Angiotensin II directly stimulates macula densa Na-2Cl-K cotransport via apical AT1 receptors

Gergely Kovács1,2, János Peti-Peterdi1,2, László Rosivall2, and P. Darwin Bell1

1 Nephrology Research and Training Center, Division of Nephrology, Departments of Medicine and Physiology, University of Alabama at Birmingham, Birmingham, Alabama 35294; and 2 International Nephrology Research and Training Center, Institute of Pathophysiology, Semmelweis University, H-1089 Budapest, Hungary


    ABSTRACT
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

ANG II is a modulator of tubuloglomerular feedback (TGF); however, the site of its action remains unknown. Macula densa (MD) cells sense changes in luminal NaCl concentration ([NaCl]L) via a Na-2Cl-K cotransporter, and these cells do possess ANG II receptors. We tested whether ANG II regulates Na-2Cl-K cotransport in MD cells. MD cell Na+ concentration ([Na+]i) was measured using sodium-binding benzofuran isophthalate with fluorescence microscopy. Resting [Na+]i in MD cells was 27.7 ± 1.05 mM (n = 138) and increased (Delta [Na+]i) by 18.5 ± 1.14 mM (n = 17) at an initial rate (Delta [Na+]i/Delta t) of 5.54 ± 0.53 × 10-4 U/s with an increase in [NaCl]L from 25 to 150 mM. Both Delta [Na+]i and Delta [Na+]i/Delta t were inhibited by 80% with 100 µM luminal furosemide. ANG II (10-9 or 10-12 M) added to the lumen increased MD resting [Na+]i and [NaCl]L-dependent Delta [Na+]i and caused a twofold increase in Delta [Na+]i/Delta t. Bath (10-9 M) ANG II also stimulated cotransport activity, and there was no additive effect of simultaneous addition of ANG II to bath and lumen. The effects of luminal ANG II were furosemide sensitive and abolished by the AT1 receptor blocker candesartan. ANG II at 10-6 M failed to stimulate the cotransporter, whereas increased cotransport activity could be restored by blocking AT2 receptors with PD-123, 319. Thus ANG II may modulate TGF responses via alterations in MD Na-2Cl-K cotransport activity.

furosemide; tubuloglomerular feedback; angiotensin receptor blockade; cytosolic sodium concentration; fluorescent microscopy


    INTRODUCTION
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

MACULA DENSA (MD) CELLS OF the distal nephron are the sensor elements of tubuloglomerular feedback (TGF), a mechanism that plays a major role in the regulation of glomerular filtration and renal hemodynamics (4, 34). These cells detect changes in luminal fluid NaCl concentration ([NaCl]L), in part, through a furosemide-sensitive apical Na-2Cl-K cotransporter (NKCC) (4, 18, 22, 24, 33). MD cells then send signals (40), which alter both afferent arteriolar resistance (TGF) and the release of renin. Previous work has shown the importance of MD NKCC activity in both TGF and renin release, because blockade of this apical ion transport process with furosemide abolishes TGF responses and markedly increases the rate of renin release (15, 39).

The vasoconstrictor hormone ANG II is generally considered to be a specific modulator of TGF (21), because it enhances feedback responses to a given [NaCl]L. It also has been shown to stimulate electrolyte transport processes in many tubular segments, including the thick ascending limb (TAL) and proximal tubule (6, 10, 29). At the present time, the site(s) at which ANG II interacts with the TGF signal transmission process remain(s) unknown. Although there are clearly AT1 receptors located in renal arterioles and mesangial cells (26), recent work established the existence of AT1 receptors in MD cells (11). This has opened up the possibility that ANG II could have effects on MD cell function that might lead to enhanced TGF responses. Indeed, recent work from our laboratory found that ANG II upregulates both MD apical (NHE2) and basolateral (NHE4) Na+/H+ exchanger activities (6, 9, 29, 30).

Because of the central role that NKCC plays in MD cell signaling, we sought to determine whether ANG II might also upregulate apical NKCC in MD cells. Because significant levels of ANG II have been detected in renal tubular fluid and MD cells also possess ANG II receptors at the apical membrane (7), the present study focused on the luminal actions of ANG II. NKCC activity was assessed by measuring intracellular Na+ concentration ([Na+]i) during elevations in [NaCl]L using the fluorescent dye sodium-binding benzofuran isophthalate (SBFI). We tested the effects of ANG on [NaCl]L-dependent changes in [Na+]i and also examined the involvement of AT1 and AT2 receptors in this process.


    METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

MD preparation. We isolated and perfused cortical TALs (cTALs) with attached glomeruli, dissected from rabbit kidney as described earlier (27-30). Briefly, individual cTALs with attached glomeruli were manually dissected from sagittal slices of kidneys obtained from New Zealand White rabbits weighing 0.5-1 kg. The dissection solution was an isosmotic, low-NaCl Ringer solution composed of (in mM) 25 NaCl, 125 N-methyl-D-glucamine, 125 cyclamic acid, 5 KCl, 1 MgSO4, 1.6 Na2HPO4, 0.4 NaH2PO4, 1.5 CaCl2, 5 D-glucose, and 10 HEPES for buffering, at 4°C. Individual preparations were transferred to a thermoregulated Lucite chamber mounted on a Leitz Fluovert inverted microscope and bathed in a modified Ringer solution (composition the same as above, except that 150 mM NaCl replaces N-methyl-D-glucamine, and cyclamate). The cTAL was cannulated and perfused with the low-NaCl Ringer solution. Both perfusate and bath solutions were bubbled with 100% O2, pH was adjusted to 7.4, and the bath temperature was maintained at 38°C. This preparation contained the otherwise inaccessible MD cells and allowed us to manipulate the composition of the tubular fluid at the apical side (perfusate) independently from the basolateral side (bath).

[Na+]i measurement. [Na+]i of MD cells was measured by fluorescent microscopy and SBFI (Teflabs, Austin, TX), using techniques similar to that described for Ca2+ and intracellular pH measurements (27, 28, 30). SBFI fluorescence was measured at an emission wavelength of 510 nm in response to excitation wavelengths of 340 and 380 nm. Cells were loaded with the dye by adding SBFI-acetoxymethyl ester (AM; 20 µM), dissolved in DMSO, to the luminal perfusate. The nonionic surfactant Pluronic F-127 was added (50 mg/ml) to DMSO to facilitate loading that required ~15 min. Luminal SBFI-AM was removed when counts for each wavelength exceeded 2 × 105 counts/s. Fifteen minutes were then allowed to elapse to ensure conversion to the free SBFI form and to allow fluorescence intensities at both wavelengths to stabilize. SBFI fluorescence ratios (340/380 nm) were converted into [Na+]i values using an equation that was derived from the calibration procedure. For SBFI calibration, both apical and basolateral membranes of MD cells were exposed to 10 µM nigericin+monensin. The Na+ concentration ([Na+]) of both bath and lumen was then varied in a stepwise manner between 0 and 150 mM to obtain the relationship between [Na+] and cell SBFI fluorescence ratio.

Measurements consisted of resting [Na+]i in MD cells under control conditions (isosmotic 25 mM luminal and 150 mM bath [NaCl]) and the magnitude (Delta [Na+]i) and initial rate (Delta [Na+]i/Delta t) of increases in [Na+]i when [NaCl]L was increased from 25 to 150 mM (calculated from a linear fit using PTI software). Experiments were performed in the presence/absence of luminal furosemide; luminal ANG II (both from Sigma, St. Louis, MO) was administered with/without the AT1 and AT2 receptor blockers candesartan (generous gift from P. Morsing, AstraZeneca) and PD-123, 319 (Sigma RBI), respectively, or with/without the AT2 agonist CGP-42112A (Sigma RBI).

Statistical analysis. Data are expressed as means ± SE. Statistical significance was tested using ANOVA. Significance was accepted at P < 0.05.


    RESULTS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Basal and [NaCl]L-dependent [Na+]i. Resting MD [Na+]i, in the presence of 25 mM NaCl in the perfusate and 150 mM NaCl in the bath, averaged 27.7 ± 1.05 mM (n = 138). As exemplified in a representative recording in Fig. 1 and summarized in Fig. 2, increasing [NaCl]L from 25 to 150 mM caused a rapid and sustained increase in [Na+]i by 18.5 ± 1.14 mM (n = 17), with a Delta [Na+]i/Delta t of 5.54 ± 0.53 × 10-4 U/s. This response was highly sensitive to the Na-2Cl-K cotransport blocker furosemide, which was added to the luminal perfusate. Furosemide reduced baseline [Na+]i by 50% and Delta [Na+]i by 80% (not shown) and also caused a significant reduction in Delta [Na+]i/Delta t after an elevation in [NaCl]L from 25 to 150 mM (Fig. 3). These results are all similar to what has recently been reported for MD cell Na+ regulation (28).


