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Kidney International, Vol. 49 (1996), pp.1712—1717

Renal

MARK A. KNEPPER, JAMES B. WADE, JAMES TERRIS, CAROLYN A. ECELBARGER, DAVID MARPLES, BEATRICE MANDON, CHUNG-LIN CHOU, B.K. KISHORE, and SØREN NIELSEN

Laborato,y of and Metabolism, National Heart, and Blood Institute, National Institutes of Health, Bethesda, Matyland, USA; Department of Cell Biology, Institute of Anatomy, University of Aarhus, Aarhus, Denmark; and Department of Physiology, University of Maiyland College of Medicine, Baltimore, and Department of Physiology, Unifornied Services University of the Health Sciences, Bethesda, Maiyland, USA

Renal aquaporins. Aquaporins (AQPs) are a newly recognized family of gate the localization and regulation of the four renal aquaporins transmembrane that function as molecular channels. At (AQP1, AQP2, AQP3 and AQP4). least four aquaporins are expressed in the kidney where they mediate is concentrated as a result of the combined function of rapid water transport across water-permeable epithelia and play critical roles in urinary concentrating and diluting processes. AQP1 is constitu- the , which generates a high osmolality in the renal tively expressed at extremely high levels in the proximal and medulla by countercurrent multiplication, and the collecting duct, descending limb of Henle's loop. AQP2, -3 and -4 are expressed predom- which, in the presence of the antidiuretic , inantly in the . AQP2 is the predominant water permits osmotic equilibration between the urine and the hyper- channel in the apical plasma membrane and AQP3 and -4arefound in the basolateral plasma membrane. Short-term regulation of collecting duct tonic medullary interstitium. Aquaporins expressed at both sites water permeability by vasopressin is largely a consequence of regulated play important roles in the overall concentrating process. AQP1 is trafficking of AQP2-containing vesicles to and from the apical plasma the predominant water channel of the loop of Henle, while AQP2, membrane. -3 and -4mediatewater transport in collecting ducts. In this review, we first consider the mechanism of water transport in the loop of Henle and then in the collecting duct. The ability of the mammalian kidney to concentrate and dilute the urine, and thus to regulate body water balance, depends on Water channels and loop of Henle water transport the presence of a discrete segmental distribution of solute and Descending ioop of Henle. The loop of Henle plays a central role water transport properties along the and collecting ductin the urinary concentration process by generating a corticomed- system [1]. Investigation of these properties by micropuncture andullary osmolality gradient in the renal interstitium. Based on the by in vitro perfusion techniques has led to remarkable progressoriginal work of Kokko [15], it has long been recognized that the over the past 20 years in our understanding of water balanceosmotic water permeability of the thin descending limb of Henle's regulation and dysregulation. The recent cloning of cDNAs forloop is extremely high, and that the high water permeability plays many of the proteins that are responsible for these transportan essential role in the countercurrent multiplication process by properties opens the door for renewed progress by providing newallowing complete osmotic equilibration of the luminal fluid with tools that are capable of revealing the fundamental mechanismsthe surrounding interstitium [1]. Figure 1 shows osmotic water of transport regulation at the level of the transporter proteins.permeability coefficients measured in the individual loop of Henle Among these transport proteins are the water channelssegments of the chinchilla, a rodent species capable of concen- (Table 1) that are responsible for rapid water transport acrosstrating its urine to above 4,000 mOsm/kg H20. As shown in Figure water-permeable epithelia in the kidney [2—5]. The cDNA for the1, the water permeability of the descending limb is extremely high first such water channel to be identified, CHIP28 (now calledthroughout most of its length. (In contrast to most of the length of aquaporin-CHIP or aquaporin-1), was cloned by Preston et al [6,the long-loop thin descending limb, the terminal pre-bend 7]afterthe protein had been purified from erythrocyte mem-(LDLI) possesses a relatively low water permeability [17]. Immu- branes in the laboratory of Peter Agre [8]. This landmark eventnocytochemical studies reveal that this part of the descending was followed very rapidly by the cloning of three more relatedlimb expressed little or no aquaporin-1 [17].) renal water channels expressed in the kidney (Table 1). Although Ascending limb of Henle. In contrast, the osmotic water perme- a variety of names were initially applied to these water channels,abilities of the thin and thick portions of the ascending limb of most workers now use the nomenclature indicated in Table 1 inHenle's loop are extremely low. Prior to the discovery of the which the aquaporins (AQPs) are numbered in order of theiraquaporin water channels, the mechanism of rapid water perme- discovery. The purpose of this short review is to discuss recentation in the descending limb was unknown. As discussed below, work (published through October 1, 1995), which has been carriedaquaporin-1 is constitutively expressed in the descending limb at a out in our laboratories utilizing polyclonal antibodies to investi-high level allowing extremely rapid water transport across the descending limb cells. Aquaporin-1 expression. In the kidney, aquaporin-1 (CHIP28) is expressed in the and descending limb of Henle's © 1996 by the International Society of Nephrology loop [8, 18, 19]. Thus far, it is the only water channel known to be

