this window]
[in a new window]
 
Fig. 3.   Pathogenesis of Gitelman's syndrome. A: DCT cells of the type 1 and type 2 variety (DCT1 and DCT2; see text for details). Under normal conditions, Na and Cl are absorbed electroneutrally by both cell types. When Gitelman's syndrome occurs, the thiazide-sensitive Na-Cl transporter is misprocessed and does not appear at the plasma membrane. Cellular chloride concentrations decline, hyperpolarizing the cell. This activates the apical amiloride-sensitive calcium channel, ECaC. In addition, the absence of electroneutral pathways for Na transport in this aldosterone (Aldo)-sensitive epithelium leads to an increase in the transepithelial voltage, which favors paracellular magnesium secretion via paracellin-1. Other secretory pathways for magnesium may also contribute.

For the increase in apical calcium entry to result in increases in transepithelial calcium transport, calcium movement from lumen to cell must be balanced by calcium movement from cell to interstitium and blood. The increase in cellular calcium consequent to increased luminal calcium entry will stimulate calcium efflux via the basolateral Na/Ca exchanger and the Ca-ATPase (84), but other factors contribute as well. First, inhibition or absence of apical NaCl entry reduces the intracellular Na activity. This stimulates 3Na/Ca exchange. Second, the hyperpolarization, noted above stimulates Na/Ca exchange because this transport protein operates in an electrogenic mode, carrying 3Na ions into the cell for each calcium ion extruded.


    MAGNESIUM HOMEOSTASIS
TOP
ABSTRACT
INTRODUCTION
CALCIUM HOMEOSTASIS
MAGNESIUM HOMEOSTASIS
REFERENCES

Whereas the pathogenesis of calcium disorders in Bartter's and Gitelman's syndromes appears relatively clear, the pathogenesis of magnesium disorders is more confusing. Gitelman's syndrome is associated with severe hypomagnesemia, whereas Bartter's syndrome is not (89). This is surprising because more magnesium is reabsorbed along the loop of Henle than along the distal tubule (80, 85) and because DCT diuretics induce less magnesium wasting, when given acutely, than do loop diuretics (25, 26, 29). Recent insights from molecular genetics, molecular anatomy, and a review of earlier physiological studies, however, shed light on this issue and present the potential to resolve some conflicts.

Simon and colleagues (97) recently used positional cloning to identify a cause of inherited magnesium wasting. They found that mutations in a novel protein, called paracellin-1, cause the disease. Immunocytochemical studies and studies using nephron-segment RT-PCR indicate that paracellin-1 is expressed predominantly in tight junctions along the thick ascending limb. Furthermore, the molecular characteristics of this protein suggest that it may be a paracellular conductive pathway for magnesium. Several insights come directly from this observation. First, it provides a molecular explanation for the previously established behavior of magnesium along the loop of Henle, where transport is driven by the lumen-positive transepithelial voltage (80). Loop diuretics such as furosemide increase urinary magnesium excretion by reducing the lumen-positive voltage and thereby the electrical gradient favoring reabsorption. This identifies a molecular component that may contribute to the magnesium wasting that sometimes accompanies Bartter's syndrome.

As mentioned, however, magnesium wasting is much more severe in Gitelman's syndrome than in Bartter's syndrome. Scheinman and colleagues (85) suggested that the magnesium wasting of Gitelman's syndrome is "determined by the balance of hormonal effects and intracellular potassium stores in the distal convoluted tubule" (85). They suggested that higher aldosterone concentrations in Bartter's patients may attenuate magnesium wasting, whereas the effects of hypokalemia predominate in patients with Gitelman's syndrome. That hypokalemia is central to the pathogenesis of magnesium wasting in Gitelman's patients is disputed by results of gene-knockout experiments. Schultheis and colleagues (87) showed that NCC-knockout mice develop hypocalciuria and hypomagnesemia. Surprisingly, these mice are normokalemic. Although the reason that NCC knockout does not cause hypokalemia in mice (whereas Gitelman's syndrome is associated with hypokalemia in humans) is not clear, the results clearly indicate that hypokalemia is not required for magnesium wasting to occur in animals that lack NCC activity. This motivates the search for other mechanisms.

One piece of data that has become available recently involves potential mechanisms of magnesium transport along the DCT. Interestingly, whereas paracellin-1 was shown to be expressed along the thick ascending limb, where its function is clear, it was also reported to be expressed along the DCT (97) (see Fig. 4). The function of paracellin-1 in this segment was not addressed by the authors, but this pattern of paracellin-1 expression is consistent with the low rate of magnesium transport that normally occurs along the DCT (80). The transepithelial voltage along the DCT is normally very low. It is near 0 mV at the proximal end and becomes only slightly lumen negative at its distal end (83). Because the luminal magnesium concentration is normally slightly below interstitial in fluid entering the distal tubule [TF/UF = 0.6 (82), where TF/UF is the tubule fluid-to-ultrafilterable ratio], and because the electrical gradient is near to zero at this site, little paracellular magnesium transport should occur, even though the paracellular pathway is potentially magnesium permeable. Calcium may also traverse paracellin-1, on the basis of the observation that patients with congenital magnesium wasting are also hypercalciuric (77). This pathway, however, is not the major route of transepithelial calcium transport along the DCT because this segment rapidly absorbs calcium even though the electrochemical gradient favors calcium secretion (20). This results from rapid calcium reabsorption via the apical ECaC (34, 42).