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Fig. 1.   Representative recordings of changes in macula densa (MD) intracellular Na+ concentration ([Na+]i) when luminal NaCl concentration ([NaCl]) was increased from 25 to 150 mM in the presence/absence of luminal 10-9 M ANG II. Na-2Cl-K cotransport activity can be assessed by measuring changes in baseline [Na+]i (arrows and dashed lines, middle), the magnitude (Delta [Na+]i), and the initial rate (Delta [Na+]i/Delta t) of luminal [NaCl]-dependent increase in MD [Na+]i. ctrl, Control.



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Fig. 2.   Effects of 10-9 M luminal ANG II with/without 100 µM luminal furosemide on MD baseline [Na+]i (A), Delta [Na+]i (B), and Delta [Na+]i/Delta t (C) when luminal [NaCl] was increased from 25 to 150 mM. Values are means ± SE; n = 17, 14, and 6. *P < 0.05.



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Fig. 3.   Dose-dependent effects of ANG II on Na-2Cl-K cotransport activity in the absence/presence of luminal furosemide. The most effective ANG II concentrations were in the 10-12 M range. Values are means ± SE; n = 17, 6, 7, 6, 14, 7, 13, and 6. ns, Nonsignificant compared with appropriate control group.*P < 0.05 compared with the appropriate control group.

Effects of ANG II. Similar experiments were performed to determine the effects of luminal ANG II, at concentrations of 10-9 and 10-12 M, on changes in MD [Na+]i with increased [NaCl]L from 25 to 150 mM. The effects of ANG II on baseline [Na+]i, and Delta [Na+]i and Delta [Na+]i/Delta t in response to an increase in [NaCl]L are depicted in Fig. 1 and summarized in Figs. 2 and 3. Luminal administration of ANG II (10-9 M) in the presence of 25 mM [NaCl]L significantly increased resting [Na+]i of MD cells (by 4.6 ± 1.1 mM, n = 14). In addition, ANG II significantly increased both magnitude and initial rate of [NaCl]L-induced increases in MD [Na+]i. On the basis of Delta [Na+]i/Delta t measurements, ANG II at 10-9 or 10-12 M caused an approximately twofold stimulation of the MD Na-2Cl-K cotransporter. However, ANG II at a concentration of 10-6 M failed to stimulate cotransport activity. Finally, as shown in Figs. 2 and 3, the stimulatory effects of 1 nM and 1 pM ANG II were markedly furosemide sensitive.

ANG II also caused a similar stimulation of Na-2Cl-K cotransport activity when added from the basolateral side. ANG II, at 10-9 M in the bath, increased Delta [Na+]i/Delta t from 5.54 ± 0.53 (n = 17) to 9.8 ± 1.4 × 10-4 U/s (n = 7). Simultaneous administration of ANG II to the lumen and bath failed to have an additive effect, and bath addition of ANG II was also inhibited by luminal furosemide (data not shown).

Effects of AT1 and AT2 receptor blockade. Candesartan and PD-123, 319 were used to determine whether ANG II stimulates [NaCl]L-induced increases in MD [Na+]i via AT1 or AT2 receptors. As summarized in Fig. 4, both candesartan and PD-123, 319 (alone) had no effect on the initial rate of increase in MD [Na+]i. However, luminal coadministration of candesartan with ANG II inhibited the stimulatory effects of 10-9 M ANG II. Interestingly, luminal coadministration of PD-123, 319 with 10-6 M ANG II restored the stimulatory effects of ANG II to the level observed with 10-12 M ANG II. These findings suggest that, at low, physiological concentrations of ANG II, MD Na-2Cl-K cotransport activity is stimulated via AT1 receptors but that high levels of ANG II may also activate an AT2-mediated inhibitory pathway.


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Fig. 4.   Effects of AT1 and AT2 receptor blockade with candesartan and PD-123, 319, respectively, on Na-2Cl-K cotransport activity in presence of ANG II. Values are means ± SE; n = 17, 6, 6, 14, 6, 6, 13, 6, and 7.