1712 Knepper et al: Renal aquaporins 1713

Table1. Properties of aquaporins

Ordinal Common Polypeptide Permeability to Mercurial Regulation by name names length (a.a.) small solutes sensitivity vasopressin References AQP1 CHIP 28 269 No Yes No [6, 8] AQP2 WCH-CD 271 No Yes Yes [9] AQP-CD AQP3 AQP-3 285 , Glycerol Yes No [10—121 AQP-CD 2 AQP4 AQP-4 301 No No No [13, 14] MIWC

Osmotic water permeabilities in chinchilla thin limbs be present in the thick or thin portions of the ascending limb l.Lm/sec where the water permeability is very low. Subcellular localization of aquaporin-1 using the immunogold technique in ultra-thin sections revealed heavy labeling of both the apical and basolateral Outer medulla plasma membranes [18, 19], suggesting that rapid water transport (outer stripe) across the proximal tubule and descending limb epithelia is mediated by aquaporin-1 at both plasma membrane barriers. 2584162 Inner medulla The descending limb of Henle's loop is heterogenous with (N=7) (inner stripe) regard to the level of aquaporin-1 expression. The terminal pre- bend region of both the short-loop [211 and long-loop [17] descending limbs appear to possess little or no immunoreactive aquaporin-1. Mathematical modeling studies by Layton and Da- vies [22] demonstrated that the presence of a water-impermeable 1520 249 pre-bend descending limb segment in the inner medulla has the LDLm Inner medulla (N=12) potential to enhance concentrating capacity by allowing luminal dilution to occur and to be fully developed prior to the beginning of the ascending limb.

Regulation of collecting duct water channels 50 15 3±2 LDL1 ATL Urinary osmolality and the rate of water excretion are regulated (N=7) (N=6) reciprocally through the control of two variables: the medullary interstitial osmolality and the collecting duct water permeability. The control of interstitial osmolality is believed to occur as a result of regulated NaCI and urea transport along the renal tubule and does not appear to involve direct regulation of water permeation Fig.1. Diagram of chinchilla long ioop of Henle showing osmotic water in the loop of Henle [1]. In contrast, in the collecting duct system permeability profile [16]. were microdissected from the chinchilla and perfused in vitro. Osmotic water permeability (in water permeability is precisely regulated to allow tight control of jLm/second) was determined by measuring the water flux resulting from an urinary water excretion. There are at least two modes of regula- imposed bath>lumen osmotic gradient using fluorescein dextran as a tion of osmotic water permeability in the collecting duct, viz. volume marker. Abbreviations are: LDL, long-loop descending limb; short-term and long-term regulation. Short-term regulation is the ATL, ascending thin limb. Subscripts refer to upper (u), middle (m), and familiar rapid increase in collecting duct water permeability in lower (I) portions of LDL. Note that the osmotic water permeability of the descending limb is extremely high throughout most of its length. The response to vasopressin, initially characterized in vasopressin- terminal pre-bend descending limb (LDLI or "papillary descending limb") responsive amphibian epithelia [reviewed in 23—26]. This response however has a much lower permeability corresponding to the site where occurs within a few minutes of vasopressin exposure and is rapidly aquaporin-1 is absent [17]. Water permeability of the ascending limb is extremely low, correlating with the absence of any known renal water reversible. Vasopressin triggers this response by binding to the V2 channel. subtype whose effector enzyme is adenylyl cyclase. The increase in water permeability is mediated by a rise in the intracellular level of cyclic AMP (see recent reviews [1, 27]). Long-term regulation, described initially by Lankford and col- expressed in these segments. Quantification of aquaporin-1 pro-leagues [28], is characterized by a sustained conditioned increase tein in microdissected rat renal tubule segments using a fluores-in collecting duct water permeability in response to prolonged cence-based ELISA [201 revealed extremely high levels of expres- antidiuresis. This response requires 24 or more hours to elicit and sion, greater than 20 million copies per cell in the proximal tubuleis not rapidly reversible. This conditioning effect has been pro- and even higher levels in descending limbs. These extraordinarilyposed to play an important role in the long-term regulation of high values correlate well with very high water permeabilityurinary concentrating capacity. In the remainder of this review we coefficients measured in isolated perfused proximal tubules andsummarize the role of the collecting duct aquaporins in short-term descending limbs. In contrast, little or no aquaporin-1 appears toregulation of water permeability. 1714 Knepperet at: Renal aquaporins