View larger version (45K):
[in this window]
[in a new window]
 
Fig. 4.   Localization of ion transport proteins along the distal tubule. Sites include the TAL, DCT (first and second segments, DCT1 and DCT2), connecting tubule (CNT), and cortical collecting duct (CCD). The glomerulus is shown (G) touching the macula densa. Sites of protein expression are shown [bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2); thiazide-sensitive Na-Cl cotransporter (NCC); paracellin-1; ENaC; epithelial calcium channel (ECaC); sodium calcium exchanger (Na/Ca)].

The possible presence of paracellin-1 along the DCT suggests that paracellular magnesium transport might occur along this segment. Earlier studies do provide evidence that magnesium secretion can occur along the distal tubule and collecting duct. The tubule fluid-to-ultrafilterable ratio of magnesium has been observed to rise along the length of the accessible distal tubule (8, 9, 79, 81, 82). Furthermore, several studies suggest that magnesium secretion may occur along the collecting duct, at least under certain conditions (8, 56, 58). Although this secretion may traverse paracellin-1, it may traverse other pathways as well. Regardless of the route by which magnesium secretion may occur, these data suggest an alternative hypothesis for the profound magnesium wasting of Gitelman's syndrome. To generate such an hypothesis, however, it is useful to consider additional anatomic and molecular information that has become available recently. During the past several years, the molecular anatomy of the mammalian distal tubule has been clarified (see Fig. 4 and Ref. 83). Shortly beyond the region of the macula densa, cortical thick ascending limb cells change abruptly to become DCT cells. Further distally, at a point >50% of the distance from the macula densa to the cortical collecting duct (CCD), the epithelium changes again to comprise connecting tubule (CNT) cells (24). Finally, just before the junction with another nephron, the epithelium changes again to comprise CCD (also called "principal") cells (52). In rabbits, each of these transitions is abrupt, but in rodents and humans the transitions from DCT to CNT and CNT to CCD are gradual. This anatomic arrangement can now be juxtaposed with the molecular organization of transport pathways along the distal tubule. In all species studied to date, including rat (69, 75, 111), mouse (63), rabbit (1, 106), and human (69), the NCC is expressed predominantly, if not exclusively, by DCT cells. The beta - and gamma -subunits of the endothelial Na channel, ENaC, are expressed conversely by CCD and CNT cells (27, 86, 107) of all species [expression of the alpha -subunit of ENaC may be more widespread (14)]. In rat, mouse, and probably human, however, the DCT comprises two distinct subsegments, DCT1 and DCT2 (62, 63, 69). The DCT1 expresses the NCC as its predominant apical Na entry pathway [it may also express type 2 Na/H exchanger (12)]. The DCT2 expresses both the NCC and the epithelial Na channel, ENaC, at it apical membrane (30, 62, 63, 69). The DCT2 also expresses 11beta -hydroxysteroid dehydrogenase, the mineralocorticoid receptor (6), and the Na/Ca exchanger (69).

Another piece of important information comes from observations about effects of aldosterone on magnesium handling. States of aldosterone excess are frequently associated with magnesium wasting, and states of aldosterone deficiency, such as Addison's disease, are associated with hypermagnesemia (45). Experiments designed to discern an acute effect of aldosterone on magnesium excretion have been contradictory. Most of the effects of aldosterone administration on magnesium excretion have been attributable to secondary extracellular fluid volume expansion (64, 65). Yet the aldosterone antagonist spironolactone has consistently shown the ability to reduce urinary magnesium excretion (2, 28, 101), an effect that can be dissociated from changes in filtered load (68). In a series of patients with Gitelman's syndrome, spironolactone reduced fractional magnesium excretion from 6.5 to 3.0% (15). Spironolactone has also been shown to increase serum magnesium and reduce urinary magnesium in normal individuals (68), in patients with primary aldosteronism (45), in patients with cirrhotic ascites (101), and in patients with hypertension. In view of the fact that spironolactone reduces urinary magnesium excretion in the setting of expanded or contracted extracellular fluid volume, it seems likely that aldostorone has direct effects on magnesium transport. The observation that acute aldosterone infusion has very little effect on renal magnesium handling and yet spironolactone reduces urinary magnesium excretion is one of several paradoxes concerning magnesium homeostasis. These are presented in Table 1 and must be resolved to understand mechanisms of renal magnesium homeostasis.

                              
View this table:
[in this window]
[in a new window]
 
Table 1.   Paradoxes of magnesium homeostasis in Gitelman's and Bartter's syndromes

The information discussed above can be used to construct an hypothesis to explain the magnesium wasting of Gitelman's syndrome that resolves some the paradoxes listed in Table 1. Gitelman's syndrome is caused by dysfunction of the NCC (87). Dysfunction of the NCC in DCT2 cells converts them from cells that transport Na predominantly coupled to chloride in an electroneutral manner to cells that transport Na predominantly alone, via electrogenic pathways (via ENaC). If this is the case, then one might predict that DCT diuretics would increase the magnitude of the transepithelial voltage in the distal tubule. Surprisingly, when DCT diuretics have been perfused into DCT segments in vivo, the transepithelial voltage has not increased (20). Under similar conditions, luminal perfusion of DCT diuretics does not increase K secretion (108). Yet, these drugs clearly cause K wasting when used chronically. The reason that chronic systemic DCT diuretics administration causes potassium and magnesium wasting is probably related to the interaction between transport inhibition and aldosterone. As noted above, cells of the DCT are aldosterone responsive (6, 105). Yet, aldosterone normally stimulates the NCC in DCT cells (13, 51, 105). This leads to an increase in Na transport but does not change the transepithelial voltage (41). In contrast, when electroneutral apical entry pathways are knocked out or dysfunctional, aldosterone would be expected to increase the magnitude of the lumen-negative transepithelial voltage, because some DCT cells express ENaC (61-63, 83). Thus knocking out or blocking the NCC generates an aldosterone-sensitive segment that absorbs Na in an electrogenic manner and may expresses paracellin-1 (see Fig. 3). The resulting large, lumen-negative transepithelial voltage should strongly favor magnesium (and potassium) secretion.

