Regulation of water movement across vertebrate renal tubules

Comparative Biochemistry and Physiology Part A 136 (2003) 479–498

Review

Regulation of water movement across vertebrate renal tubules夞 Hiroko Nishimura*, Zheng Fan Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, USA Received 23 January 2003; received in revised form 2 June 2003; accepted 3 June 2003

Abstract Kidneys play an essential role in fluid-ion balance, but the mechanisms of renal handling of water vary depending on structural organization of kidneys and the environment. Fishes and amphibians in a hypoosmotic environment excrete excess water by forming dilute urine, whereas terrestrial tetrapods require water conservation by the kidney for survival. Diluting segments operated by a luminal Naq –Kq –2Cly cotransporter coupled with a basolateral Naq –Kq pump are essential in forming dilute urine. In birds and mammals, the diluting segment that has the same transport characteristics now serves, with the development of additional architectural organization, for countercurrent urine concentration and water conservation. Recently, a number of aquaporin (AQP) water channels have been identified in various transporting epithelia. AQPs conserve the NPA (asparagine–proline–alanine) motif, forming pores selective to water. Although all vertebrate kidneys presumably possess AQP water channels, AQP homologues have been cloned only from amphibian, avian and mammalian renal systems. Studies on expression sites, function and regulation of AQPs will provide important insight into cellular and molecular mechanisms of epithelial water transport and its control by humoral, neural and hemodynamic mechanisms. 䊚 2003 Elsevier Science Inc. All rights reserved. Keywords: Aquaporins; Fluid homeostasis; Urine dilution; Urine concentration; Vasotocin; Water transport; Renal handling of water; Osmotic challenge; Vertebrate kidneys

1. Body fluid compartments and fluid balance Approximately 60% of the body weight is water. In living organisms, equilibration between extraAbbreviations: ADH, antidiuretic hormone; AQP, aquaporin; AVT, arginine vasotocin; AL, ascending limb; CD, collecting duct; FW, fresh water; GFR, glomerular filtration rate; NDI, nephrogenic diabetes insipidus; SW, seawater; UT, urea transporter; UyP, urine to plasma ratio; MIP, major intrinsic protein; CHIP, channel-forming integral protein. 夞 This paper is based on a presentation given in the symposium ‘Regulation of Vertebrate Renal Function: A Comparative Approach’, part of the American Physiological Society meeting The Power of Comparative Physiology: Evolution, Integration, and Application, San Diego, California, USA, August 24–28, 2002. *Corresponding author. Tel.: q1-901-448-5132, 5840; fax: q1-901-448-7126. E-mail address: [email protected] (H. Nishimura).

cellular and intracellular fluid compartments is maintained by movement of water. Water movement is a passive transmembrane process, driven by osmotic gradients that are formed by ionic and non-ionic solutes. The rate of water transport or permeability of the epithelial membrane is determined by membrane composition; for example, the membrane may consist of thin lipid layers (high permeability) or may contain high cholesterol (low permeability), as in the collecting duct (CD) of the kidney. During a physiological process, changes in the rate of water transport are induced by: (1) stimulating (or inhibiting) hormones (such as antidiuretic hormone, ADH); (2) changing the rate of water delivery (as often seen in nephrons); and (3) inserting water channels into the membrane. In non-mammalian vertebrates, several osmoregulatory organs besides the kidney play important

1095-6433/03/$ - see front matter 䊚 2003 Elsevier Science Inc. All rights reserved. doi:10.1016/S1095-6433(03)00162-4