AQPZ AQP2 in isolated perfused tubules before and after exposure to Apical vasopressin [33] (see below). Aquaporins 3 and 4. Immunofluorescence and immunoperoxi- dase localization of aquaporin-3 [12, 35, 36] and aquaporin-4 [35, 37] at a light microscopical level in the rat kidney has revealed that both water channels are present in the basolateral region of collecting duct principal cells and inner medullary collecting duct cells, but not elsewhere in the kidney. Using immunoperoxidase techniques in semi-thin cryosections [36], we have demonstrated that aquaporin-3 is distributed throughout the collecting duct system from cortex to papillary tip, whereas aquaporin-4 is restricted predominantly to the collecting ducts of the outer third of the inner medulla and the inner stripe of the outer medulla. Immunoelectron microscopy (immunogold technique) showed that aquaporin-3 and aquaporin-4 are predominantly present in the basolateral plasma membrane of collecting duct principal Basolateral AQP3 0rAQP4 cells, consistent with the proposed role for both as mediators of basolateral water transport in the collecting duct. Unlike aqua- Fig. 2. Diagram of collecting duct principal cell showing localization of aquaporin water channels. Symbols are: (-U-) Aquaporin-2; (-ti-)Aqua- -2, neither aquaporin-3 or aquaporin-4 was abundant in porin-3; (V-) Aquaporin-4. intracellular vesicles, suggesting that neither is regulated by membrane shuttling. Although both aquaporin-3 and aquaporin-4 were localized to the basolateral plasma membrane, the two water channels differed with regard to distribution between basal and lateral domains [37], with predominance of aquaporin-3 in the Cellular and subcellular immunolocalization of collecting duct lateral membrane and a nearly equal distribution of aquaporin-4 water channels between lateral and basal domains. Figure 2 summarizes the localization of the three collecting duct water channels. Aquaporin-2 is found predominantly in the Mechanism of short-term regulation of inner medulla.'y collecting apical plasma membrane and in intracellular vesicles within duct (IMCD) water permeability by vasopressin collecting duct principal cells of cortex, outer medulla, and inner Vasopressin triggers a rapid increase in the transepithelial medulla. Aquaporin-3 and -4 are present predominantly in thewater permeability of the renal collecting duct [38, 39], accounting basolateral membrane of collecting duct principal cells. Thefor the ability of the kidney to rapidly regulate water excretion. evidence for this localization is reviewed in the remainder of thisWe have investigated the kinetics of the vasopressin response in section. isolated perfused IMCD segments using a fluorescent marker, Aquaporin-2. Immunolocalization studies at the light micro-fluorescein sulfonate, to monitor transepithelial water flux [40, scopical level using immunofluorescence [9] and immunoperoxi-41]. The osmotic water permeability begins to rise within 40 dase techniques [29] revealed that aquaporin-2 is expressedseconds of exposure of the IMCD to vasopressin [40]. A rapid rise predominantly in the apical region of the collecting duct principalin water permeability ensues with a half-maximal response within cells and inner medullary collecting duct cells. Quantification ofeight minutes and a full response within 40 to 50 minutes of AQP2 protein in microdissected rat renal tubule segments using avasopressin exposure [40, 41]. Upon washout of vasopressin, the highly-sensitive fluorescence-based ELISA technique [30] haswater permeability rapidly falls. Similar kinetics are seen in revealed high levels of expression throughout the collecting ductresponse to exposure of isolated IMCDs to cyclic AMP analogs, system. In the middle part of the IMCD, an average of 12 millionindicating that binding of vasopressin to V2 receptors and gener- copies per cell was found, correlating with the high permeabilityation of cyclic AMP within the cells is not rate-limiting for the of this segment in the presence of vasopressin. In contrast, little oroverall response. Flamion and Spring [42] showed that vasopres- no AQP2 protein could be detected in proximal tubules or loop ofsin increases transepithelial water permeability chiefly by increas- Henle segments. Unexpectedly, AQP2 was found also in connect-ing the water permeability of the apical plasma membrane. This ing tubule arcades from rats [31]. The presence of AQP2 infinding, together with the observation that AQP2 is the predom- connecting tubule segments was confirmed by immunocytochem-inant water channel of the apical plasma membrane of collecting ical colocalization with two connecting tubule markers, kallikreinduct principal cells (see above), suggested that AQP2 is the and the Na/Ca exchanger. "vasopressin-regulated water channel." Indeed, as noted above, Subcellular immunolocalization of AQP2 in rat collecting ductthe presence of AQP2 in both the apical plasma membrane and in principal cells using the immunogold technique revealed strongintracellular vesicles suggests the possibility that the short-term labeling of both the apical plasma membrane and of smallaction of vasopressin to increase apical membrane water perme- subapical vesicles (Fig. 3) [29, 32, 331.Thislocalization is fullyability in collecting duct cells may be a consequence of exocytosis consistent with the hypothesis that AQP2 may shuttle fromof water-channel containing intracellular vesicles resulting in intracellular vesicles to the apical plasma membrane via vasopres-insertion of AQP2 water channels into the apical plasma mem- sin-stimulated exocytosis, as originally proposed by Wade et albrane (the "shuttle hypothesis"). [34] (the "shuttle hypothesis"). We have subsequently directly Shuttle mechanism. To test the shuttle hypothesis in IMCDs, we demonstrated such a shuttling process by immunolocalization ofused our antibody to AQP2 for quantitative immunoelectron Knepper et al: Renal aquaporins 1715 / A --' NJ