Effects of AT2 agonist CGP-42112A. To test our hypothesis that high-dose ANG II (10-6 M) activates both AT1 and AT2 receptors and that AT2 receptors antagonize the stimulation of Na-2Cl-K cotransport activity by AT1 receptors, we used CGP-42112A, an AT2-receptor agonist. As shown in Fig. 5, when 10 nM CGP-42112A was administered alone into the lumen, there was no change in the initial rate of increase in MD [Na+]i when [NaCl]L was elevated. Coadministration of this AT2-receptor agonist with low-dose ANG II completely abolished the stimulatory effects of ANG II on Delta [Na+I]/Delta t, whereas there was no effect of CGP-42112A in the presence of a high concentration of ANG II.


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Fig. 5.   Effect of AT2 receptor agonist CGP-42112A on Na-2Cl-K cotransport activity in the presence of low (10-9 M)- and high-dose (10-6 M) ANG II. Values are means ± SE; n = 17, 6, 14, 6, 13, and 6. ns, Nonsignificant compared with appropriate control group.*P < 0.05 compared with the appropriate control group.


    DISCUSSION
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Previous studies have established that ANG II is an important and specific modulator of TGF (13, 21, 35, 36). Mitchell and Navar (21) reported that peritubular capillary infusions of ANG I or ANG II augmented TGF responses as assessed by orthograde microperfusion and stop-flow pressure measurements. Schnermann and Briggs (35) found that ANG II was able to restore TGF feedback responses that were suppressed by prior volume expansion. Recently, Schnermann and co-workers (36) found that feedback responses were markedly suppressed in an AT1A receptor-deficient mouse. Finally, Huang et al. (13) suggested that the effects of modulation of TGF responses by ANG II may be independent of the vasoconstrictive properties of this hormone. This latter finding, coupled with the recent report of AT1 receptors in MD cells (11), makes it attractive to speculate that ANG II may have a modulator role in TGF at the level of the MD.

In this regard, we have recently shown that both NHE2 and NHE4 activities in MD cells are stimulated by physiological concentrations of ANG II via AT1 receptors located at both apical and basolateral cell membranes (6, 29). Whether this stimulation of Na+/H+ exchange by ANG II plays a role in TGF signaling or in modulating TGF responsiveness is, as yet, unknown. What is known, however, is the important role that the Na-2Cl-K cotransporter plays in MD cell signaling. TGF responses are clearly inhibited by loop diuretics that block this cotransporter (39). Thus it was logical to ask the question of whether ANG II stimulates the apical Na-2Cl-K cotransporter in MD cells (4, 20, 33).

These studies used the fluorescent Na-sensitive probe SBFI in the isolated perfused MD preparation. We used [NaCl]L-dependent changes in [Na+]i, as an assay for measuring the activity of the MD apical Na-2Cl-K cotransporter. Elevations in MD [Na+]i in response to increasing [NaCl]L were very sensitive to furosemide, a specific blocker of NKCC. Furosemide reduced baseline [Na+]i as well as [NaCl]L-dependent changes in [Na+]i both under control conditions and, most importantly, in the presence of ANG II. This is strong support that measurements of [Na+]i can be used to assess NKCC activity.

Previously, we used a NH<UP><SUB>4</SUB><SUP>+</SUP></UP> technique to assess cotransport activity because NH<UP><SUB>4</SUB><SUP>+</SUP></UP> substitutes for K+ on the cotransporter (16, 17, 20). Cotransport activity can then be assessed by the rate of cell acidification as NH<UP><SUB>4</SUB><SUP>+</SUP></UP> is transported into MD cells. However, in the present studies, this technique was not satisfactory because application of luminal ANG II strongly stimulates Na+/H+ exchanger activity and thus opposes NH<UP><SUB>4</SUB><SUP>+</SUP></UP>-induced cell acidification. Furthermore, studies cannot simply be done in the presence of Na+/H+ exchange blockade because this alone induces a large cellular acidification. It is possible that other transporters or channels contributed to ANG II stimulation of Na+ entry. However, no Na+ currents have been detected at the apical membrane of MD cells, and there appears to be only a small conductive pathway for Na+ at the basolateral membrane (14, 19). Also, in response to increased luminal [NaCl]L, MD cells depolarize, which clearly would not facilitate the entry of Na+ through a conductive pathway (5). It could be argued that ANG II might be inhibiting a Na+ efflux pathway; however, recent studies of Na+ dynamics in MD cells (28) suggest that there is little Na+-K+-ATPase activity at the basolateral membrane. Thus, although we cannot exclude the effects of ANG II on other transporters and channels, the most straightforward explanation of our results is that [NaCl]L-dependent changes in [Na+]i reflect the activity of NKCC and that ANG II stimulates cotransport activity.