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roles in body fluid-ion balance; these include the gill, gastrointestinal tract, skin and more specific organs, such as salt glands in birds and rectal glands in elasmobranchs. Also, the role of the kidney changes depending on environment and habitat. This brief review will focus on (1) the role of the kidney, specifically the distal nephron andyor renal medulla, in water homeostasis in vertebrates that live in aquatic and terrestrial environments; and (2) aquaporin (AQP) water channels, one of the more recent topics in water homeostasis research in both mammalian and nonmammalian vertebrates. Readers should refer to the reviews by Yokota (2003) and Dantzler (2003) in the present symposium proceedings for the discussion of water movement via glomeruli and renal proximal tubules. 2. Nephron structure and water balance in vertebrates 2.1. Aquatic vertebrates The role of the kidney can be classified in three categories: (1) excretion of excess water as a dilute urine, as exemplified in hyperosmoregulation by fresh water (FW) fishes and aquatic amphibians; (2) water conservation in hyperosmotic media by marine fish or in arid environments by certain species of amphibians and reptiles; and (3) conservation of water by urine concentration, as seen in birds and mammals (for review, see Dantzler, 1989; Braun and Dantzler, 1997; Elger et al., 2000; Nishimura, 2000; Nishimura and Fan, 2002). The kidneys of the most primitive living vertebrates, marine cyclostomes, have large glomeruli and archinephric ducts and solute and water absorptions from renal tubules are only minimal. Their internal osmolality largely depends on that of the external media, and their urine–plasma (Uy P) osmolal ratio is one (Table 1). In contrast, FW cyclostomes, such as river lampreys, have acquired the CD as a distal nephron segment. FW lampreys excrete the excess volume of water invading their body along the osmotic gradient as copious urine, while the distal nephron selectively reabsorbs NaCl to maintain internal osmolality constant (Logan et al., 1980a,b). Thus, the evolution of distal nephrons, such as CD acquisition, enables animals

to survive in hypoosmotic media by maintaining internal osmolality higher than that of the surrounding environment. In elasmobranchs, another evolutionary line of cartilaginous fish, the kidney grows by continuous formation of new nephrons; hence, their renal corpuscles, often suffused by multiple afferent arterioles, vary in size and in the state of differentiation (Hentschel, 1991). Plasma osmolarity is maintained equivalent to the surrounding seawater (SW) by recycling the osmotically active substances such as urea and trimethylamine oxide (Elger et al., 2000; Friedman and Hebert, 1990), possibly via a specific urea transporter (UT) (Smith and Wright, 1999). Elasmobranchs ingest SW, and much of the reabsorbed NaCl (usually two-thirds of the filtered amount is reabsorbed with great variation) can be secreted via a rectal gland (for review, Braun and Dantzler, 1997). Net fluid secretion usually occurs in the second segment of the proximal tubule and in the distal nephrons (Schmidt-Nielsen, 2003). This fluid secretion may be important, first, for excreting divalent ions when the glomerular filtration rate (GFR) is low (Braun and Dantzler, 1997) and second, for diluting the urea concentration in urine (Schmidt-Nielsen, 2003). The highly complex organization of elasmobranch tubule segments, forming in part a countercurrent arrangement, may contribute to the effective reabsorption and possible recirculation of urea; but, differing from the loop of Henle in birds and mammals, the countercurrent organization of elasmobranch kidneys cannot form hyperosmotic urine (Elger et al., 2000). In FW teleosts and aquatic amphibians, the nephron segments are more complex than in FW cyclostomes. Their nephrons consist of well-developed glomeruli, the first and second segments of proximal tubules, early distal tubules and collecting tubules and CDs (for review, see Hickman and Trump, 1969; Elger et al., 2000). The major role of the kidney in terms of fluid homeostasis is to eliminate excess water while retaining ions. The GFR of teleosts is in general higher in FW than in SW (Table 1). Fluid and solute reabsorption across the proximal tubules is primarily isoosmotic, whereas the early distal segment acts as a diluting segment in which NaCl is selectively reabsorbed, leaving water behind (see Section 3.1). Approximately 60–80% of filtered water can be

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481

Table 1 Urine dilution and concentration Species

Environmenty GFR UF Osm Inulin UFyGFR Refs. Treatment (mlØkgy1Øhy1) (mlØkgy1Øhy1) (UyP) (UyP) (%)