This hypothesis predicts that DCT diuretics should also lead to magnesium wasting. Although data on acute effects of DCT diuretics on magnesium excretion tend to suggest little effect (25), their chronic use is clearly associated with changes in magnesium balance. In the Multiple Risk Factor Intervention Trial, DCT diuretics were shown to have a small but measurable effect on plasma magnesium (53), a finding that usually indicates severe magnesium depletion. In other studies, DCT diuretics led to small but reproducible reductions in serum magnesium concentration (44). Recall, however, that in this, as in most recent trials of the antihypertensive effect of DCT diuretics, the dose was limited and given once per day. Such low doses do not deplete the extracellular fluid volume enough to strongly stimulate aldosterone secretion. Like the side effect hypokalemia, the side effect hypomagnesemia is strongly dose related (72).

Recent molecular information also helps to resolve another paradox of magnesium homeostasis (Table 1). Magnesium uptake into mouse DCT cells grown in culture was shown to be enhanced by thiazide diuretics (21) and by amiloride (22). In animals and humans, these drugs have opposite effects on renal magnesium handling (15, 44). Furthermore, although aldosterone alone does not affect magnesium transport in mouse DCT cells, it potentiates the effects of antidiuretic hormone and glucagon to stimulate magnesium uptake (23). In humans, this hormone tends to cause magnesium wasting, as discussed above. One explanation for these discrepancies is that the mouse DCT cells used to study magnesium uptake are not polarized and do not have tight junctions (74). Thus studies of magnesium uptake into these cells may not mimic effects of physiological perturbations in vivo, where paracellular effects may predominate and paracellin-1 expression plays a vital role. This is in contrast to effects on calcium transport by the DCT, where transcellular transport pathways clearly predominate. Thus the effects of perturbations on calcium transport by DCT cells in vitro closely mimic effects observed in vivo (33).

Many of the concepts reviewed in this paper remain speculative. Even if magnesium secretion does occur along the distal tubule and collecting duct, it may traverse pathways that are independent of paracellin-1. Yet, on the basis of recent molecular insights, it has become increasingly possible to resolve the paradoxes cited above and to construct hypotheses that do fit available data. Understanding magnesium and calcium homeostasis is of more than scientific interest. Disorders of magnesium balance may contribute importantly to patient morbidity in congestive heart failure and even hypertension. In fact, interventions that improve magnesium balance in patients with congestive heart failure (spironolactone) reduce cardiac ectopy (2) and prolong life (73).


    ACKNOWLEDGEMENTS

The author thanks Professor Sebastian Bachmann, Heino Velázquez Ph.D., and Dr. Robert Reilly for continuing collaborations and advice.


    FOOTNOTES

Work in the author's laboratory is supported by grants from the National Institutes of Health Grants RO1 DK-51496 and P50 HL-55007 and the Department of Veterans Affairs.

Present address and address for reprint requests and other correspondence: D. H. Ellison, Div. of Nephrology, 3314 SW US Veterans Hospital Rd. Suite PP262, Portland, OR 97201-2940 (E-mail: EllisonD{at}OHSU.edu).

1  DCT cells express both K channels and Cl channels at their basolateral cell membranes. The voltage across this membrane, therefore, is determined by the relative permeabilities of the two ions and by their concentration gradients Delta V=(RT/F) ln[(PKcKo+PClcCli)/(PKcKi+PClcClo)]. If one assumes that the relative permeabilities of the DCT basolateral membrane to K and Cl are 0.7 and 0.3 (112), and that the concentrations are Ko 4, Ki 80, Clo 100, Cli 15 mM, then raising intracellular chloride by 10 mM should depolarize the membrane by approximately 10 mV.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
CALCIUM HOMEOSTASIS
MAGNESIUM HOMEOSTASIS
REFERENCES

1.   Bachmann, S, Velázquez H, Obermüller N, Reilly RF, Moser D, and Ellison DH. Expression of the thiazide-sensitive Na-Cl cotransporter by rabbit distal convoluted tubule cells. J Clin Invest 96: 2510-2514, 1995[ISI][Medline].

2.   Barr, CS, Lang CC, Hanson J, Arnott M, Kennedy N, and Struthers AD. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol 76: 1259-1265, 1995[ISI][Medline].

3.   Bettinelli, A. Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. J Pediatr 120: 38-43, 1992[ISI][Medline].

4.   Bettinelli, A, Bianchetti MG, Borella P, Volpini E, Metta MG, Basilico E, Selicorni A, Bargellini A, and Grassi MR. Genetic heterogeneity in tubular hypomagnesemia-hypokalemia with hypocalcuria (Gitelman's syndrome). Kidney Int 47: 547-551, 1995[ISI][Medline].

5.   Bettinelli, A, Vezzoli G, Colussi G, Bianchetti MG, Sereni F, and Casari G. Genotype-phenotype correlations in normotensive patients with primary renal tubular hypokalemic metabolic alkalosis. J Nephrol 11: 61-69, 1998[ISI][Medline].

