Macula Densa Cell Signaling

21 Jan 2003

12:23

AR

AR177-PH65-20.tex

AR177-PH65-20.sgm

LaTeX2e(2002/01/18) P1: GCE 10.1146/annurev.physiol.65.050102.085730

Annu. Rev. Physiol. 2003. 65:481–500 doi: 10.1146/annurev.physiol.65.050102.085730 c 2003 by Annual Reviews. All rights reserved Copyright ° First published online as a Review in Advance on January 9, 2003

MACULA DENSA CELL SIGNALING P. Darwin Bell1,Jean Yves Lapointe2, and János Peti-Peterdi1 Annu. Rev. Physiol. 2003.65:481-500. Downloaded from www.annualreviews.org Access provided by University of Southern California (USC) on 07/15/16. For personal use only.

1

Nephrology Research and Training Center, Division of Nephrology, Departments of Medicine and Physiology, University of Alabama at Birmingham, Birmingham, Alabama 35294 and 2Membrane Transport Research Group, University of Montreal, Montreal, Quebec, Canada H3C 3J7; email: [email protected]; [email protected]; [email protected]

Key Words kidney, tubuloglomerular feedback, renal hemodynamics, cell-to-cell, communication ■ Abstract Macula densa cells are renal sensor elements that detect changes in distal tubular fluid composition and transmit signals to the glomerular vascular elements. This tubuloglomerular feedback mechanism plays an important role in regulating glomerular filtration rate and blood flow. Macula densa cells detect changes in luminal sodium chloride concentration through a complex series of ion transport-related intracellular events. NaCl entry via a Na:K:2Cl cotransporter and Cl exit through a basolateral channel lead to cell depolarization and increases in cytosolic calcium. Na/H exchange (NHE2) results in cell alkalization, whereas intracellular [Na] is regulated by an apically located H(Na)-K ATPase and not by the traditional basolateral Na:K ATPase. Communication from macula densa cells to the glomerular vascular elements involves ATP release across the macula densa basolateral membrane through a maxianion channel. The adaptation of multi-photon microscopy is providing new insights into macula densa-glomerular signaling.

INTRODUCTION Within the kidney, the juxtaglomerular apparatus (JGA) is the site for the formation and regulation of glomerular filtration. This hemodynamic-filtration unit is morphologically complex (Figure 1), consisting of a hemodynamic conduit that includes the terminal segment of the afferent arteriole, the glomerular capillary network, and efferent arteriole. Glomerular capillaries, which are surrounded by Bowman’s capsule, are also structurally and functionally connected with mesangial cells. In normal adult humans, filtration through this capillary network occurs at a rate of 180 liters a day, and this filtrate is modified and processed by passage through specialized tubular segments into final urine. A unique feature of each nephro-vascular unit is that near the terminal portion of the nephron, the tubule returns to and is closely associated with the JGA. At this site, the morphologically distinct tubular cells, called macula densa cells, face the JGA. These cells monitor tubular fluid flow and composition and send signals that regulate 0066-4278/03/0315-0481$14.00

481

14 Jan 2003

14:10

Annu. Rev. Physiol. 2003.65:481-500. Downloaded from www.annualreviews.org Access provided by University of Southern California (USC) on 07/15/16. For personal use only.

482

AR

BELL

AR177-PH65-20.tex

¥

LAPOINTE

¥

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)

P1: GCE

PETI-PETERDI

renal hemodynamics and the rate of filtration; this process has been termed tubuloglomerular feedback (TGF) (1–4). Macula densa cells reside within the cortical thick ascending limb (cTAL), and it is this segment that is water impermeable and possesses the apically located, loop diuretic-sensitive, Na:K:2Cl cotransporter. The cTAL is responsible for the dilution of tubular fluid. Upon reaching the macula densa segment, reabsorption of NaCl results in a reduction of luminal sodium chloride ([NaCl]) concentration to as low as ∼25 mM, as well as a reduction in luminal osmolality (5–6). The degree to which [NaCl] is reduced, however, is highly dependent upon flow rate, with elevations in flow rate resulting in increases in luminal [NaCl]. Thus perturbations that elevate glomerular filtration rate (GFR) lead to enhanced flow, an elevation in luminal [NaCl] at the macula densa resulting in the transmission of a TGF signal that causes vasoconstriction and return of GFR to normal (1–4, 7). Most studies indicate that TGF plays an essential role in the regulation of GFR and renal hemodynamics and therefore in the maintenance of salt and water balance (1). Over the past few years there has been intense interest in understanding the biology and functional characteristics of macula densa cells and their role in the cell-to-cell communication process that forms the TGF signaling pathway. In addition, other studies have focused on the involvement of macula densa cell signaling in the control of renin release, but this area is not reviewed here. Instead, we focus on what is currently known about macula densa cells and on the latest concepts regarding the TGF signaling process. The TGF signaling pathway involves an initial change in luminal fluid composition that is detected by macula densa cells. Macula densa cells then signal the underlying mesangial cells, which leads to the propagation of signals to other JGA structures, most notably, to the smooth muscle cells of the afferent arteriole (1–4). Because under normal conditions, TGF-mediated changes in renal hemodynamics involves concomitant reductions in glomerular capillary pressure, blood flow and GFR, the effector site for TGF is generally considered to be the afferent arteriole; i.e., TGF vasoconstrictor responses do not occur at the efferent arteriole (8). Nonetheless, there may be involvement of intraglomerular elements that can modify capillary filtration, the consequence of which is reflected by TGF-induced changes in the glomerular capillary ultrafiltration coefficient (9–10). Because initiation of TGF involves concomitant changes in luminal fluid [NaCl] and osmolality, work has focused on defining and characterizing the transport processes in macula densa cells and how these processes may be involved in the detection of changes in luminal fluid composition. In addition, early in vivo work (11) found that the loop diuretic furosemide blocked TGF responses, which clearly focused subsequent efforts in identification of how these cells transport NaCl and how transport-related events might lead to the activation of intracellular signaling/messenger systems (12). Since extensive reviews in the Annual Review of Physiology in 1987 (3, 9), work in this area has greatly benefited by the continuing development of several techniques. Each nephro-vascular unit contains a macula densa plaque of

14 Jan 2003

14:10

AR

AR177-PH65-20.tex

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)


MACULA DENSA CELLS

P1: GCE

483

∼20 cells; these cells are inaccessible using standard in vivo techniques and thus microdissection and in vitro perfusion of the cTAL-glomerulus that contains the macula densa cells are necessary to obtain direct access. In combination with fluorescence microscopy, electrophysiology, and patch-clamp techniques, these approaches have provided substantial information concerning the transport characteristics of macula densa cells (10, 12–13). In addition, immunofluorescence work has been useful in providing evidence for the existence of specific transporter isoforms. Recently, knockout mice models have been used to test for the effects of specific deletions of transporters, etc., on TGF responses.

Na:K:2Cl COTRANSPORT AND MEMBRANE POTENTIAL Macula densa cells are exposed at the apical membrane to varying levels of luminal [NaCl] and osmolality based on the rate of delivery of fluid from prior nephron segments. At the apical membrane, there is a Na:K:2Cl cotransporter (NKCC2 or BSC1) that is the primary means for NaCl entry into macula densa cells (7). Currently, there are three splice variants of NKCC2 (A, B, and F) that vary in distribution along the TAL, as well as demonstrate differences in ionic affinities and regulation (14–17). Macula densa cells appear to predominantly express the B isoform of NKCC2 (14). In recent expression studies, this isoform has been shown to exhibit the highest affinity for Cl relative to the other two isoforms (16– 17). This makes sense because the lowest values for luminal [NaCl] occur at the macula densa, which is located at or very near the end of the TAL. Thus the highaffinity–low-capacity of the B isoform of NKCC2 appears to be well suited for transporting NaCl in an environment where luminal [NaCl] fluctuates around a value of ∼25 mM. As estimated by Lapointe et al. (7), at this low level of luminal [NaCl], the macula densa cotransporter is still functioning to reabsorb NaCl; however, it is operating at or near equilibrium values. With increases in luminal [NaCl], the cotransporter exhibits functional saturation and maximal transport rates at approximately 60 mM [NaCl] (16–18). This finding is consistent with TGF studies in which maximal feedback-mediated changes in GFR and glomerular capillary pressure occur when luminal [NaCl] is increased to ∼60 mM (19). The relationship between luminal [NaCl] and TGF responses is shown in Figure 2A. Using the isolated perfused thick ascending limb with attached glomeruli, it was possible to impale macula densa cells with microelectrodes and measure the basolateral membrane potential (Vbl) to alternations in luminal [NaCl]. Both our laboratory (20) and Schlatter et al. (21) reported that Vbl was responsive to changes in luminal [NaCl]. We reported that there was a marked and sustained depolarization of Vbl of >30 mV, with increases in luminal [NaCl]. Because the cotransporter is electrically neutral, membrane potential depolarization most likely reflects intracellular accumulation of Cl, with Cl egress through a basolateral Cl channel. This model is supported by a number of findings including a predominant Cl conductance at the basolateral membrane (22), an estimate that intracellular [Cl]