Cyclostomes Hagfish SW River lamprey FW 50% SW

0.31 25.1"2.3 4.6"1.5

0.29 14.0"1.2 1.5"0.6

1.0 0.13

Elasmobranchs Dogfish

SW

3.5"0.1

1.2"0.1

0.80

FW FW SW SW

8.2"1.1 2.2"0.4 2.1"0.2 1.4"0.3

6.6"0.5 1.5"0.2 0.8"0.2 0.5"0.1

0.23 0.15 0.59 0.97

FW Semiaquatic

26.2"2.6

14.2"1.6

0.17

7.4"1.0

4.9"0.2

4.7"0.7 2.8"0.9 10.3"2.0 104.0"18.0 124.0"33.1 127.4"28.4 52.8"2.4 9.0"1.2

Teleosts Catfish Eel Flounder Amphibians Bullfrog Mud puppy Reptiles FW turtle

Controlb Salt load Water load

Birds Domestic fowl Dehydration Salt load Water load Desert quail Controlc Salt-load

93 55.7 32.6

Hickman and Trump, 1969 Logan et al., 1980a Logan et al., 1980b

34.2

Hickman and Trump, 1969

1.27 1.30 3.81

80.5 68.2 38.0 35.7

Nishimura, 1977 Schmidt-Nielsen and Renfro, 1975 Schmidt-Nielsen and Renfro, 1975 Renfro, 1980

3.51

54.1

Long, 1973

0.15

66.2

Garland et al., 1975

1.3"0.2 0.4"0.1 3.6"0.9

0.62 0.84 0.60

3.38a 27.6 8.30a 14.3 3.56a 34.9

1.58 1.06 0.37 0.99

Water load

83.4"13.2

1.1"0.2 10.9"8.0 17.9"8.9 11.2"0.5 80% decrease 6.24"1.08

Controlb Dehydration DI

107 107 107

1.42 0.29 13.9

1.05 1.87 8.0

84.7 19.8 9.62 4.7 3.2

1.05 8.79 14.1 21.2

7.5

Mammals Humand

Dantzler and Schmidt-Nielsen, 1966 Dantzler and Schmidt-Nielsen, 1966 Dantzler and Schmidt-Nielsen, 1966 Skadhauge and Schmidt-Nielsen, 1967 Skadhauge and Schmidt-Nielsen, 1967 Skadhauge and Schmidt-Nielsen, 1967 Dantzler and Braun, 1980

Guyton and Hall, 1996 Dantzler, 1989

White rat Sand rat

1.0 4.8 0.1 8.9 17.0

1.3 0.3 12.9 Dantzler, 1989 Dantzler, 1989

a Creatinine UyP ratio. bNormal hydration. c Mannitol infusion, dAssumed body mass of 70 kg. GFR: glomerular filtration rate; UF: urine flow. SW: seawater; FW: fresh water.

excreted as dilute urine; hence, the osmolal UyP ratio is low (Table 1). The role of the kidney in fluid balance in marine teleosts is entirely different. Marine teleosts are exposed to the danger of constant salt loading and dehydration. Hence, marine teleosts drink SW, absorb both water and minerals from the gut, and retain water, while NaCl is excreted primarily from the gill. Marine teleosts have well-developed proximal tubules, but the glomeruli are smaller and the distal nephrons show various degrees of degeneration. Nephrons reabsorb NaCl to restore water, but the osmolal UyP ratio is nearly unity because

of divalent ions (mainly those such as Mg and sulfate) excreted in the urine (Table 1) (Renfro, 1999). Thus, the percentage of filtered water excreted (urine flowyGFR) may be as high as 35– 40%, indicating that, although marine teleosts have to conserve water, their kidneys are still losing a considerable amount of water. 2.2. Vertebrates on land For terrestrial vertebrates, water economy is a prerequisite for survival. Their major osmoregulatory organ is the kidney, supplemented by the gut,