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\-fr - .--_ p re -AVP I IIIt II, II I' 3 1 B \%_a\ i. -"--S -—. .-,.-'..-. - I' .b—i•..

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Fig.3. Immunogold localization of aquaporin-2 in cells from isolated perfttsed inner medullaiy collecting ducts prior to vasopressin exposure (pre- A VP), 40 minutes after vasopressin addition (A VP), and 40 minutes after vasopressin washout (post-A VP) [33]. Quantification of gold particle M,VB distribution (Fig. 4) documented that - ._ vasopressin exposure induced a reversible translocation of aquaporin-2 from intracellular vesicles to the apical plasma membrane, post -AVP providing direct evidence for the shuttle hypothesis. microscopy in tubules that were perfused in vitro and fixed on theaccompanied by a shift in AQP2 labeling back to intracellular perfusion pipets in the presence and absence of exposure tovesicles. These results therefore demonstrate directly that vaso- arginine vasopressin (AVP) [33]. This approach allowed us topressin induces a reversible translocation of AQP2 water channels assess the distribution of AQP2 water channels between intracel-from intracellular vesicles to the apical plasma membrane and lular vesicles and the apical plasma membrane in tubules in whichhence provides direct verification of the shuttle hypothesis. Addi- osmotic water permeability was measured fluorometrically justtional studies both by us [43] and others [44, 45] have also prior to addition of fixative. Three groups of tubules were studied:demonstrated vasopressin-induced translocation of AQP2 to the pre-AVP, AVP, and post-AVP IMCDs. The pattern of labeling inapical plasma membrane of collecting duct cells in vivo, providing representative ultrathin sections from each of the three groups ofbroad support for the shuttle hypothesis and demonstrating that tubules is shown in Figure 3 [33] and the measured distribution ofAQP2 trafficking is relevant to the in vivo regulation of collecting AQP2 labeling is shown in Figure 4. As illustrated in both figures,duct water permeability. there was a clear shift in AQP2 labeling from intracellular vesicles Possible role of vesicle ta,geting receptors ("SNAREs"). The (IV) to the apical plasma membrane (APM) in response tofinding of vasopressin-stimulated exocytosis of AQP2-containing exposure of the collecting ducts measured increase in osmoticvesicles raises additional questions regarding the mechanism: (1) water permeability in the same tubules. Furthermore, whenHow are the AQP2-containing vesicles targeted to the apical vasopressin was washed out of the peritubular bath surroundingplasma membrane? (2) What is the molecular switch by which a the perfused tubules, there was a decrease in water permeabilityrise in intracellular cyclic AMP initiates translocation of vesicles? 1716 Knepper et al: Renal aquaporins

A B 500 1.6 Fig. 4. Osmotic water permeability values and ratios of gold particles in apical plasma - 450 1.4 membrane (APM) to intracellular vesicles (IV) of 400 inner medullaty collecting ducts fixed for .2 1.2 immuno-electron microscopy. A. Osmotic water 350 permeability. As normally seen, vasopressin exposure induced a large increase in 300 transepithelial water permeability. Vasopressin withdrawal decreased the permeability. 250 0.8 Numerals in bars show the number of tubules 200 perfused in each group. B. Ratio of gold 0.6 particles in apical plasma membrane (APM) to 150 intracellular vesicles (IV) of the same inner < 0.4 medullary collecting ducts summarized in A 100 above. In association with the rise in water E 0.2 permeability, there was a marked increase in 0(1) 50 apical membrane labeling with an overall 0 0.0 increase in the APM:IV labeling ratio. With vasopressin washout, the increase in the APM: Pre-AVP AVP Post-AVP Pre-AVP AVP Post-AVP IV labeling ratio was reversed.