14 Jan 2003

14:10

BELL

AR177-PH65-20.tex

¥

LAPOINTE

¥

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)

P1: GCE

PETI-PETERDI


484

AR

Figure 2 The relationship between luminal fluid [NaCl] and (A) tubuloglomerular feedback responses using in vivo micropuncture (adapted from Reference 19). Feedback responses were assessed using stop flow pressure as an index of glomerular capillary pressure. (B) Basolateral membrane potential, measured with microelectrodes in the isolated perfused TAL-glomerular preparation (taken from Reference 20), and (C ) macula densa cell [Na] measured with the fluorescent dye SBFI (taken from Reference 48).

14 Jan 2003

14:10

AR

AR177-PH65-20.tex

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)


MACULA DENSA CELLS

P1: GCE

485

is above equilibrium potential (23), and a finding that both furosemide and the Cl channel blocker NPPB hyperpolarize macula densa cells and block Vbl changes with alterations in luminal [NaCl] (20, 21). It was also found that the degree of depolarization was dependent upon the level of luminal [NaCl] over the range of 10 to 60 mM. In fact, the relationship between Vbl and TGF responses versus luminal [NaCl] were virtually equivalent, as shown in Figure 2B. The importance of macula densa membrane potential in TGF was further supported by the work of Ren et al. (24) in which TGF responses were assessed in vitro by measuring changes in afferent arteriolar diameter with alterations in luminal [NaCl]. With the use of the ionophores, nystatin and valinomycin, Ren et al. found that maneuvers assumed to depolarize macula densa cell membrane potential were associated with TGF signaling. Thus a simple model of apical cotransport of NaCl followed by exit of Cl via a basolateral channel and subsequent membrane depolarization serves as the foundation for further understanding the TGF signaling process. A current model for transport by macula densa cells is shown in Figure 3.

Apical K Conductance As described for the TAL, Na:K:2Cl cotransport with its obligatory K transport site, requires a continuous supply of K for efficient transport activity. Because TAL luminal [K] is at or below plasma values (24–27), continued NaCl transport requires that K be continuously re-cycled from cell to lumen. K secretion from cell to lumen in TAL and in macula densa is thought to involve an inwardly rectifying

Figure 3 Current model of channels and transporters that have been identified in macula densa cells. In addition, these cells appear to be permeable to water, which is distinctly different from the surrounding thick ascending limb cells.

14 Jan 2003

14:10


486

AR

BELL

AR177-PH65-20.tex

¥

LAPOINTE

¥

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)

P1: GCE

PETI-PETERDI

K channel that has a conductance of ∼20–50 pS. ROMK, a cloned K channel, has been identified immunologically in TAL and macula densa and may be responsible for all or part of apical K secretion (28–31). Previous patch-clamp studies using cell attached and inside-out patches by Hurst et al. (32) found a remarkably high abundance of K channel activity at the apical membrane of macula densa cells, at least relative to the TAL. This channel was inhibited by intracellular Ca and acidic pH but was insensitive to ATP. This latter finding is unusual because ROMK generally has been found to be inhibited by ATP. However, as discussed by Wang (31), ROMK may interact with associate proteins. Therefore, it is possible that this K secretory pathway may have a unique set of characteristics in relationship to macula densa cells. The reason for the high level of K channel activity in macula densa cells is not known; however, because of the unique manner in which macula densa cells transport Na and K (discussed in a subsequent section), a much higher level of K channel activity compared with that in the TAL may be necessary. In addition to K recycling, this K channel may be responsible for hyperpolarization and regulation of macula densa cells membrane potential. In particular, it may function in the cell hyperpolarization observed when luminal [NaCl] is reduced from high to low levels. Nevertheless, this K channel is essential in TGF responses. Previous in vivo micropuncture studies have found that pharmacological blockade of luminal K channels leads to attenuation of TGF responses (25, 27). Also, as recently reported (33–34), TGF responses and renal function are severely impaired in mice with Type II Bartters syndrome in which ROMK has been genetically deleted. Thus the addition of an apical K recycling mechanism also appears to be an essential component in the macula densa mediation of TGF signaling.

Na/H Exchangers Along with the Na:K:2Cl cotransporter, previous work has established the existence of Na/H exchange activity in macula densa cells. Fowler et al. (35) were the first to report that increases in luminal [Na] from 20 to 150 mM alkalinized macula densa cells in excess of .17 pH units. These studies were performed using the isolated perfused TAL-glomerular preparation in combination with fluorescence microscopy. In this case, macula densa cells were loaded with the pH sensitivefluorescent probe BCECF, and intracellular pH was monitored using either photometry or imaging analysis. Unlike cotransport, which exhibits saturation at ∼60 mM luminal [NaCl], there was a linear relationship between luminal [NaCl] and macula densa cell pH up to 150 mM (35). Na/H exchange activity was verified by blocking apical Na-induced changes in cell pH with amiloride or derivatives of this compound. Currently, at least eight isoforms of the Na/H exchanger have been identified. NHE1 is the nearly ubiquitous housekeeping isoform, which functions in cell pH regulation, whereas the other isoforms appear to play varying roles in pH and cell volume regulation, as well as Na and bicarbonate transport (36). In many polarized epithelial cells, NHE isoforms are located at both the apical and the basolateral

21 Jan 2003

12:24

AR

AR177-PH65-20.tex

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)


MACULA DENSA CELLS

P1: GCE

487

membranes. In TAL, current evidence for the configuration of NHEs shows NHE2 and NHE3 located at the the apical membrane and NHE1 and NHE4 located at the basolateral membrane (36–42). In the TAL, NHE3 functions in Na and bicarbonate reabsorption (41–43). Recently, work from our laboratory (44), using both functional and immunological techniques, has identified the presence of NHE2 at the apical membrane of macula densa cells but the NHE3 isoform was not found. The presence of NHE2 was firmly established based on the IC50s for both EIPA and HOE-694 and by using antibodies that were specific for the NHE2 isoform, as shown in Figure 4. Thus this isoform appears to be solely responsible for the luminal [Na]-induced alterations in macula densa cell pH. At the basolateral membrane of macula densa cells, the presence of NHE4 was detected using antibodies directed toward this isoform. Interestingly, there appears to be virtually no NHE1 in macula densa cells as assessed using both inhibitors (this isoform is highly sensitive to amiloride and its derivatives) and antibodies (44). This finding is highly unusual, although the reason or the consequences of the lack of NHE1 in macula densa cells is presently unknown. As reported in the TAL, NHE4 is localized at the basolateral aspects of these cells but appears to be mostly associated with intracellular vesicles. In TAL, a stimulus such as hyper-osmolality or cell shrinkage is necessary to active NHE4 (44). In contrast, NHE4 is expressed in macula densa cells both in intracellular vesicles and at the basolateral membrane (see Figure 4). This expression of NHE4 at the basal-plasma membrane is further suggested by the findings that NHE4 activity appears to be constitutively active. Thus simply reducing the Na gradient across the basolateral membrane results in a profound acidification that can be blocked by very high concentrations of EIPA or HOE 694, which is consistent with the insensitivity of this NHE isoform to derivatives of amiloride. However, the activity of NHE4 can be greatly enhanced in macula densa cells by raising bath osmolality independently of [Na] so that it is stimulated by cell shrinkage, similar to what has been reported for TAL. The role of NHE4 in macula densa, or for that matter in other cell types, has not been resolved. Macula densa cells exhibit marked changes in cell shape and volume so it is possible that NHE4 may serve in the cell volume regulatory machinery. However, this notion needs to be examined experimentally. The role of Na/H exchange in TGF signaling is not known. Work of Wang et al. (43), using inhibitors of NHE3 (S3226) and NHE2 (HOE 694), have recently demonstrated that bicarbonate reabsorption in TAL is unaffected by HOE 694, whereas transport is markedly inhibited by the NHE3 inhibitor. In addition, transgenic studies in NHE3-deficient mice have also shown that the absence of this isoform results in profound and deleterious effects on renal excretion of salt and water, GFR, and blood pressure (45, 46). There are enhanced TGF responses in this model, likely the result of NHE3-deficient-volume contraction, which has been shown to enhance TGF sensitivity. In contrast, NHE2 knockout mice do not exhibit observable changes in blood pressure or renal function, including Na excretion (46). Current evidence regarding TGF responses in NHE2 knockout mice

14 Jan 2003

14:10

488

AR

BELL

AR177-PH65-20.tex

¥

LAPOINTE

¥

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)

P1: GCE

PETI-PETERDI

remains equivocal (J. Lorenz, personal communication). Thus the role of the NHEs in macula densa function and TGF signaling remains to be determined.