The relatively high resting MD [Na+]i and [NaCl]L-dependent changes in MD [Na+]i are consistent with recent data from our laboratory (28) that demonstrated a high rate of Na-2Cl-K cotransport activity in MD cells but less efficient Na+ efflux. Na+ reabsorption in MD occurs through the apical Na-2Cl-K cotransporter and NHE2 (4, 20). Under steady-state conditions where lumen and bath [NaCl] were constant, luminal ANG II produced a significant increase in MD resting [Na+]i. Similarly, luminal ANG II greatly stimulated the increase in MD [Na+]i in response to elevations in [NaCl]L. These effects were sensitive to luminal furosemide, clearly indicating stimulation of the MD Na-2Cl-K cotransport activity by ANG II. Also, luminal ANG II still tended to have a small effect on MD Na+ dynamics even in the presence of furosemide, which is consistent with the previously published stimulatory effect of ANG II on MD NHE2 activity (29). We estimate that ~80% of Na+ entry occurs via the cotransporter, whereas most of the remaining Na+ entry is through Na+/H+ exchange.

Because the stimulatory effect of ANG II on TGF responses was shown with systemic or peritubular administration of ANG II, we also investigated the effect of basolateral ANG II on apical Na-2Cl-K cotransport activity. We found no difference between apical and basolateral addition of ANG II and no additive effect when ANG II was simultaneously added to both sides of MD cells. These findings, along with previous results from our laboratory (29), suggest a common intracellular signaling pathway of ANG II for either apically or basolaterally located AT receptors.

We found that nanomolar-to-picomolar luminal ANG II stimulated MD NKCC activity, whereas micromolar ANG II failed to alter cotransport activity. This biphasic effect of ANG II appears to be a general phenomenon and has also been described for NKCC activity in TAL (2) and several NHE activities along the nephron (10, 29, 32). Nearly all previous studies have focused on the effects of ANG II on the other main NKCC isoform (NKCC1), which is found in nonpolar cells and at the basolateral membrane in certain polarized epithelial cells. In mesangial cells (11), vascular smooth muscle cells (1, 25, 37), and endothelial cells (23), there is, generally, a dose- and time-dependent stimulation of NKCC1 by ANG II. We are aware of only one study (2) concerning the regulation of NKCC2 in renal tubular epithelial cells by ANG II. Amlal et al. demonstrated, using the NH<UP><SUB>4</SUB><SUP>+</SUP></UP> technique, that low-dose ANG II inhibited, whereas high-dose ANG II stimulated, the apical Na-2Cl-K cotransporter in medullary TAL via AT1 receptors. However, as indicated previously, the NH<UP><SUB>4</SUB><SUP>+</SUP></UP> technique is problematic in studies of this nature due to the effects of ANG II on Na+/H+ exchange. Thus our studies are consistent with those obtained for the NKCC1 isoform, where low-dose ANG II stimulates cotransport activity.

Coadministration of candesartan with ANG II clearly inhibited the stimulatory effects of 10-9 M luminal ANG II, suggesting an AT1 receptor-mediated response. Interestingly, coadministration of PD-123, 319 with high-dose (10-6 M) luminal ANG II restored the stimulatory effects of ANG II to the level observed with 10-12 M luminal ANG II. This finding suggests that other, inhibitory ANG II receptor subtypes (AT2) are involved in the overall ANG II response in MD cells. In addition, it would appear that this inhibitory pathway is activated, or its activity is manifested, only at high concentrations of ANG II. At the present time, this is a little puzzling because, as reviewed by Ardalliou (3), both AT1 and AT2 receptors appear to have similar affinities for ANG II (IC50 ~1 nM). Also, we found that administration of an AT2-receptor agonist blocked the effects of 1 nM luminal ANG II on cotransport activity, further supporting an inhibitory role for AT2 receptors in MD cells. On the other hand, it is also possible that there are receptor-independent effects of ANG II on cell function, especially at high micromolar concentrations of this hormone.