Although answers to these questions are not available at this 3. NIELSEN S, AGRE P: The aquaporin family of water channels in kidney. point, we have begun to identify proteins present in AQP2- Kidney mt 48:1057—1068, 1995 containing vesicles and in the apical plasma membrane that could 4. VERKMAN AS, SHI L-B, FRIGERI A, HASEGAWA H, FARINAS J, MITRA A, SKACH W, BROWN D, VAN HOEK AN, MA T: Structure and function potentially play an important role in the docking and fusion of of kidney water channels. Kidney mt 48:1069—1081, 1995 AQP2-containing vesicles. 5. SASAKI S, FUsHIMI K, IsHIBAsHI K, MARUMO F: Water channels in the An important group of proteins has recently been identified kidney collecting duct. Kidney mt 48:1082—1087, 1995 that mediates vesicle targeting in the Golgi apparatus and the 6. PRESTON GM, AGRE P: Isolation of the eDNA for erythrocyte integral exocytosis of synaptic vesicles [461.Thesevesicle-targeting pro- membrane protein of 28 kD: Member of an ancient channel family. teins (also called "SNAREs" or "SNAP-receptors") are intrinsic Proc NatlAcad Sci USA 88:11110—11114, 1991 7. PRESTON GM, CARROLL TP, GUGGINO WP, AORE P: Appearance of membrane proteins that are present either in translocating vesi- water channels in Xenopus oocytes expressing red cell CHIP28 des ["VAMPs" ("vesicle-associated membrane proteins") or protein. Science 256:385—387, 1992 "synaptobrevins"] or in the target membrane ("syntaxins"). These 8. DENKER BM, SMITH BL, KUHAJDA FP, AGRE P: Identification, proteins are believed to determine the specificity of vesicular purification, and partial characterization of a novel Mr 28,000 integral docking and fusion. We have immuriolocalized one of these membrane protein from erythrocytes and renal tubules. J Biol Chem proteins, VAMP-2, to intracellular vesicles of collecting duct cells 263:15634—15642, 1988 9. FUSHIMIK,UCHIDA S, HARA Y, HIRATA Y, MARUMO F, SASAKI S: [47] and have demonstrated using two methods (double-labeling Cloning and expression of apical membrane water channel of rat immunoelectron microscopy and immuno-isolation of vesicles) kidney collecting tubule. Nature 361:549—552, 1993 that VAMP-2 is present in AQP2-containing vesicles. Thus, we 10. ECHEVARRIA M, WINDHAGER EE, TATE SS, FRINDT G: Cloning and hypothesize that VAMP-2 may play a role in targeting of water expression of AQP3, a water channel from the medullary collecting channel containing vesicles to the plasma membrane, although duct of rat kidney. Proc NatlAcad Sci USA 