Macula Densa Cell Sodium Regulation As stated, cotransport of NaCl into macula densa cells leads to elevation in intracellular [Cl] (47), which then exits across the basolateral membrane. The question remains; what happens to cell Na? Cellular extrusion of Na occurs against its electrochemical gradient, and the classic model by which this occurs is via basolateral Na/K-ATPase. However, as reported a number of years ago, macula densa cells do not have an abundance of this enzyme (9). In fact, early work indicated that the level of Na/K-ATPase might be as little as 1/40th of that expressed in the TAL. Thus there was some early indication that macula densa cells might regulate cell [Na] in a novel manner. This idea was borne out in recent studies (48) that assessed intracellular [Na] dynamics in macula densa cells using SBFI, a Na-sensitive fluorescent probe. Measurement of intracellular [Na] in macula densa cells in the presence of 25 mM NaCl in the lumen and 150 mM NaCl in the bath averaged around 30 mM. This was significantly higher than that found in the adjacent TAL (∼13 mM) and is also higher than that reported in other epithelial cells (48). Elevations in luminal [NaCl] to 150 mM resulted in large increases in intracellular [Na] to around 70 mM, whereas much smaller changes were observed in the TAL. One of the most interesting aspects of this study was the relationship between macula densa intracellular [Na] and luminal [NaCl]. There was an almost linear increase in intracellular [Na] over the range of 0 to 60 mM NaCl, with no further increase in cell [Na] between 60 and 150 mM (see Figure 2C). The relationship between luminal [NaCl] and cell [Na] was the same as that found for Vbl and for TGF responses. This finding is remarkable because other cells appear to precisely regulate [Na] levels in response to external perturbations. The concept that has now emerged is that intracellular [Na] (and most likely [Cl]) tracks or reflects luminal [NaCl]. This makes sense in terms of the sensor function of macula densa cells; i.e., to have intracellular [NaCl] reflect changes in luminal [NaCl] over the range where TGF responses occur. Using measurements of macula densa intracellular [Na], studies showed that, in the presence of low luminal [Na], addition of furosemide lowered cell [Na] and greatly inhibited (∼80 %) increases in [Na] with elevations in luminal [Na]. This residual increase in cell [Na] appears to occur via the Na/H exchanger, which further substantiates the 80–20% split in terms of apical Na entry that had previously been suggested for the Na:K:2Cl cotransporter and Na/H exchanger (23, 48). Interestingly, the addition of basolateral ouabain failed to alter macula densa [Na], whereas it was effective in raising TAL [Na] (48). Apical addition of ouabain, however, was very effective in raising macula densa cell [Na]. These recent observations suggest that macula densa cells regulate cell [Na] via an apically located colonic form of the H/K-ATPase that is sensitive to ouabain. As reported in expression studies, this member of the ATPase family not only transports H and K but can also transport Na, albeit less efficiently than the Na/K-ATPase (49, 50). The

14 Jan 2003

14:10

AR

AR177-PH65-20.tex

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)


MACULA DENSA CELLS

P1: GCE

489

presence of this ATPase has been identified both functionally (48) and immunologically. Verlander et al. (51) have recently reported the presence of a HKα 2c at the apical membrane of macula densa cells. Thus it is clear that macula densa cells possess an Na-H/K-ATPase at the apical membrane and that it can function as a Na efflux pathway. The presence and abundance of subunits of the Na/K-ATPase in macula densa cells is less clear. The α 1-subunit of Na/K-ATPase appears to be virtually absent in rabbit macula densa cells, whereas it is detected at low levels in rat (44, 52). Recently, Wetzel & Sweadner (52) reported, in the rat, the presence of high levels of expression of the γ -subunit of the Na/K-ATPase in macula densa cells, but not in surrounding TAL. This subunit has been shown to reduce the affinity of this ATPase for both Na and K (52). What has emerged from this work is a new model for cell Na/K regulation. In macula densa cells, Na extrusion and K entry occur at the apical membrane via a Na-H/K-ATPase. The fact that intracellular [Na] tracks luminal [NaCl] may be due to the reduced efficiency of this pump for Na removal. The finding that low levels of Na/K-ATPase, along with the γ -subunit, are expressed at the basolateral membrane suggests that this ATPase does not greatly participate in Na dynamics under normal conditions. However, it is possible that physiological perturbations could increase the contribution of basolateral Na/K-ATPase to macula densa [Na] regulation. This notion may not be applicable to only macula densa cells, it may be more generalized with regard to cellular regulation of [Na]. Thus cellular regulation of [Na] may be controlled by the pattern of ATPase expression.

Macula Densa Cytosolic Calcium Regulation As discussed above, there are multiple effects of increases in luminal [NaCl] on macula densa cells such as increases in cell pH, elevations in cellular [NaCl], and depolarization of the basolateral membrane potential. Recent work has also reported that elevations in luminal [NaCl] result in increases in cytosolic [Ca] (53). This report is somewhat controversial because a previous report indicated no luminal [NaCl]-dependent elevations in [Ca] (54). However, this discrepancy may be related to technical issues regarding prior exposure to conditions that may have caused sustained increases in [Ca] before the actual experiments were performed. Nevertheless, it is now clear that increasing luminal [NaCl] will, in fact, cause a modest elevation in macula densa [Ca], as measured using the Ca-sensitive fluorescence probe, fura 2. It would also appear that the increase in [Ca] is from depolarization-induced Ca entry through a calcium channel across the basolateral membrane. Increases in [Ca] can be blocked by high (1 µM) concentrations of the voltage-operated calcium channel blocker, nifedipine, whereas the calcium channel agonist BAY K 8644, added to the bath, directly increased macula densa [Ca]. Finally, increases in [Ca] were blocked either by the addition of furosemide to the lumen or by adding NPPB, the Cl channel blocker, to the bath (53). As reported by Lapointe et al. (55) in patch-clamp experiments, there is a ∼20 pS non-selective cation channel in the basolateral membrane of macula densa cells that is activated by depolarization and by elevations in [Ca]. This channel has a

14 Jan 2003

14:10


490

AR

BELL

AR177-PH65-20.tex

¥

LAPOINTE

¥

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)

P1: GCE

PETI-PETERDI

moderate Ca permeability and is very similar to TRPM4, a member of the TRP family known to be expressed in kidney (55a). Although its physiological role is, at present, uncertain it may serve in helping to maintain Vbl depolarization and may also participate in Ca entry. However, this channel is not nifedipine sensitive so it is not clear whether this is the primary Ca entry pathway that was suggested based on cytosolic [Ca] measurements. In other work, Liu et al. (56) reported the existence of ATP purinergic receptors, most likely of the P2Y2 variety, at the basolateral but not at the apical membrane of macula densa cells. Since recent work has shown the release of ATP across the basolateral membrane (see below), it is possible that during TGF signaling, ATP-activation of purinergic receptors helps to maintain elevations in [Ca]. Consistent with the sensor function of macula densa cells, sustained elevations in luminal [NaCl] results in sustained elevations in [Ca] and decreases in Vbl. The non-selective cation channel and the purinergic receptors may help in the maintenance of feedback signaling.