6.   Bostanjoglo, M, Reeves WB, Reilly RF, Velázquez H, Robertson N, Litwack G, Morsing P, JDørup Bachmann S, and Ellison DH. 11beta -hydroxysteroid dehydrogenase, mineralocorticoid receptor and thiazide-sensitive Na-Cl cotransporter expression by distal tubules. J Am Soc Nephrol 9: 1347-1358, 1998[Abstract].

7.   Briggs, JP, and Schnermann J. Macula densa control of renin secretion and glomerular vascular tone: evidence for common cellular mechanisms. Renal Physiol 9: 193-203, 1986[ISI][Medline].

8.   Brunette, MG, Vigneault N, and Carriere S. Micropuncture study of magnesium transport along the nephron in the young rat. Am J Physiol 227: 891-896, 1974[ISI][Medline].

9.   Brunette, MG, Vigneault N, and Carriere S. Micropuncture study of renal magnesium transport in magnesium-loaded rats. Am J Physiol 229: 1695-1701, 1975[ISI][Medline].

10.   Burg, MB. Tubular chloride transport and the mode of action of some diuretics. Kidney Int 9: 189-197, 1976[ISI][Medline].

11.   Burg, MB, Stoner L, Cardinal J, and Green N. Furosemide effect on isolated perfused tubules. Am J Physiol 225: 119-124, 1973[ISI][Medline].

12.   Chambrey, R, Warnock DG, Podevin RA, Bruneval P, Mandet C, Belair MF, Bariety J, and Paillard M. Immunolocalization of the Na+/H+ exchanger isoform NHE2 in rat kidney. Am J Physiol Renal Physiol 275: F379-F386, 1998[Abstract/Free Full Text].

13.   Chen, Z, Vaughn DA, Blakeley P, and Fanestil DD. Adrenocortical steroids increase renal thiazide diuretic receptor density and response. J Am Soc Nephrol 5: 1361-1368, 1994[Abstract].

14.   Ciampolillo, F, McCoy DE, Green RB, Karlson KH, Dagenais A, Molday RS, and Stanton BA. Cell-specific expression of amiloride-sensitive Na+-conducting ion channels in the kidney. Am J Physiol Cell Physiol 271: C1303-C1315, 1996[Abstract/Free Full Text].

15.   Colussi, G, Rombola G, De Ferrari ME, Macaluso M, and Minetti L. Correction of hypokalemia with antialdosterone therapy in Gitelman's syndrome. Am J Nephrol 14: 127-135, 1994[ISI][Medline].

16.   Costanzo, LS. Comparison of calcium and sodium transport in early and late rat distal tubules: effect of amiloride. Am J Physiol Renal Fluid Electrolyte Physiol 246: F937-F945, 1984[Abstract/Free Full Text].

17.   Costanzo, LS. Localization of diuretic action in microperfused rat distal tubules: Ca and Na transport. Am J Physiol Renal Fluid Electrolyte Physiol 248: F527-F535, 1985[ISI][Medline].

18.   Costanzo, LS, and Weiner IM. On the hypocalciuric action of chlorothiazide. J Clin Invest 54: 628-637, 1974[ISI][Medline].

19.   Costanzo, LS, and Weiner IM. Relationship between clearances of Ca and Na: effect of distal diuretics and PTH. Am J Physiol 230: 67-73, 1976[ISI][Medline].

20.   Costanzo, LS, and Windhager EE. Calcium and sodium transport by the distal convoluted tubule of the rat. Am J Physiol Renal Fluid Electrolyte Physiol 235: F492-F506, 1978[Abstract/Free Full Text].

21.   Dai, LJ, Friedman PA, and Quamme GA. Cellular mechanisms of chlorothiazide and potassium depletion on Mg2+ uptake in mouse distal convoluted tubule cells. Kidney Int 51: 1008-1017, 1997[ISI][Medline].

22.   Dai, LJ, Friedman PA, and Quamme GA. Mechanisms of amiloride stimulation of Mg2+ uptake in immortalized mouse distal convoluted tubule cells. Am J Physiol Renal Physiol 272: F249-F256, 1997[Abstract/Free Full Text].

23.   Dai, LJ, Ritchie G, Bapty B, and Quamme GA. Aldosterone potentiates hormone-stimulated Mg2+ uptake in distal convoluted tubule cells. Am J Physiol Renal Physiol 274: F336-F341, 1998[Abstract/Free Full Text].

24.   Dørup, J. Ultrastructure of three-dimensionally localized distal nephron segments in superficial cortex of the rat kidney. J Ultrastruct Res 99: 169-187, 1988[ISI].

25.   Duarte, CG. Effects of chlorothiazide and amipramizide (MK 870) on the renal excretion of calcium, phosphate and magnesium. Metabolism 17: 420-429, 1968[ISI][Medline].

26.   Duarte, CG. Effects of ethacrynic acid and furosemide on urinary calcium, phosphate and magnesium. Metabolism 17: 867-76, 1968[ISI][Medline].

27.   Duc, C, Farman N, Canessa CM, Bonvalet JP, and Rossier BC. Cell-specific expression of epithelial sodium channel alpha , beta , and gamma  subunits in aldosterone-responsive epithelia from the rat: localization by in situ hybridization and immunocytochemistry. J Cell Biol 127: 1907-1921, 1994[Abstract].

28.  Dyckner T and Wester PO. Intracellular magnesium loss after diuretic administration. Drugs 28,Suppl 1 161-166. 84.

29.   Eknoyan, G, Suki WN, and Martinez-Maldonado M. Effect of diuretics on urinary excretion of phosphate, calcium, and magnesium in thyroparathyroidectomized dogs. J Lab Clin Med 76: 257-266, 1970[ISI][Medline].