The present paradigm has been that, as ANG II levels increase, there is an AT1 receptor-mediated, concentration-dependent activation of various cell-signaling pathways. Recent studies (10, 12, 23, 37) suggest that ANG II receptors can be coupled to a number of signal transduction pathways, including adenylate cyclase, protein kinases A and C, phospholipase C and A2, cytosolic Ca2+ system, and P-450-arachidonic acid metabolites. This progressive recruitment of signal transduction pathways has been one means of explaining the biphasic effects of ANG II. We speculate that, in MD cells, there may also be a concentration-dependent activation of different AT receptors and that this may also contribute to the biphasic actions of ANG II.

The role of AT2 receptors in the adult has been difficult to ascertain, but it is generally reported (8) that activation of the AT2 receptor opposes the actions of the AT1 receptor. Our results may be another example whereby AT2 receptors function in a manner that is opposite to the actions of the AT1 receptor. Interestingly, Carey et al. (8) have reported that at least some of the effects of AT2 receptor activation may be mediated by the nitric oxide (NO) system. In this regard, MD cells have a high level of calcium dependent-neuronal NO synthase (nNOS) expression (38). Thus it is plausible that high concentrations of ANG II cause MD cell calcium to rise, thereby activating calcium sensitive-nNOS and the generation of NO, although this has not yet been tested experimentally. Recently, Plato et al. (31) reported that NO production inhibits cotransport activity in the TAL. However, extensive studies will be required to further characterize the signaling pathways mediating the effects of AT1 and AT2 receptor activation on MD NKCC activity.

In summary, both luminal and basolateral ANG II, in the nanomolar range, stimulated MD Na-2Cl-K cotransport. This effect of luminal ANG II on cotransport activity occurred via activation of AT1 receptors at the apical membrane. At higher concentrations (10-6 M), ANG II did not stimulate cotransport activity, most likely because of the opposing actions of apical AT2 receptors. Thus ANG II modulation of TGF responses at the MD may occur through AT receptor alterations in Na-2Cl-K cotransport.


    ACKNOWLEDGEMENTS

We especially thank Peter Morsing (AstraZeneca) for providing candesartan and Martha Yeager for secretarial assistance.


    FOOTNOTES

This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK-32032), AstraZeneca, and the Hungarian Research Foundation (OTKA 29260, FKFP-316). Gergely Kovacs is a postdoctoral fellow from the Institute of Pathophysiology, Semmelweis University Medical School, Budapest, Hungary. Janos Peti-Peterdi is supported by a postdoctoral fellowship from the National Kidney Foundation.

Address for reprint requests and other correspondence: P. D. Bell, UAB Station, 865 Sparks Ctr., Univ. of Alabama at Birmingham, Birmingham, AL 35294 (E-mail: dbell{at}nrtc.uab.edu).

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.

First published October 23, 2001; 10.1152/ajprenal.00129.2001

Received 21 April 2001; accepted in final form 4 October 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Akar, F, Skinner E, Klein JD, Jena M, Paul RJ, and O'Neill WC. Vasoconstrictors and nitrovasodilators reciprocally regulate Na+-K+-2Cl- cotransport in rat aorta. Am J Physiol Cell Physiol 276: C1383-C1390, 1999[Abstract/Free Full Text].

2.   Amlal, H, LeGeoff C, Vernimmen C, Soleimani M, Palliard M, and Bichara M. ANG II controls Na+-K+(NH<UP><SUB>4</SUB><SUP>+</SUP></UP>)-2Cl- cotransport via 20-HETE and PKC in medullary thick ascending limb. Am J Physiol Cell Physiol 274: C1047-C1056, 1998[Abstract/Free Full Text].

3.   Ardaillou, R. Angiotensin II receptors. J Am Soc Nephrol 10: 30-39, 1999.

4.   Bell, PD, and Lapointe JY. Characteristics of membrane transport processes of macula densa cells. Clin Exp Pharmacol Physiol 24: 541-547, 1997[ISI][Medline].

5.   Bell, PD, Lapointe JY, and Cardinal J. Direct measurement of basolateral membrane potentials from cells of the macula densa. Am J Physiol Renal Fluid Electrolyte Physiol 257: F463-F468, 1989[Abstract/Free Full Text].

6.   Bell, PD, and Peti-Peterdi J. Angiotensin II stimulates macula densa basolateral sodium/hydrogen exchange via type I angiotensin II receptors. J Am Soc Nephrol 10: 225-229, 1999.