Regulation of Macula Densa Transport Numerous studies have investigated the regulation of TGF under a variety of physiological conditions. In general, low-volume states such as dietary salt restriction lead to enhanced TGF responses. Among the many identified modulators of TGF responses, angiotensin II (ANG II) has been the most extensively studied (1, 57– 61). ANG II AT1 receptors, which mediate the vasoconstrictive properties of this hormone, are located throughout the JGA, including arteriolar smooth muscle cells and mesangial cells, and are clearly expressed at both apical and basolateral membranes of macula densa cells (62). Previous in vivo micropuncture studies have shown that ANG II enhances TGF responses, whereas blockade or inhibition of the renin angiotensin system leads to a blunting of TGF (57). Schnermann et al. (58, 60) reported an almost complete blockade of TGF signaling in mice in which the renin angiotensin system had been disrupted either at the level of the AT1 receptor or by eliminating converting enzyme. Recent studies have focused on the direct effect of ANG II on macula densa cells. As shown by Wang et al. (63), luminal administration of ANG II enhances TGF responses in vitro as assessed by changes in afferent arteriolar diameter with increases in luminal [NaCl]. This effect was inhibited by co-administration of an AT1 receptor blocker. Other studies have examined the effects of ANG II on transport mechanisms of macula densa cells. Our laboratory (64, 65) found that ANG II, added at nanomolar concentrations to either the lumen or bath, stimulated both the apical and basolateral Na/H exchangers. This stimulatory effect was blocked by an AT1 receptor blocker, and furthermore, high micromolar concentrations did not stimulate or significantly inhibited exchanger activity. This inhibitory effect was not blocked by Candesartan, an AT1 receptor blocker, suggesting that high levels of ANG II might activate other receptors such as the AT2 receptor. However, Wang et al. (63) reported no effect of PD 01233190121B, an AT2 receptor blocker, on ANG II stimulated TGF responses. Other studies by Kovacs et al. (66) have also reported that ANG II stimulates the Na:K:2Cl cotransporter. Using measurements of cell [Na], it was also found

14 Jan 2003

14:10

AR

AR177-PH65-20.tex

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)


MACULA DENSA CELLS

P1: GCE

491

that low concentrations of ANG II stimulated cotransporter activity, whereas high concentrations failed to enhance it. Interestingly, in this study, addition of the AT2 receptor blocker in the presence of micromolar concentrations of ANG II restored the stimulatory effects of ANG II. Taken together, these findings suggest that ANG II may specifically enhance TGF responses by acting on macula densa cell transport. However, the cellular mechanisms by which ANG II affects macula densa cell function is not known. It has been suggested that ANG II receptors can be coupled to a number of different pathways, including adenylate cyclase, protein kinases A and C, phospholipase C and A2, cytosolic Ca, and P-450 arachidonic acid metabolites. However, previous work found that cAMP inhibits in vivo TGF responses, and has a direct inhibitory effect on the macula densa Na:K:2Cl cotransporter (67). Therefore, the effects of ANG II to stimulate cotransport activity probably do not occur through the protein kinase A pathway. In addition, for reasons that are unclear, it has been difficult to obtain ANG II-induced Ca-transients in macula densa cells (P.D. Bell, unpublished observations). In terms of regulation of the Na:K:2Cl cotransporter, previous studies by Laamarti et al. (67) suggest that intracellular [Cl] may play a key role in controlling or regulating cotransport activity. This is consistent with studies in other cells in which intracellular [Cl] may lead directly or indirectly to phosphorylation of the cotransporter at least for the NKCC1, the basolateral form of the cotransporter (67). There are additional complexities, because macula densa cells express high levels of the neuronal form of nitric oxide synthase, which forms nitric oxide, and the COX2 enzyme, which helps metabolize ararchidonic acid (68– 72). It is beyond the scope of this review to delve into the details and regulation of these two systems, and the reader is referred to the review by Schnermann & Levine in this volume (10). However, it is likely that the inhibitor effects of nitric oxide on TGF may be due, at least in yeast, to inhibition of the cotransporter. It has also been demonstrated that nitric oxide inhibits Na:K:2Cl cotransport activity in macula densa cells (P.D. Bell, unpublished observations) and thick ascending limb (73), and it may inhibit other transporter and channels and interact with other intracellular messenger systems. In terms of COX2, current work is focused on its role in regulation of renin release. Evidence from putative cultured macula densa cells indicates that low ambient NaCl may increase prostaglandin production via a tyrosine kinase, ERK, p38 pathway (74). Preliminary work from our laboratory also supports the idea that macula densa cells can release prostaglandins (most likely PGE2) in response to a reduction in luminal [NaCl]. Additional studies are needed to clarify the roles of nNOS, COX2, and other pathways that play a significant role in modulating TGF signaling and responses.

MULTI-PHOTON IMAGING OF THE JUXTAGLOMERULAR APPARATUS One of the exciting advances in macula densa-TGF signaling has been the recent application of two-photon excitation fluorescence imaging to the macula densaJGA complex (75). This technique is a radical departure from traditional confocal

14 Jan 2003

14:10


492

AR

BELL

AR177-PH65-20.tex

¥

LAPOINTE

¥

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)

P1: GCE

PETI-PETERDI

Figure 5 Two-photon photomicrograph of a living JGA preparation that is perfused both from the TAL and from the afferent arteriole (AA). This high-resolution section is taken at a depth of approximately 50 µM within the glomerulus (G) in a preparation that was loaded with the membrane staining dye, TMA-DPH.

microscopy and has the distinct advantages of markedly improved image quality and deep optical sectioning of living tissue. As recently reported (75), this technique allows for high-resolution optical sectioning of the entire glomerulus and macula densa-mesangial cell-afferent arteriole complex. Figure 5 is an example of such an optical section, showing the various structures of the JGA in a preparation in which both the TAL and afferent arteriole were perfused. This new technique has revealed several exciting and provocative findings, including the response of macula densa (MD) cells to alterations in luminal fluid [NaCl]. As shown most clearly in video images, there are increases in macula densa cell volume with concomitant increases in luminal [NaCl] and osmolality, conditions that mimic normal physiology. This increase presumably occurs as the result of NaCl entry and the movement of water into the cell. Other work, at constant luminal fluid [NaCl] but varying osmolality, has demonstrated water flow across the macula densa plaque and into the mesangial cell field. This work substantiates earlier studies that reported finite water permeability of the macula densa plaque (13, 76). Finally, TGF responses have also been assessed using the double-perfused TAL-glomerular preparation. It should be noted that prior in vitro (59, 61) studies have measured TGF responses

14 Jan 2003

14:10

AR

AR177-PH65-20.tex

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)


MACULA DENSA CELLS

P1: GCE

493

as changes in afferent arteriolar diameter at a site that is close to but outside of the glomerulus. These studies have uniformly reported, at best, modest changes (∼10%) in luminal diameter, with increases in luminal [NaCl]. With two-photon microscopy, it has been possible to obtain intra-glomerular optical sections of afferent arteriole immediately before it branches into the capillary network. TGF signaling with increases in luminal [NaCl] led to an almost complete closure of the intra-glomerular afferent arteriole. There appeared to be an almost sphincterlike activity at this site. This new finding suggests that the effector site for TGF signaling is primarily located at an arteriolar site that is adjacent to the macula densa cells and within the glomerulus. Thus two-photon microscopy offers exciting new possibilities to examine glomerular physiology, JGA function, and macula densa signaling.