91:10997—11001, 1994 11. MA T, FRIGERI A, HASEGAWA H, VERKMAN AS: Cloning of a water such a role has not been definitively established. channel homolog expressed in brain meningeal cells and kidney collecting duct that functions as a stilbene-sensitive glycerol trans- Acknowledgments porter. J Biol Chem 269:21845—21849, 1994 The work described herein was supported by the intramural budget of 12. ISHIBASHI K, SASAKI 5, Fusi-uMI K, UCI-IIDA 5, KUWAHARA M, SAIT0 the National Heart, Lung, and Blood Institute (iT, CAE, BM, BKK, CC, H, FURUKAWA T, NAKAJIMA K, YAMAGUCHI Y, G0J0B0RI T, MA- MAK), as well as the Danish Research Academy, the Novo Nordic RUMO F: Molecular cloning and expression of a member of the Foundation, the Danish Medical Council, the University of Aarhus aquaporin family with permeability to glycerol and urea in addition to Research Foundation, the Danish Foundation for the Advancement of water expressed at the basolateral membrane of kidney collecting duct Medical Science, and the Biomembrane Research Center (DM and SN) cells. Proc NatlAcad Sci USA 91:6269—6273, 1994 and NIDDK grant #DK-32839 (JBW). CE was supported by NIH 13. HASEGAWA H, MA T, SKACH W, MATrHAY MA, VERKMAN AS: National Research Service Award Fellowship #DK08832-02. Molecular cloning of a mercurial-insensitive water channel expressed in selected water-transporting tissues. J Biol Chem 269:5497—5500, Reprint requests to Mark A. Knepper, MD., Ph.D., National Institutes of 1994 Health, Building 10, Room 6N307, 10 Center Drive MSC 1598, Bethesda, 14. JUNGJS,BHAT RV, PRESTON GM, GUGGINO WB, BARABAN JM, Maryland 20892-1598, USA. E-mail: [email protected] AGRE P: Molecular characterization of an aquaporin eDNA from brain: Candidate osmoreceptor and regulator of water balance. Proc References NatlAcad Sci USA 91:13052—13056, 1994 15. KOKKO JP: chloride and water transport in the descending 1. KNEPPER MA, RECTOR FC JR: Urinary concentration and dilution, in limb of Henle. J Clin Invest 49:1838—1846, 1970 The Kidney, edited by BRENNER BM, RECTOR FC JR, Philadelphia, 16. CHOU CL, KNEPPER MA: In vitro perfusion of chinchilla thin limb Saunders, 1995, pp 532—570 segments: Segmentation and osmotic water permeability. Am J Physiol 2. KNEPPER MA: The aquaporin family of molecular water channels. 263:F417—F426, 1992 Proc NatlAcad Sci USA 91:6255—6258, 1994 17. CHOU CL, NIELSEN 5, KNEPPER MA: Structural-functional correlation Knepper et al: Renal aquaporins 1717

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