7.   Braam, B, Mitchell KD, Fox J, and Navar LG. Proximal tubular secretion of angiotensin II in rats. Am J Physiol Renal Fluid Electrolyte Physiol 264: F891-F898, 1993[Abstract/Free Full Text].

8.   Carey, RM, Jun X, Wang Z, and Siragy HM. Nitric oxyde: a physiological mediator of the type 2 (AT2) angiotensin receptor. Acta Physiol Scan 168: 65-71, 2000[ISI][Medline].

9.   Fowler, BC, Chang YS, Laamarti MA, Higdon M, Lapointe JY, and Bell PD. Evidence for apical sodium proton exchange in macula densa cells. Kidney Int 47: 746-751, 1995[ISI][Medline].

10.   Harris, PJ, Hiranyachattada S, Antoine AM, Walker L, Reilly AM, and Eitle E. Regulation of renal tubular sodium transport by angiotensin II and atrial natriuretic factor. Clin Exp Pharmacol Physiol 3: S112-S118, 1996.

11.   Harrison-Bernard, LM, Navar LG, Ho MM, Vinson GP, and El-Dahr SS. Immunohistochemical localization of ANG II AT1 receptor in adult rat kidney using a monoclonal antibody Am J Physiol Renal Physiol 273: F170-F177, 1997[Abstract/Free Full Text].

12.   Homma, T, Burns KD, and Harris RC. Agonist stimulation of Na+/K+/2Cl- cotransport in rat mesangial cells. Evidence for protein kinase C-dependent and Ca2+/calmodulin-dependent pathways. J Biol Chem 265: 17613-17620, 1990[Abstract/Free Full Text].

13.   Huang, WC, Bell PD, Harvey D, Mitchell KD, and Navar LG. Angiotensin influences on tubuloglomerular feedback mechanism in hypertensive rats. Kidney Int 34: 631-637, 1988[ISI][Medline].

14.   Hurst, AM, Lapointe JY, Laamarti MA, and Bell PD. Basic properties and potential regulators of the apical K+ channel in macula densa cells. J Gen Physiol 103: 1055-1070, 1994[Abstract].

15.   Itoh, S, and Carretero OA. Role of macula densa in renin release. Hypertension 7: I49-I54, 1985[ISI][Medline].

16.   Laamarti, MA, Bell PD, and Lapointe JY. Transport and regulatory properties of the apical Na-K-2Cl cotransporter of macula densa cells. Am J Physiol Renal Physiol 275: F703-F709, 1998[Abstract/Free Full Text].

17.   Laamarti, MA, and Lapointe JY. Determination of NH<UP><SUB>4</SUB><SUP>+</SUP></UP>/NH3 fluxes across apical membrane of macula densa cells: a quantitative analysis. Am J Physiol Renal Physiol 273: F817-F824, 1997[Abstract/Free Full Text].

18.   Lapointe, JY, Bell PD, and Cardinal J. Direct evidence for apical Na+-2Cl--K+ cotransport in macula densa cells. Am J Physiol Renal Fluid Electrolyte Physiol 258: F1466-F1469, 1990[Abstract/Free Full Text].

19.   Lapointe, JY, Bell PD, Hurst AM, and Cardinal J. Basolateral ionic permeabilites of macula densa cells. Am J Physiol Renal Fluid Electrolyte Physiol 260: F856-F860, 1991[Abstract/Free Full Text].

20.   Lapointe, JY, Laamarti MA, and Bell PD. Ionic transport in macula densa cells. Kidney Int 54: S58-S64, 1998[ISI].

21.   Mitchell, KD, and Navar LG. Enhanced tubuloglomerular feedback during peritubular infusions of angiotensins I and II. Am J Physiol Renal Fluid Electrolyte Physiol 255: F383-F390, 1988[Abstract/Free Full Text].

22.   Nielsen, S, Maunsbach AB, Ecelbarger CA, and Knepper MA. Ultrastructural localization of Na-K-2Cl cotransporter in thick ascending limb and macula densa of rat kidney. Am J Physiol Renal Physiol 275: F885-F893, 1998[Abstract/Free Full Text].

23.   O'Donnell, ME. Endothelial cell sodium-potassium-chloride cotransport. Evidence of regulation by Ca2+ and protein kinase C. J Biol Chem 266: 11559-11566, 1991[Abstract/Free Full Text].