MACULA DENSA CELL SIGNALING: ROLES OF ATP AND ADENOSINE A lingering question that has remained in the field of TGF has been the nature of the signal that emanates from macula densa cells to initiate renal vasoconstriction and decreases in GFR. The current consensus is that a substance is released from the basolateral membrane of macula densa cells that then signals mesangial cells and/or afferent arteriolar smooth muscle cells. One reason for this notion is that there are no specialized connections, such as gap junctions, between macula densa cells and the underlying mesangial cells (77, 78). At present, there are two candidates (adenosine and ATP) for the mediator of TGF, although these two candidates are not mutually exclusive. There is evidence for an involvement of adenosine in TGF signaling (79–86). This comes from both pharmacological studies as well as from knockout mice studies. Brown et al. (80) and Sun et al. (81) have reported that mice deficient in the adenosine A1 receptor lack TGF responses. Ren et al. (83) and Thomson et al. (84) have reported that acute blockade of adenosine A1 receptors inhibits TGF responses. In addition, preventing variations in adenosine levels by addition of a constant level of adenosine administration in the presence of a 50 -nucleotidase inhibitor also greatly attenuates TGF efficiency. Although these results provide support for a role of adenosine in TGF, some uncertainties remain concerning whether it has a permissive or mediator role. First, mesangial cells (when studied in culture), which normally lie adjacent to macula densa cells, do not respond to adenosine with increases in cytosolic [Ca] (87). It is also clear that mesangial cells are activated by TGF and that, as shown in previous work (88), can act as a functional syncytium, thereby transmitting signals to the smooth muscle cells and intraglomerular elements. Second, the vasoconstrictive responses of afferent arterioles to adenosine are transitory and wane with continued administration of this nucleotide (85). Third, adenosine A2 receptors are also present, and activation of these receptors clearly results in vasodilation. The other potential mediator is ATP (85, 89–93). Afferent arterioles express P2X receptors, which, when activated by ATP, result in sustained vasoconstriction.

14 Jan 2003

14:10


494

AR

BELL

AR177-PH65-20.tex

¥

LAPOINTE

¥

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)

P1: GCE

PETI-PETERDI

As discussed by Navar et al. (1, 85) and Inscho et al. (90), there is also a body of work that has demonstrated the role of ATP and purinergic receptors in renal autoregulation of blood flow and GFR, which is likely a reflection, at least in part, of TGF. In addition, Nishiyama et al. (92) found that renal interstitial ATP levels correlate with autoregulatory responses. We have recently examined this issue (93) in patch-clamp experiments of the basolateral membrane of macula densa cells and have identified a maxi-anion channel at the basolateral membrane that is in the order of 300 pS. It is anion selective and, most interesting, in inside-out patches, conducts ATP. A similar channel, at least in terms of its biophysical properties, has been extensively characterized in C127 cells (94–95). In macula densa cells, this maxi-anion channel is dependent upon extracellular NaCl, and channel activity is greatly attenuated by removing NaCl. In other work, a biosensor probe was used to measure ATP release at the basolateral membrane of macula densa cells. This involved the use of a PC12 cell that has purinergic receptors (P2X) and, when activated by ATP, has channel properties and also allows for Ca influx. By placing a PC12 cell at the basolateral membrane, it has been shown that macula densa cells release ATP when there is a specific increase in luminal [NaCl]. No luminal [NaCl]-dependent release of ATP was seen from surrounding TAL cells. Thus macula densa cells release ATP at the basolateral membrane in a manner that is consistent with TGF signaling. It is possible that ATP and adenosine are both involved in TGF signaling (85, 86). Obviously, once ATP is released, it can be broken down into adenosine. Therefore, it is possible that ATP is the initial signaling molecule and that adenosine, which

Figure 6 Current scheme for the transmission of tubuloglomerular feedback signals. 1. Luminal sodium chloride is transported into macula densa cells primarily through a Na:K:2Cl cotransporter; 2., 3. this results in increased cell [Cl], membrane depolarization and elevations in [Ca] and pH; 4. ATP release from macula densa cells via a maxi-anion channel; 5. ATP activation of P2 receptors in mesangial cells, and 6. Gap junction conductance to the smooth muscle cells of the afferent arteriole, ultimately resulting in vasoconstriction and decreases in glomerular filtration rate.

14 Jan 2003

14:10

AR

AR177-PH65-20.tex

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)


MACULA DENSA CELLS

P1: GCE

495

is subsequently formed, acts as part of the signaling cascade. However, it is very clear that mesangial cells do possess purinergic receptors and that ATP, but not adenosine, causes depolarization and increases in mesangial cell cytosolic [Ca]. As recently reported by Ren et al. (96), mesangial cells are critical for TGF signaling. These workers found that damaging mesangial cells with a Thy 1-1 antibody or disruption of gap junctions between mesangial cells and smooth muscle cells resulted in a loss of TGF responses. This supports the notion that transmission of feedback signals occurs from macula densa cells through the mesangial cell field and to the vascular smooth muscle cells of the afferent arteriole. In this scheme, release of ATP across the basolateral membrane of macula densa cells may be the critical step in transmission of feedback signals (Figure 6). The Annual Review of Physiology is online at http://physiol.annualreviews.org

LITERATURE CITED 1. Navar LG, Inscho EW, Majid SA, Imig JD, Harrison-Bernard LM, Mitchell KD. 1996. Paracrine regulation of the renal microcirculation. Physiol. Rev. 76:425–536 2. Barajas L. 1979. Anatomy of the juxtaglomerular apparatus. Am. J. Physiol. Renal Physiol. 7:F333–F43 3. Navar LG, Ploth DW, Bell PD. 1980. Distal tubular feedback control of renal hemodynamics and autoregulation. Annu. Rev. Physiol. 49:557–71 4. Schnermann J, Traylor T, Yang T, Arend L, Huang YG, et al. 1998. Tubuloglomerular feedback: new concepts and developments. Kidney Int. 54:S40–S45 5. Greger R. 1988. Chloride transport in thick ascending limb, distal convolution and collecting duct. Annu. Rev. Physiol. 50:111–22 6. Reeves WB, Winters CJ, Andreoli TE. 2001. Chloride channels in the loop of Henle. Annu. Rev. Physiol. 63:631–45 7. LaPointe J-Y, Laamarti A, Bell PD. 1998. Ionic transport in macula densa cells. Kidney Int. 54:S58–S64 8. Ren Y, Garvin JL, Carretero OA. 2001. Efferent arteriole tubuloglomerular feedback in the renal nephron. Kidney Int. 59:222–29 9. Briggs JP, Schnermann J. 1987. The tubu-

10.

11.

12.

13.

14.

15.

loglomerular feedback mechanism: functional and biochemical aspects. Annu. Rev. Physiol. 49:251–73 Schnermann J, Levine DZ. 2003. Paracrine factors in tubuloglomerular feedback: adenosine, ATP, and nitric oxide. Annu. Rev. Physiol. 65:501–29 Wright FS, Schnermann J. 1974. Interference with feedback control of glomerular filtration rate by furosemide, triflocin, and cynamide. J. Clin. Invest. 53:1695–708 Bell PD, LaPointe J-Y. 1997. Characteristics of membrane transport processes of macula densa cells. Clin. Exp. Pharmacol. Physiol. 24:541–54 Kirk K, Bell PD, Barfuss D, Ribadeneira MD. 1985. Direct visualization of the isolated perfused renal macula densa. Am. J. Physiol. Renal Physiol. 248:F890–F94 Yang T, Huand YG, Singh I, Schnermann J, Briggs JP. 1996. Localization of bumetanide- and thiazide-sensitive Na-KCl cotransporters along the rat nephron. Am. J. Physiol. Renal Physiol. 271: F931– F39 Plata C, Meade P, Hall A, Welch RC, Vázquez N, et al. 2001. Alternatively spliced isoform of apical Na(+)-K(+)-Cl(−) cotransporter gene encodes a furosemidesensitive Na(+)-Cl(−) cotransporter. Am.

14 Jan 2003

14:10

496

16.


17.

18.

19.

20.

21.

22.

23.

24.

25.