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cloaca, skin or salt gland. Although the kidneys of amphibians (and perhaps reptiles) possess a diluting segment having virtually the same transport properties as the thick ascending limb (thick AL) of Henle of mammalian kidneys, amphibian and reptilian kidneys cannot form hyperosmotic urine because of their lack of architectural structure. In avian kidneys, two types of nephrons are present: short cortical loopless nephrons that cannot form concentrated urine, and medullary looped nephrons that have Henle’s loop and CDs running in parallel. Thus, birds have the anatomical basis for operating a countercurrent multiplier mechanism for urine concentration (for review, see Dantzler and Braun, 1980; Dantzler, 1989; Nishimura, 1993; Braun and Dantzler, 1997). In general, however, the urineconcentrating and diluting ability of birds appears limited (see Section 3.3). After water deprivation, domestic fowl still lose over 1% of filtered water (Table 1). The usual maximal osmolal UyP ratio after dehydration is 1.5–2.5. In mammalian kidneys, the homeostasis of extracellular fluid volume and ion concentration is well maintained by renal mechanisms involving neural and humoral control systems that allow the maintenance of plasma osmolarity within a narrow range. In mammals, in which the kidney is the sole osmoregulatory organ, the osmolal UyP ratio is generally higher than in birds and varies among species. The urine-concentrating ability of rodents, particularly those living in desert areas, is high (Table 1) (for review, see Dantzler and Braun, 1980; Dantzler, 1989; Braun and Dantzler, 1997). One of the major structural differences between long-looped nephrons of mammalian kidneys and looped nephrons of avian kidneys is that the mammalian long-looped nephron has a thin AL as part of the inner medulla. Filtered water is usually reabsorbed from the proximal tubule (65% or more) and descending limb of Henle (approx. 15%). The rest of the water is absorbed from distal convoluted segments, connecting tubules and collecting tubules and CDs, depending on the permeability of epithelial tissues determined by the level of ADH. The thin AL, thick AL and early distal tubules are water-impermeable. Water deprivation can reduce the excreted amount of filtered water to ;0.3%, whereas as much as 13% of filtered water is excreted if no ADH is present (complete diabetes insipidus); yet fluid homeostasis is maintained in humans so long as sufficient water and salt intake continues (Table 1).

Fig. 1. Schematic presentation of epithelial ion and water transport in diluting segments obtained from early distal tubules of teleosts and amphibians and the thick ascending limb of birds. The luminal Naq –Kq –2Cly co-transporter and Naq –Hq exchanger operate on the basis of a steep Naq gradient formed by an active basolateral Naq –Kq –ATPase pump. Transtubular voltage (Vt) is positive in the lumen against peritubular fluid. Kq Cly are moved out of cells by diffusion or via the Kq or Cly channel. Data are from Dietl and Stanton (1993), Nishimura et al. (1983, 1986), Miwa and Nishimura (1986) and Guggino et al. (1988) or reproduced with permission from BIOS Scientific Publishers Ltd., Nishimura and Fan (2002).

3. Urine dilution and concentration 3.1. Diluting segment of fresh water fish and aquatic amphibians The distal tubule from FW trout perfused in vitro shows a furosemide- and ouabain-sensitive lumen-positive transtubular voltage that requires the presence of luminal Naq and Cly ions (Fig. 1; Table 2). Net Cly absorption (net lumen to bath flux) is present, whereas water permeability is low (Nishimura et al., 1983). Stoichiometric studies of early distal tubules from aquatic amphibians (Stoner, 1977; Oberleithner et al., 1982; Guggino et al., 1988) indicate that Naq –Kq –2Cly cotransport and high Kq conductance exist in luminal membranes. It, therefore, appears that in the distal tubuleyearly distal tubule of FW teleosts and amphibians, luminal Cly enters the cell against the electrical gradient along a high Naq concentration gradient, maintained by a basolateral ATP-

Species

Jv (nlØmy1Øminy1) Fishes River lamprey, FW (Lampetra fluviatilis) Dogfish, SW (Squalus acanthias)f Rainbow Trout (Oncorhynchus mykiss) Amphibians Frog (Rana pipiens) Congo eel (Amphiuma means)

Net solute fluxa

Water flux Lp (10y9 cm2 sy1 atmy1)

0.07a

Refs.