30.  Ellison DH, Reilly RF, Obermüller N, Canessa C, and Bachmann S. Molecular localization of Na and Ca transport pathways along the renal distal tubule. J Am Soc Nephrol 6: 947.

31.   Ellison, DH, Velázquez H, and Wright FS. Thiazide-sensitive sodium chloride cotransport in the early distal tubule. Am J Physiol Renal Fluid Electrolyte Physiol 253: F546-F554, 1987[Abstract/Free Full Text].

32.   Ellison, DH, Velázquez H, and Wright FS. Adaptation of the distal convoluted tubule of the rat: structural and functional effects of dietary salt intake and chronic diuretic infusion. J Clin Invest 83: 113-126, 1989[ISI][Medline].

33.   Friedman, PA. Codependence of renal calcium and sodium transport. Annu Rev Physiol 60: 179-197, 1998[ISI][Medline].

34.   Friedman, PA, and Gesek FA. Cellular calcium transport in renal epithelia: measurement, mechanisms, and regulation. Physiol Rev 75: 429-471, 1995[Abstract/Free Full Text].

35.   Friedman, PA, and Hebert SC. Site and Mechanism of Diuretic Action. San Diego, CA: Academic, 1997, p. 75-111.

36.   Gesek, FA, and Friedman PA. Mechanism of calcium transport stimulated by chlorothiazide in mouse distal convoluted tubule cells. J Clin Invest 90: 429-438, 1992[ISI][Medline].

37.   Gill, JR, Frölich JC, Bowden RE, Taylor AA, Keiser HR, Seyberth HW, Oates JA, and Bartter FC. Bartter's syndrome: a disorder characterized by high urinary prostaglandins and a dependence of hyperreninemia on prostaglandin synthesis. Am J Med 61: 43-51, 1976[ISI][Medline].

38.   Greger, R, and Schlatter E. Presence of luminal K+, a prerequisite for active NaCl transport in the cortical thick ascending limb of Henle's loop of rabbit kidney. Pflügers Arch 392: 92-94, 1981[ISI][Medline].

39.   Greger, R, and Schlatter E. Cellular mechanism of action of loop diuretics on the thick ascending limb of Henle's loop. Klin Wochenschr 61: 1019-1027, 1983[ISI][Medline].

40.   Guay-Woodford, LM. Bartter's syndrome: unraveling the pathophysiologic enigma. Am J Med 105: 151-161, 1998[ISI][Medline].

41.   Hirsch, D, Kashgarian M, Boulpaep EL, and Hayslett JP. Role of aldosterone in the mechanism of potassium adaptation in the initial collecting tubule. Kidney Int 26: 798-807, 1984[ISI][Medline].

42.   Hoenderop, JG, van der Kemp AW, Hartog A, van de Graaf SF, van Os CH, Willems PH, and Bindels RJ. Molecular identification of the apical Ca2+ channel in 1, 25-dihydroxyvitamin D3-responsive epithelia. J Biol Chem 274: 8375-8378, 1999[Abstract/Free Full Text].

43.   Hoenderop, JG, van der Kemp AW, Hartog A, van Os CH, Willems PH, and Bindels RJ. The epithelial calcium channel, ECaC, is activated by hyperpolarization and regulated by cytosolic calcium. Biochem Biophys Res Commun 261: 488-492, 1999[ISI][Medline].

44.   Hollifield, JW. Thiazide treatment of systemic hypertension: effects on serum magnesium and ventricular ectopy. Am J Cardiol 63: 22G-25G, 1989[Medline].

45.   Horton, R, and Biglieri EG. Effect of aldosterone on the metabolism of magnesium. Metabolism 22: 1187-1192, 1962.

46.   Hropot, M, Fowler N, Karlmark B, and Giebisch G. Tubular action of diuretics: distal effects on electrolyte transport and acidification. Kidney Int 28: 477-489, 1985[ISI][Medline].

47.   Ishikawa, T, Marunaka Y, and Rotin D. Electrophysiological characterization of the rat epithelial Na+ channel (rENaC) expressed in MDCK cells. Effects of Na+ and Ca2+. J Gen Physiol 111: 825-846, 1998[Abstract/Free Full Text].

48.   Kamel, KS, Harvey E, Douek K, Parmar MS, and Halperin ML. Studies on the pathogenesis of hypokalemia in Gitelman's syndrome: role of bicarbonaturia and hypomagnesemia. Am J Nephrol 18: 42-49, 1998[ISI][Medline].

49.   Kaplan, MR, Plotkin MD, Lee WS, Xu ZC, Lytton J, and Hebert SC. Apical localization of the Na-K-Cl cotransporter, rBSC1, on rat thick ascending limbs. Kidney Int 49: 40-47, 1996[ISI][Medline].

50.   Khuri, RN, Wiederholt M, Strieder N, and Giebisch G. Effects of graded solute diuresis on renal tubular sodium transport in the rat. Am J Physiol 228: 1262-1268, 1975[ISI][Medline].

51.   Kim, GH, Masilamani S, Turner R, Mitchell C, Wade JB, and Knepper MA. The thiazide-sensitive Na-Cl cotransporter is an aldosterone-induced protein. Proc Natl Acad Sci USA 95: 14552-14557, 1998[Abstract/Free Full Text].

52.   Kriz, W, and Kaissling B. Structural organization of the mammalian kidney. In: The Kidney: Physiology and Pathophysiology, edited by Seldin DW, and Giebisch G.. New York: Raven, 1992, p. 779-802.