AR

BELL

AR177-PH65-20.tex

¥

LAPOINTE

¥

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)

P1: GCE

PETI-PETERDI

J. Physiol. Renal Physiol. 280:F574– F82 Plata C, Meade P, Vázquez N, Herbert SC, Gamba G. 2002. Functional properties of the apical Na+-K+-2Cl− cotransporter isoforms. J. Biol. Chem. 277: 11001– 12 Giménez I, Isenring P, Forbush B. 2002. Spatially distributed alternative splice variants of the renal Na-K-Cl cotransporter exhibit dramatically different affinities for the transported ions. J. Biol. Chem. 277: 8767–70 LaPointe J-Y, Bell PD, Cardinal J. 1990. Direct evidence for an apical Na:2Cl:K co-transport in macula densa cells. Am. J. Physiol. Renal Physiol. 258:F1466– F69 Bell PD, Navar LG. 1982. Relationship between tubuloglomerular feedback responses and perfusate hypotonicity. Kidney Intern. 22:234–39 Bell PD, LaPointe J-Y, Cardinal J. 1989. Direct measurement of basolateral membrane potential in cells of the macula densa. Am. J. Physiol. Renal Physiol. 257:F463–F68 Schlatter E, Salomonson M, Persson AE, Greger R. 1989. Macula densa cells sense luminal NaCl concentration via furosemide sensitive Na+2Cl−K+ cotransport. Pflügers Arch. 414:286–90 LaPointe J-Y, Bell PD, Hurst AM, Cardinal J. 1991. Basolateral ionic permeabilities of macula densa cells. Am. J. Physiol. Renal Physiol. 260:F856–F60 LaPointe J-Y, Laamarti A, Hurst AM, Fowler BC, Bell PD. 1995. Activation of Na:2Cl:K cotransport by luminal chloride in macula densa cells. Kidney Int. 47:752– 57 Ren Y, Yu H, Wang H, Carretero OA, Garvin JL. 2001. Nystatin and valinomycin induce tubuloglomerular feedback. Am J. Physiol. Renal Physiol. 281:F1102– F8 Vallon V, Osswald H, Blantz RC, Thomson S. 1997. Potential role of luminal

26.

27.

28.

29.

30.

31.

32.

33.

34.

potassium in tubuloglomerular feedback. J. Am. Soc. Nephrol. 8:1831–37 Vallon V, Osswald H, Blantz RC, Thomson S. 1998. Luminal signal in tubuloglomerular feedback: what about potassium? Kidney Int. Suppl. 67:S177–79 Schnermann J. 1995. Effects of barium ions on tubuloglomerular feedback. Am. J. Physiol. Renal Physiol. 268:F960–F66 Xu JZ, Hall AE, Peterson LN, Bienkowski MJ, Eessalu TE, Hebert SC. 1997. Localization of the ROMK protein on apical membranes of rat kidney nephron segments. Am. J. Physiol. Renal Physiol. 273:F739–F48 Hebert SC. 1998. Roles of Na-K-2Cl and Na-Cl cotransporters and ROMK potassium channels in urinary concentrating mechanism. Am. J. Physiol. Renal Physiol. 275:F325–F27 Ecelbarger CA, Kim GH, Knepper MA, Liu J, Tate M, et al. 2001. Regulation of potassium channel Kir 1.1 (ROMK) abundance in the thick ascending limb of Henle’s loop. J. Am. Soc. Nephrol. 12:10– 18 Wang W. 1999. Regulation of the ROMK channel: interaction of the ROMK with associate proteins. Am. J. Physiol. Renal Physiol. 277: F826–F31 Hurst AM, LaPointe J-Y, Laamarti A, Bell PD. Basic properties and potential regulators of the apical K channel in macula densa cells. J. Gen. Physiol. 103:1055– 70 Lorenz JN, Baird NR, Judd LM, Noonan WT, Andringa A, et al. 2002. Impaired renal NaCl absorption in mice lacking the potassium channel, a model for type II Bartter’s syndrome. J. Biol. Chem. 277:37871–78 Lu M, Wang T, Yan Q, Yang X, Dong K, et al. 2002. Absence of small-conductance K+ channel (SK) activity in apical membranes of thick ascending limb and cortical collecting duct in ROMK (Bartter’s) knockout mice. J. Biol. Chem. 277: 37881–87

14 Jan 2003

14:10

AR

AR177-PH65-20.tex

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)


MACULA DENSA CELLS 35. Fowler BC, Chang Y-S, Laamarti A, Higdon M, LaPointe J-Y, Bell PD. 1995. Evidence for apical sodium-proton exchange in macula densa cells. Kidney Int. 47:746– 51 36. Orlowski J, Grinstein S. 1997. Na-H exchangers of mammalian cells. J. Biol. Chem. 272:22373–76 37. Amemiya M, Loffing J, Lotscher M, Kaissling B, Alpern RJ, Moe OW. 1995. Expression of NHE-3 in the apical membrane of rat renal proximal tubule and thick ascending limb. Kidney Int. 48: 1206–15 38. Biemesderfer D, Reilly RF, Exner M, Igarashi P, Aronson PS. 1992. Immunocytochemical characterization of Na+H+ exchanger isoform NHE-1 in rabbit kidney. Am. J. Physiol. Renal Physiol. 263:F833–F40 39. Chambrey R, Warnock DG, Podevin RA, Bruneval P, Mandet C, et al. 1998. Immunolocalization of the Na+/H+ exchanger isoform NHE2 in rat kidney. Am. J. Physiol. Renal Physiol. 275:F379–F86 40. Chambrey R, St John PL, Eladari D, Quentin F, Warnock DG, et al. 2001. Localization and functional characterization of Na+/H+ exchanger isoform NHE4 in rat thick ascending limbs. Am. J. Physiol. Renal Physiol. 281:F707–F17 41. Vallon V, Schwark JR, Richter K, Hropot M. 2000. Role of Na(+)/H(+) exchanger NHE3 in nephron function: micropuncture studies with S3226, an inhibitor of NHE3. Am. J. Physiol. Renal Physiol. 278:F375–F79 42. Sun AM, Liu Y, Dworkin LD, Tse CM, Donowitz M, Yip KP. 1997. Na+/H+ exchanger isoform 2 (NHE2) is expressed in the apical membrane of the medullary thick ascending limb. J. Membr. Biol. 160:85–90 43. Wang T, Hropot M, Aronson PS, Giebisch G. 2001. Role of NHE isoforms in mediating bicarbonate reabsorption along the nephron. Am. J. Physiol. Renal Physiol. 281:F1117–F22

P1: GCE

497

44. Peti-Peterdi J, Chambrey R, Bebok Z, St John PL, Abrahamson DR, et al. 2000. Macula densa Na:H exchange activities mediated by apical NHE2 and basolateral NHE4 isoforms. Am. J. Physiol. Renal Physiol. 278: F452–F63 45. Lorenz JN, Schultheis PJ, Traynor T, Shull GE, Schnermann J. 1999. Micropuncture analysis of single-nephron function in NHE3-deficient mice. Am. J. Physiol. Renal Physiol. 277:F447–F53 46. Ledoussal C, Lorenz JN, Nieman ML, Soleimani M, Schultheis PJ, Shull GE. 2001. Renal salt wasting in mice lacking NHE3 Na+/H+ exchanger but not in mice lacking NHE2. Am. J. Physiol. Renal Physiol. 281:F718–F27 47. Salomonsson M, Gonzales E, Westerlund P, Persson AE. 1991. Chloride concentration in macula densa and cortical thick ascending limb cells. Kidney Int. 32:S51– S54 48. Peti-Peterdi J, Bebok Z, LaPointe J-Y, Bell PD. 2002. Cytosolic [Na+] regulation in macula densa cells: novel role for an apical H:K ATPase. Am. J. Physiol. Renal Physiol. 282:F324–F29 49. Codina M, Pressley TA, DuBose TD. 1999. The colonic H, K-ATPase functions as a Na-dependent K (NH4)-ATPase in apical membranes from rat distal colon. J. Biol. Chem. 274:19693–98 50. Cougnon M, Bouyer P, Planelles G, Jaisser F. 1998. Does the colonic H,K ATPase also act as a Na,K-ATPase? Proc. Natl. Acad. Sci. USA 95:6516–20 51. Verlander JW, Moudy RM, Campbell WG, Cain BD, Wingo CS. 2001. Immunohistochemical localization of HK-ATPase alpha(2c)-subunit in rabbit kidney. Am. J. Physiol. Renal Physiol. 281:F357–F65 52. Wetzel RK, Sweadner KJ. 2001. Immunocytochemical localization of Na-KATPase and subunits in rat kidney. Am. J. Physiol. Renal Physiol. 281:F531 53. Peti-Peterdi J, Bell PD. 2000. Cytosolic [Ca2+] signaling pathway in macula

14 Jan 2003

14:10

498


54.

55.

55a.

56.

57.

58.

59.

60.

61.