24.   Obermuller, 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].

25.   Owen, NE, and Ridge KM. Mechanism of angiotensin II stimulation of Na-K-Cl cotransport of vascular smooth muscle cells. Am J Physiol Cell Physiol 257: C629-C636, 1989[Abstract/Free Full Text].

26.   Paxton, WG, Runge M, Horaist C, Cohen C, Alexander RW, and Bernstein KE. Immunohistochemical localization of rat angiotensin AT1 receptor. Am J Physiol Renal Fluid Electrolyte Physiol 264: F989-F995, 1993[Abstract/Free Full Text].

27.   Peti-Peterdi, J, and Bell PD. Cytosolic [Ca2+] signaling pathway in macula densa cells. Am J Physiol Renal Physiol 277: F472-F476, 1999[Abstract/Free Full Text].

28.   Peti-Peterdi, J, Bebok Zs, Lapointe J-Y, and Bell PD. Novel regulation of cell [Na+] in macula densa cells: apical Na+-recycling by H-K-ATPase. Am J Physiol Renal Physiol 282: F324-F329, 2001[Medline]. First published October 10, 2001; 10.1152/ajprenal.00251.2001.

29.   Peti-Peterdi, J, and Bell PD. Regulation of macula densa Na-H exchange by angiotensin II. Kidney Int 54: 2021-2028, 1998[ISI][Medline].

30.   Peti-Peterdi, J, Chambrey R, Bebok Zs, Biemesderfer D, St John PL, Abrahamson DR, Warnock DG, and Bell PD. Macula densa Na+/H+ exchange activites mediated by apical NHE2 and basolateral NHE4 isoforms. Am J Physiol Renal Physiol 278: F452-F463, 2000[Abstract/Free Full Text].

31.   Plato, CF, Shesely EG, and Garvin JL. eNOS mediates L-arginine induced inhibition of thick ascending limb chloride flux. Hypertension 35: 319-323, 2000[Abstract/Free Full Text].

32.   Really, AM, Harris PJ, and Williams DA. Biphasic effect of angiotensin II on intracellular sodium concentration in rat proximal tubules. Am J Physiol Renal Fluid Electrolyte Physiol 269: F374-F380, 1995[Abstract/Free Full Text].

33.   Schlatter, E, Salomonsson M, Persson AEG, and Greger R. Macula densa cells sense luminal concentration via furosemide sensitive Na+:2Cl-:K+ cotransport. Pflügers Arch 414: 286-290, 1989[ISI][Medline].

34.   Schnermann, J, and Briggs JP. The Kidney, edited by Seldin DW, and Giebisch G.. New York: Raven, 2000, p. 945-981.

35.   Schnermann, J, and Briggs JP. Restoration of tubuloglomerular feedback in volume-expanded rats by angiotensin II. Am J Physiol Renal Fluid Electrolyte Physiol 259: F565-F572, 1990[Abstract/Free Full Text].

36.   Schnermann, JB, Traynor T, Yang T, Huang YG, Oliverio MI, Coffman T, and Briggs JP. Absence of tubuloglomerular feedback responses in AT1A receptor-deficient mice. Am J Physiol Renal Physiol 273: F315-F320, 1997[Abstract/Free Full Text].

37.   Smith, JB, and Smith L. Na+/K+/Cl- cotransport in cultured smooth muscle cells: stimulation by angiotensin II and calcium ionophores, inhibition by cyclic AMP and calmodulin antagonists. J Membr Biol 99: 51-63, 1987[ISI][Medline].

38.   Wilcox, CS. Role of macula densa NOS in tubuloglomerular feedback. Curr Opin Nephrol Hypertens 7: 443-449, 1998[ISI][Medline].

39.   Wright, FS, and Schnermann J. Interference with feedback control of glomerular filtration rate by furosemide, triflocin and cyanide. J Clin Invest 53: 1695-1708, 1974[ISI][Medline].

40.   Yang, T, Park JM, Arend L, Huang Y, Topaloglu R, Pasumarhty A, Praetorius H, Spring K, Briggs JP, and Schnermann J. Low chloride stimulation of prostaglandin E2 release and cyclooxygenase-2 expression in mouse macula densa cell line. J Biol Chem 275: 37922-37929, 2000[Abstract/Free Full Text].


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