53.   Kuller, L, Farrier N, Caggiula A, Borhani N, and Dunkle S. Relationship of diuretic therapy and serum magnesium levels among participants in the multiple risk factor intervention trial. Am J Epidemiol 122: 1045-1059, 1985[Abstract].

55.   Kunchaparty, S, Palcso M, Berkman J, Velázquez H, Desir GV, Bernstein P, Reilly RF, and Ellison DH. Defective processing and expression of thiazide-sensitive Na-Cl cotransporter as a cause of Gitelman's Syndrome. Am J Physiol Renal Physiol 277: F643-F649, 1999[Abstract/Free Full Text].

56.   Kuntziger, H, Amiel C, Roinel N, and Morel F. Effects of parathyroidectomy and cyclic AMP on renal transport of phosphate, calcium, and magnesium. Am J Physiol 227: 905-911, 1974[ISI][Medline].

57.   Kurtz, I. Molecular pathogenesis of Bartter's and Gitelman's syndromes. Kidney Int 54: 1396-1410, 1998[ISI][Medline].

58.   Le Grimellec, C, Roinel N, and Morel F. Simultaneous Mg, Ca, P,K,Na and Cl analysis in rat tubular fluid. II. During acute Mg plasma loading. Pflügers Arch 340: 197-210, 1973[ISI][Medline].

59.   Lemmink, HH, Lambert PW, van den Heuvel J, van Dijk HA, Merkx GF, Smilde TJ, Taschner PE, Monnens LA, Hebert SC, and Knoers NV. Linkage of Gitelman syndrome to the thiazide-sensitive cotransporter gene with identification of mutations in three Dutch families. Pediatr Nephrol 10: 403-407, 1996[ISI][Medline].

60.   Lemmink, HH, van den Heuvel LP, van Dijk HA, Merkx GF, Smilde TJ, Taschner PE, Monnens LA, Hebert SC, and Knoers NV. Linkage of Gitelman syndrome to the thiazide-sensitive sodium-chloride cotransporter gene with identification of mutations in Dutch families. Pediatr Nephrol 10: 403-407, 1996[ISI][Medline].

61.   Loffing, J, Loffing-Cueni D, Hegyi I, Kaplan MR, Hebert SC, Le Hir M, and Kaissling B. Thiazide treatment of rats provokes apoptosis in distal tubule cells. Kidney Int 50: 1180-1190, 1996[ISI][Medline].

62.   Loffing, J, Loffing-Cueni D, Macher AHSC, Olson B, Knepper MA, Rossier BC, and Kaissling B. Localization of epithelial sodium channel and aquaporin-2 in rabbit kidney cortex. Am J Physiol Renal Physiol 278: F530-F539, 2000[Abstract/Free Full Text].

63.   Loffing, J, Valderrabano V, Froesch P, Kaplan M, Knepper M, Hebert S, Rossier B, and Kaissling B. Segmentation of the mouse distal nephron: morphology and distribution of transport proteins (Abstract). J Am Soc Nephrol 9: 39A, 1998.

64.   Massry, SG, Coburn JW, Chapman LW, and Kleeman CR. The acute effect of adrenal steroids on the interrelationships between the renal excretion of sodium, calcium, and magnesium. J Lab Clin Med 70: 563-570, 1967[ISI][Medline].

65.   Massry, SG, Coburn JW, Chapman LW, and Kleeman CR. The effect of long-term desoxycorticosterone acetate administration on the renal excretion of calcium and magnesium. J Lab Clin Med 71: 212-219, 1968[ISI].

66.   Mastrioianni, N, De Fusco M, Bettinelli A, Ballabio A, Basilico E, Colussi G, Claris Appiani A, and Casari G. Gitelman syndrome is caused by mutations in the human Na-Cl cotransporter gene: molecular analysis in Italian families. J Am Soc Nephrol 7: 16-17, 1996.

67.   Matsunaga, H, Stanton BA, Gesek FA, and Friedman PA. Epithelial Ca2+ channels sensitive to dihydropyridines and activated by hyperpolarizing voltages. Am J Physiol Cell Physiol 267: C157-C165, 1994[Abstract/Free Full Text].

68.   Mountokalakis, T, Merikas G, Skipelitis P, Vardakis M, Sevastos N, and Alivisatos J. Changes of fractional renal clearance of magnesium after spironolactone administration in normal subjects. Klin Wochenschr 53: 633-635, 1975[ISI][Medline].

69.   Obermüller, N, Bernstein PL, Velázquez H, Reilly R, Moser D, Ellison DH, and Bachmann S. Expression of the thiazide-sensitive Na-Cl cotransporter in rat and human kidney. Am J Physiol Renal Fluid Electrolyte Physiol 269: F900-F910, 1995[Abstract/Free Full Text].

70.   Obermüller, N, Kunchaparty S, Ellison DH, and Bachmann S. Expression of the Na-K-2Cl cotransporter by macula densa and thick ascending limb cells of rat and rabbit nephron. J Clin Invest 98: 635-640, 1996[Abstract/Free Full Text].

71.   Okusa, MD, Velazquez H, Ellison DH, and Wright FS. Luminal calcium regulates potassium transport by the renal distal tubule. Am J Physiol Renal Fluid Electrolyte Physiol 258: F423-F428, 1990[Abstract/Free Full Text].

72.   Pecker, MS. Pathophysiologic effects and strategies for long-term diuretic treatment of hypertension. In: Hypertension: Pathophysiology, Diagnosis, and Management, edited by Laragh JH, and Brenner BM.. New York: Raven, 1990, p. 2143-2168.