AR

BELL

AR177-PH65-20.tex

¥

LAPOINTE

¥

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)

P1: GCE

PETI-PETERDI

densa cells. Am. J. Physiol. Renal Physiol. 277:F472–F76 Salomonsson M, Gonzalez E, Westerlund P, Persson AE. 1991. Intracellular cytosolic free calcium concentration in the macula densa and in ascending llimb cells at different luminal concentrations of sodium chloride and with added furoesemide. Acta Physiol. Scand. 142:283– 90 Lapointe J-Y, Bell PD, Sabirov R, Okada Y. 2002. Calcium-activated non-selective cation channel in macula densa cells Am. J. Physiol. Renal Physiol. Submitted Montell C, Birnbaumer L, Flockerzi V. 2002. The TRP channels, a remarkably functional family. Cell 108:595–98 Liu R, Bell PD, Peti-Peterdi J, Kovacs G, Johansson A, Persson AEG. 2002. Identification of purinergic receptors on rabbit macula densa cells. J. Am. Soc. Nephrol. 13:1145–51 Mitchell KD, Navar LG. 1988. Enhanced tubuloglomerular feedback during pertitubular infusion of angiotensins I and II. Am. J. Physiol. Renal Physiol. 255:F383– F90 Traynor T, Yang T, Huang YG, Krege JH, Briggs JP, et al. 1999. Tubuloglomerular feedback in ACE-deficient mice. Am. J. Physiol. Renal Physiol. 276:F751–F57 Yamamoto T, Hayashi K, Matsuda H, Kubota E, Tanaka H, et al. 2001. In vivo visualization of angiotensin II- and tubuloglomerular feedback-mediated renal vasoconstriction. Kidney Int. 60:364– 69 Schnermann JB, Traynor T, Yang T, Huang YG, Oliverio MI, et al. 1997. Absence of tubuloglomerular feedback responses in AT1A receptor-deficient mice . Am. J. Physiol. Renal Physiol. 273:F315– F20 Ren Y, Carretero OA, Ito S. 1996. Influence of NaCl concentration at the macula densa on angiotensin II-induced constriction of the afferent arteriole. Hypertension 27:649–52

62. Harrison-Bernard LM, Navar LG, Ho MM, Vinson-Dahr GP, El SS. 1997. Immunohistochemical localization of ANG II AT1 receptor in adult rat kidney using monoclonal antibody. Am. J. Physiol. Renal Physiol. 273:F170–F77 63. Wang H, Garvin JL, Carretero OA. 2001. Angiotensin II enhances tubuloglomerular feedback via luminal AT(1) receptors on the macula densa. Kidney Int. 60:1851– 57 64. Peti-Peterdi J, Bell PD. 1998. Regulation of macula densa Na:H exchange by angiotensin II. Kidney Int. 54:2021–28 65. Bell PD, Peti-Peterdi J. 1999. Angiotensin II stimulates macula densa basolateral sodium/hydrogen exchange via type 1 angiotensin II receptor. J. Am. Soc. Nephrol. 10:S225–29 66. Kovacs G, Peti-Peterdi J, Rosivall L, Bell PD. 2002. Angiotensin II directly stimulates macula densa Na:2Cl:K cotransport via apical AT1 receptors. Am. J. Physiol. Renal Physiol. 282: F301–F6 67. Laamarti MA, Bell PD, Lapointe J-Y. 1998. Transport and regulatory properties of the apical Na:K:2Cl cotransporter of macula densa cells. Am. J. Physiol. Renal Physiol. 275:F703–F9 68. Welch WJ, Wilcox CS, Thomson SC. 1999. Nitric oxide and tubuloglomerular feedback. Semin. Nephrol. 19:251–62 69. Ren Y, Garvin JL, Carretero OA. 2000. Role of macula densa nitric oxide and cGMP in the regulation of tubuloglomerular feedback. Kidney Int. 54:2053–60 70. Welch WJ, Wilcox CS. 2002. What is brain nitric oxide synthase doing in the kidney? Curr. Opin. Nephrol. Hypertens. 11:109–15 71. Vallon V, Traynor T, Barajas L, Huang YG, Briggs JP, Schnermann J. 2001. Feedback control of glomerular vascular tone in neuronal nitric oxide synthase knockout mice. J. Am. Soc. Nephrol. 12:1599– 606 72. Harris RC, Breyer MD. 2001. Physiological regulation of cyclooxygenase-2 in the

14 Jan 2003

14:10

AR

AR177-PH65-20.tex

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)

MACULA DENSA CELLS

73.


74.

75.

76.

77.

78.

79.

80.

81.

kidney. Am. J. Physiol. Renal Physiol. 281:F1–F11 Ortiz PA, Garvin JL. 2001. NO inhibits NaCl absorption by rat thick ascending limb through activation of cGMPstimulated phosphodiesterase. Hypertension 37:467–71 Yang T, Park JM, Arend L, Huang Y, Topaloglu R, et al. 2000. Low chloride stimulation of prostaglandin E2 release and cyclooxygenase-2 expression in a mouse macula densa cell line. J. Biol. Chem. 275:37922–29 Peti-Peterdi J, Morishima-Peterdi S, Bell PD, Okada Y. 2002. Two-photon excitation fluorescence imaging of the living juxtaglomerular apparatus. Am. J. Physiol. Renal Physiol. 283:F197–F201 Gonzalez E, Salomonsson M, MullerSuur C, Persson AE. 1988. Measurements of macula densa cell volume changes in isolated and perfused rabbit cortical thick ascending limb. II. Apical and basolateral cell osmotic water permeabilities. Acta Physiol. Scand. 133:159–66 Pricam C, Humbert F, Perrelet A, Orci L. 1974. Gap junctions in mesangial and lacis cells. J. Cell. Biol. 63:349–54 Taugner R, Schiller A, Kaissling B, Kriz W. 1978. Gap junctions coupling between the JGA and glomerular tuft. Cell Tissue Res. 186:279–85 Traynor T, Yang T, Huang YG, Arend L, Oliverio MI, et al. 1998. Inhibition of adenosine-1 receptor-mediated preglomerular vasoconstriction in AT1A receptor-deficient mice. Am. J. Physiol. Renal Physiol. 275:F922–27 Sun D, Samuelson LC, Yang T, Huang Y, Paliege A, et al. 2001. Mediation of tubuloglomerular feedback by adenosine: evidence from mice lacking adenosine 1 receptors. Proc. Natl. Acad. Sci. USA 98:9983–88 Brown R, Ollerstam A, Johansson B, Skott O, Gebre-Medhin S, et al. 2001. Abolished tubuloglomerular feedback and increased plasma renin in adenosine

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

P1: GCE

499

A1receptor-deficient mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281:R1362– R67 Persson PB. 2001. Tubuloglomerular feedback in adenosine A1 receptordeficient mice . Am. J. Physiol. Regul. Integr. Comp. Physiol. 281:R1361 Ren Y, Arima S, Carretero OA, Ito S. 2002. Possible role of adenosine in macula densa control of glomerular hemodynamics. Kidney Int. 61:169–76 Thomson S, Bao D, Deng A, Vallon V. 2000. Adenosine formed by 50 -nucleotidase mediates tubuloglomerular feedback. J. Clin. Invest. 106:289–98 Nishiyama A, Navar LG. 2002. ATP mediates tubuloglomerular feedback. Am. J. Physiol. Regul. Integr. Comp. Physiol. 283:R273–R75 Schnermann J. 2002. Adenosine mediates tubuloglomerular feedback. Am. J. Physiol. Regul. Integr. Comp. Physiol. 283:R276–R77 Gutierrez AM, Lou X, Erik A, Persson G, Ring A. 1999. Ca2+ response of rat mesangial cells to ATP analogues. Eur. J. Pharmacol. 369:107–12 Iijima K, Moore LC, Goligorsky MS. 1991. Syncytial organization of cultured mesangial cells. Am. J. Physiol. Renal Physiol. 260:F848–F55 Mitchell KD, Navar LG. 1993. Modulation of tubuloglomerular feedback responsiveness by extracellular ATP. Am. J. Physiol. Renal Physiol. 264:F458–F66 Inscho EW, Cook AK, Navar LG. 1996. Pressure-mediated vasoconstriction of juxtamedullary afferent arterioles involves P2-purinoceptor activation. Am. J. Physiol. Renal Physiol. 271:F1077–F85 Inscho EW, Cook AK, Mui V, Miller J. 1998. Direct assessment of renal microvascular responses to P2-purinoceptor agonists. Am. J. Physiol. Renal Physiol. 274:F218–F27 Nishiyama A, Majid DS, Taher KA, Miyatake A, Navar LG. 2000. Relation between renal interstitial ATP concenrations