72a.  Peng JB, Chen XZ, Berger UV, Vassilev PM, Brown EM, and Hediger MA. A rat kidney-specific calcium transporter in the distal nephron. J Biol Chem. In press.

73.   Pitt, B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, and Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 341: 709-717, 1999[Abstract/Free Full Text].

74.   Pizzonia, JH, Gesek FA, Kennedy SM, Coutermarsh BA, Bacskai BJ, and Friedman PA. Immunomagnetic separation, primary culture, and characterization of cortical thick ascending limb plus distal convoluted tubule cells from mouse kidney. In Vitro Cell Dev Biol 27A: 409-416, 1991[ISI].

75.   Plotkin, MD, Kaplan MR, Verlander JW, Lee WS, Brown D, Poch E, Gullans SR, and Hebert SC. Localization of the thiazide sensitive Na-Cl cotransporter, rTSC1, in the rat kidney. Kidney Int 50: 174-183, 1996[ISI][Medline].

76.   Pollak, MR, Delaney VB, Graham RM, and Hebert SC. Gitelman's syndrome (Bartter's variant) maps to the thiazide-sensitive cotransporter gene locus on chromosome 16q13 in a large kindred. J Am Soc Nephrol 7: 2244-2248, 1996[Abstract].

77.   Praga, M, Vara J, Gonzalez-Parra E, Andres A, Alamo C, Araque A, Ortiz A, and Rodicio JL. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. Kidney Int 47: 1419-1425, 1995[ISI][Medline].

78.   Puschett, JB, Greenberg A, Mitro R, Piraino B, and Wallia R. Variant of Bartter's syndrome with a distal tubular rather than loop of Henle defect. Nephron 50: 205-211, 1988[ISI][Medline].

79.   Quamme, GA. Effect of calcitonin on calcium and magnesium transport in rat nephron. Am J Physiol Endocrinol Metab 238: E573-E578, 1980[Abstract/Free Full Text].

80.   Quamme, GA. Renal magnesium handling: new insights in understanding old problems. Kidney Int 52: 1180-1195, 1997[ISI][Medline].

81.   Quamme, GA, and Dirks JH. Intraluminal and contraluminal magnesium on magnesium and calcium transfer in the rat nephron. Am J Physiol Renal Fluid Electrolyte Physiol 238: F187-F198, 1980[ISI][Medline].

82.   Quamme, GA, and Dirks JH. Magnesium transport in the nephron. Am J Physiol Renal Fluid Electrolyte Physiol 239: F393-F401, 1980[ISI][Medline].

83.   Reilly, RF, and Ellison DH. Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy. Physiol Rev 80: 277-313, 2000[Abstract/Free Full Text].

84.   Reilly, RF, Shugrue CA, Lattanzi D, and Biemesderfer D. Immunolocalization of the Na+/Ca2+ exchanger in rabbit kidney. Am J Physiol Renal Fluid Electrolyte Physiol 265: F327-F332, 1993[Abstract/Free Full Text].

85.   Scheinman, SJ, Guay-Woodford LM, Thakker RV, and Warnock DG. Mechanisms of disease: genetic disorders of renal electrolyte transport. N Engl J Med 340: 1177-1187, 1999[Free Full Text].

86.   Schmitt, R, Ellison DH, Farman N, Rossier B, Reilly RF, Kunchaparty S, Reeves WB, Oberbäumer I, Tapp R, and Bachmann S. Developmental expression of sodium entry pathways in rat distal nephron. Am J Physiol Renal Physiol 276: F367-F381, 1999[Abstract/Free Full Text].

87.   Schultheis, PJ, Lorenz JN, Meneton P, Nieman ML, Riddle TM, Flagella M, Duffy JJ, Doetschman T, Miller ML, and Shull GE. Phenotype resembling Gitelman's syndrome in mice lacking the apical Na+-Cl- cotransporter of the distal convoluted tubule. J Biol Chem 273: 29150-29155, 1998[Abstract/Free Full Text].

88.   Simon, DB, Bindra RS, Mansfield TA, Nelson-Williams C, Mondonca E, Stone R, Schurman S, Nayir A, Alpay H, Bakkaloglu A, Rodriguez-Soriano J, Morales JM, Sanjd SA, Taylor CM, Pilz D, Brem A, Trachtman H, Griswold W, Richard GA, John E, and Lifton RP. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nat Genet 17: 171-178, 1998[ISI].

89.   Simon, DB, Cruz DN, Lu Y, and Lifton RP. Genotype-phenotype correlation of NCCT mutations and Gitelman's syndrome (Abstract). J Am Soc Nephrol 9: 111A, 1998.

90.   Simon, DB, Karet FE, Hamdan JM, DePietro A, Sanjad SA, and Lifton RP. Bartter's syndrome: hypokalaemic alkalosis with hypercalciuria is caused by mutations in the Na-K-2Cl cotransproter NKCC2. Nat Genet 13: 183-188, 1996[ISI][Medline].

91.   Simon, DB, Karet FE, Rodriquez-Soriano J, Hamdan JH, DiPietro A, Trachtman H, Sanjad SA, and Lifton RP. Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K + channel, ROMK. Nat Genet 14: 152-156, 1996[ISI][Medline].

92.   Simon, DB, Karet FE, Rudin A, Trachtman H, Fischbach M, Calo L, Hulton S, Sehi G, Unwin R, and Lifton RP. The molecular basis of inherited hypokalemic alkalosis: Bartter's and Gitelman's syndromes. J Am Soc Nephrol 7: 16-23, 1996.