14 Jan 2003

14:10


500

AR

BELL

AR177-PH65-20.tex

¥

LAPOINTE

¥

AR177-PH65-20.sgm

LaTeX2e(2002/01/18)

P1: GCE

PETI-PETERDI

and autoregulation-mediated changes in renal vascular resistance. Circ. Res. 86:656–62 93. Bell PD, Lapointe J-Y, Sabirov R, Hayashi S, Peti-Peterdi J, et al. 2002. Macula densa signaling involves ATP release through a maxi-anion channel. Proc. Natl Acad. Sci. USA. Submitted 94. Dutta AK, Okada Y, Sabirov RZ. 2002. Regulation of an ATP-conductive largeconductance anion channel and swelling-

induced ATP release by arachidonic acid. J. Physiol. 542:803–16 95. Sabirov RZ, Dutta AK, Okada Y. 2001. Volume-dependent ATP-conductive large-conductance anion channel as a pathway for swelling-induced ATP release. J. Gen. Physiol. 118:251–66 96. Ren Y, Carretero, Garvin JL. 2002. Role of mesangial cells and gap junctions in tubuloglomerular feedback. Kidney Int. 62:525–31


22 Jan 2003

21:8

AR

AR177-20-COLOR.tex

AR177-20-COLOR.SGM

LaTeX2e(2002/01/18)

P1: GDL

Figure 1 (A) Depiction of a nephro-vascular unit which illustrates that the distal tubule returns to its own glomerulus and forms a close association. MD, macula densa cells; PT, proximal tubule; TAL, thick ascending limb; DT, distal tubule; CD, collecting duct. (B) Illustration of the relationship between the thick ascending limb with macula densa and the glomerular mesangial cells and vascular elements. This figure also illustrates the tubuloglomerular feedback signal pathway from macula densa to afferent arteriole. (C ) Photomicrograph showing the isolated perfused thick ascending limb-glomerular preparation. The macula densa plaque is clearly visible.

21:8 AR AR177-20-COLOR.tex AR177-20-COLOR.SGM

Figure 4 Immuofluorescence of: (A) apically located NHE2, (B) basolateral NHE4, and (C ) the lack of Na/K ATPase in macula densa cells (taken from 44, 48).


22 Jan 2003 LaTeX2e(2002/01/18) P1: GDL

P1: FDS

January 17, 2003

11:23

Annual Reviews

AR177-FM

Annual Review of Physiology, Volume 65, 2003


CONTENTS Frontispiece—Jean D. Wilson

xiv

PERSPECTIVES, Joseph F. Hoffman, Editor A Double Life: Academic Physician and Androgen Physiologist, Jean D. Wilson

1

CARDIOVASCULAR PHYSIOLOGY, Jeffrey Robbins, Section Editor Lipid Receptors in Cardiovascular Development, Nick Osborne and Didier Y.R. Stainier Cardiac Hypertrophy: The Good, the Bad, and the Ugly, N. Frey and E.N. Olson Stress-Activated Cytokines and the Heart: From Adaptation to Maladaptation, Douglas L. Mann

23 45 81

CELL PHYSIOLOGY, Paul De Weer, Section Editor Cell Biology of Acid Secretion by the Parietal Cell, Xuebiao Yao and John G. Forte Permeation and Selectivity in Calcium Channels, William A. Sather and Edwin W. McCleskey Processive and Nonprocessive Models of Kinesin Movement, Sharyn A. Endow and Douglas S. Barker

103 133 161

COMPARATIVE PHYSIOLOGY, George N. Somero, Section Editor Origin and Consequences of Mitochondrial Variation in Vertebrate Muscle, Christopher D. Moyes and David A. Hood Functional Genomics and the Comparative Physiology of Hypoxia, Frank L. Powell Application of Microarray Technology in Environmental and Comparative Physiology, Andrew Y. Gracey and Andrew R. Cossins

177 203

231

ENDOCRINOLOGY, Bert W. O’Malley, Section Editor Nuclear Receptors and the Control of Metabolism, Gordon A. Francis, Elisabeth Fayard, Frédéric Picard, and Johan Auwerx

261 vii

P1: FDS

January 17, 2003

viii

11:23

Annual Reviews

AR177-FM

CONTENTS

Insulin Receptor Knockout Mice, Tadahiro Kitamura, C. Ronald Kahn, and Domenico Accili The Physiology of Cellular Liporegulation, Roger H. Unger

313 333

GASTROINTESTINAL PHYSIOLOGY, John Williams, Section Editor


The Gastric Biology of Helicobacter pylori, George Sachs, David L. Weeks, Klaus Melchers, and David R. Scott Physiology of Gastric Enterochromaffin-Like Cells, Christian Prinz, Robert Zanner, and Manfred Gratzl Insights into the Regulation of Gastric Acid Secretion Through Analysis of Genetically Engineered Mice, Linda C. Samuelson and Karen L. Hinkle

349 371 383

NEUROPHYSIOLOGY, Richard Aldrich, Section Editor In Vivo NMR Studies of the Glutamate Neurotransmitter Flux and Neuroenergetics: Implications for Brain Function, Douglas L. Rothman, Kevin L. Behar, Fahmeed Hyder, and Robert G. Shulman

401

Transducing Touch in Caenorhabditis elegans, Miriam B. Goodman and Erich M. Schwarz

429

Hyperpolarization-Activated Cation Currents: From Molecules to Physiological Function, Richard B. Robinson and Steven A. Siegelbaum

453

RENAL AND ELECTROLYTE PHYSIOLOGY, Steven C. Hebert, Section Editor Macula Densa Cell Signaling, P. Darwin Bell, Jean Yves Lapointe, and János Peti-Peterdi Paracrine Factors in Tubuloglomerular Feedback: Adenosine, ATP, and Nitric Oxide, Jürgen Schnermann and David Z. Levine Regulation of Na/Pi Transporter in the Proximal Tubule, Heini Murer, Nati Hernando, Ian Forster, and Jürg Biber Mammalian Urea Transporters, Jeff M. Sands Terminal Differentiation of Intercalated Cells: The Role of Hensin, Qais Al-Awqati

481 501 531 543 567

RESPIRATORY PHYSIOLOGY, Carole R. Mendelson, Section Editor Current Status of Gene Therapy for Inherited Lung Diseases, Ryan R. Driskell and John F. Engelhardt The Role of Exogenous Surfactant in the Treatment of Acute Lung Injury, James F. Lewis and Ruud Veldhuizen Second Messenger Pathways in Pulmonary Host Defense, Martha M. Monick and Gary W. Hunninghake

585 613 643

P1: FDS

January 17, 2003

11:23

Annual Reviews

AR177-FM

CONTENTS

Alveolar Type I Cells: Molecular Phenotype and Development, Mary C. Williams


SPECIAL TOPIC: LIPID RECEPTOR PROCESSES, Donald W. Hilgemann, Special Topic Editor Getting Ready for the Decade of the Lipids, Donald W. Hilgemann Aminophospholipid Asymmetry: A Matter of Life and Death, Krishnakumar Balasubramanian and Alan J. Schroit Regulation of TRP Channels Via Lipid Second Messengers, Roger C. Hardie Phosphoinositide Regulation of the Actin Cytoskeleton, Helen L. Yin and Paul A. Janmey Dynamics of Phosphoinositides in Membrane Retrieval and Insertion, Michael P. Czech

SPECIAL TOPIC: MEMBRANE PROTEIN STRUCTURE, H. Ronald Kaback, Special Topic Editor Structure and Mechanism of Na,K-ATPase: Functional Sites and Their Interactions, Peter L. Jorgensen, Kjell O. H˚akansson, and Steven J. Karlish G Protein-Coupled Receptor Rhodopsin: A Prospectus, Slawomir Filipek, Ronald E. Stenkamp, David C. Teller, and Krzysztof Palczewski

ix

669

697 701 735 761 791

817

851

INDEXES Subject Index Cumulative Index of Contributing Authors, Volumes 61–65 Cumulative Index of Chapter Titles, Volumes 61–65

ERRATA An online log of corrections to Annual Review of Physiology chapters may be found at http://physiol.annualreviews.org/errata.shtml

881 921 925