93.   Simon, DB, and Lifton RP. Mutations in renal ion transporters cause Gitelman's and Bartter's syndromes of inherited hypokalemic alkalosis. Adv Nephrol Necker Hosp 27: 343-359, 1997[Medline].

94.  Simon DB and Lifton RP. Ion transporter mutations in Gitelman's and Bartter's syndromes. Curr Opin Nephrol Hypertens 1998.

95.   Simon, DB, and Lifton RP. Ion transporter mutations in Gitelman's and Bartter's syndromes. Curr Opin Nephrol Hypertens 7: 43-47, 1998[ISI][Medline].

96.   Simon, DB, and Lifton RP. Mutations in Na(K)Cl transporters in Gitelman's and Bartter's syndromes. Curr Opin Cell Biol 10: 450-454, 1998[ISI][Medline].

97.   Simon, DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, Casari G, Bettinelli A, Colussi G, Rodriguez-Soriano J, McCredie D, Milford D, Sanjad S, and Lifton RP. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 285: 103-106, 1999[Abstract/Free Full Text].

98.   Simon, DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE, Molina AM, Vaara I, Iwata F, Cushner HM, Koolen M, Gainza FJ, Gitelman HJ, and Lifton RP. Gitelman's variant of Bartter's syndrome, inherited hypokalemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet 12: 24-30, 1996[ISI][Medline].

99.   Skott, O, and Briggs JP. Direct demonstration of macula densa-mediated renin secretion. Science 237: 1618-1620, 1987[ISI][Medline].

100.   Stanton, BA, and Kaissling B. Adaptation of distal tubule and collecting duct to increased sodium delivery. II. Na+ and K+ transport. Am J Physiol Renal Fluid Electrolyte Physiol 255: F1269-F1275, 1988[Abstract/Free Full Text].

101.   Stergiou, GS, Mayopoulou-Symvoulidou D, and Mountokalakis TD. Attenuation by spironolactone of the magnesiuric effect of acute frusemide administration in patients with liver cirrhosis and ascites. Miner Electrolyte Metab 19: 86-90, 1993[ISI][Medline].

102.   Sutton, RA, Mavichak V, Halabe A, and Wilkins GE. Bartter's syndrome: evidence suggesting a distal tubular defect in a hypocalciuric variant of the syndrome. Miner Electrolyte Metab 18: 43-51, 1992[ISI][Medline].

103.   Takeuchi, K, Kure S, Kato T, Taniyama Y, Takahashi N, Ikeda Y, Abe T, Narisawa K, Muramatsu Y, and Abe K. Association of a mutation in thiazide-sensitive Na-Cl cotransporter with familial Gitelman's syndrome. J Clin Endocrinol Metab 81: 4496-4499, 1996[Abstract].

104.   Vargas-Poussou, R, Feldmann D, Vollmer M, Konrad M, Kelly L, van den Heuvel LP, Tebourbi L, Brandis M, Karolyi L, Hebert SC, Lemmink HH, Deschenes G, Hildebrandt F, Seyberth HW, Guay-Woodford LM, Knoers NV, and Antignac C. Novel molecular variants of the Na-K-2Cl cotransporter gene are responsible for antenatal Bartter syndrome. Am J Hum Genet 62: 1332-1340, 1998[ISI][Medline].

105.   Velázquez, H, Bartiss A, Bernstein PL, and Ellison DH. Adrenal steroids stimulate thiazide-sensitive NaCl transport by the rat renal distal tubule. Am J Physiol Renal Fluid Electrolyte Physiol 270: F211-F219, 1996[Abstract/Free Full Text].

106.   Velázquez, H, Naray-Fejes-Toth A, Reilly RF, and Ellison DH. NaCl cotransporter and 11-beta -hydroxysteroid dehydrogenase are coexpressed in rabbit distal convoluted tubule (Abstract). FASEB J 10: A368, 1996.

107.   Velázquez, H, Silva T, and Andujar E. The rabbit DCT does not express ENaC (amiloride-sensitive) activity (Abstract). J Am Soc Nephrol 9: 47A, 1998.

108.   Velázquez, H, and Wright FS. Effects of diuretic drugs on Na, Cl, and K transport by rat renal distal tubule. Am J Physiol Renal Fluid Electrolyte Physiol 250: F1013-F1023, 1986[Medline].

109.   Wright, FS. Flow dependent transport processes: filtration, absorption, secretion. Am J Physiol Renal Fluid Electrolyte Physiol 243: F1-F11, 1982[Abstract/Free Full Text].

110.   Xu, JZ, Hall AE, Peterson LN, Bienkowski MJ, Eessalu TE, and Hebert SC. Localization of the ROMK protein on the apical membranes of rat kidney nephron segments. Am J Physiol Renal Physiol 273: F739-F748, 1997[ISI][Medline].

111.   Yang, TX, Huang YNG, Singh I, Schnermann J, and Briggs JP. Localization of bumetanide- and thiazide-sensitive Na-K-Cl cotransporters along the rat nephron. Am J Physiol Renal Fluid Electrolyte Physiol 271: F931-F939, 1996[Abstract/Free Full Text].

112.   Yoshitomi, K, Shimizu T, Taniguchi J, and Imai M. Electrophysiological characterization of rabbit distal convoluted tubule cell. Pflügers Arch 414: 457-463, 1989[ISI][Medline].


Am J Physiol Renal Fluid Electrolyte Physiol 279(4):F616-F625
0363-6127/00 $5.00 Copyright © 2000 the American Physiological Society