Na (pEqØmmy1Øminy1)

Cl (pEqØmmy1Øminy1)

;17.6b

;17.6b ;150b

;0

Moriarty et al., 1978 Logan et al., 1980a Friedman and Hebert, 1990

0.12"0.11

13.8"3.5

—

66.5"20.6d

Nishimura et al., 1983

0.07"0.09c 0.07c

5.0 —

81.1"10.1 —

56.6"6.7 33.4"1.4

Stoner, 1977 Oberleithner et al., 1982

Birds Quail (Coturnix coturnix)

y0.01"0.04

12.8"2.1

242"49

271.8"32.9d

Miwa and Nishimura, 1986 Osono and Nishimura, 1994

Mammals Rabbit (Oryctolagus cuniculus) Cortex Medulla Mouse (Mus musculus)

0.13"0.02c y0.02"0.01e y0.01"0.04

5.0"0.7 0.9"2.2 7.5"0.9

79.2"8.4 28"8 —

59"10 19"5 94"8 135d

Burg and Green, 1973a,b Rocha and Kokko, 1973 Hall and Varney, 1980 Hall and Varney, 1980

a Net solute fluxes were measured with isomotic bath and perfusate using concentrations (in mM) of 120–150 Na and 114–151 Cl in all species shown except frog (115 Na, 95 Cl) and Congo eel (97 Na, 84–100 Cl). bData from Braun and Dantzler, 1997. cMeasured with osmotic gradient. d Difference between efflux and influx. e Units of nl miny1. f Intermediate segment IV is perfused. Jvsnet volume flux. Lpsosmotic water permeability.

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Table 2 Transport properties of diluting segments from representative species

483

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Fig. 2. Left: A proposed model for urine concentration in the mammalian-type nephron of quail Coturnix coturnix, showing transport properties of NaCl and water in various nephron segments. NaCl is actively extruded from the thick ascending limb (TAL) and enters the descending limbs (DLs) by simple diffusion without the osmotic accompaniment of water; the NaCl is recirculated for maximum operation of a single-effect countercurrent multiplier system. Active NaCl transport in the TAL appears to be enhanced by perfusion flow rate or luminal NaCl concentration. Immunohistochemical and molecular studies indicate that AQP2 and AQP4 are present in the CD, regulating water transport across the CDs. Right: Hypothetical cascade transport of NaCl in medullary cone, showing that more NaCl extrusion occurs near the tip of the cone, which may help enhance an osmotic gradient (reproduced with modification from Nishimura et al., 1989, with permission from the American Physiological Society). PT: proximal tubule.

ase-operated Naq –Kq pump. Cly leaves the cell by a passive mechanism. By this secondary active NaCl cotransport mechanism without the accompaniment of water, dilution of tubular urine occurs during its passage through the ‘diluting segment.’ Micropuncture studies of the river lamprey (Logan et al., 1980a) indicate that the majority of NaCl reabsorption takes place in the distal nephron with only little water accompaniment. The cellular mechanism of the lamprey distal segment, however, has not been elucidated. The NaqKqCly cotransporter (NKCC1) was identified in the salt-secreting rectal gland of the dogfish shark, Squalus acanthias (Forbush et al., 1992), and a kidney specific isoform (NKCC2), which has been cloned mainly from higher vertebrates, has also been identified in shark kidney (Gagnon et al., 2002). The immunoreactive NaqKqCly cotransporter is expressed predominantly along the apical membrane of both the proximal (PI segment) and distal tubule segment

(Biemesderfer et al., 1996). The contribution of this cotransporter to water movement in shark, however, remains to be determined. 3.2. Water conservation in avian kidneys The urine concentrating mechanism depends upon the maintenance of a gradient of increasing osmolarity along the medullary pyramids. In avian kidneys, the thick AL of Henle has characteristics of a diluting segment (Nishimura et al., 1986; Miwa and Nishimura, 1986) (Fig. 2). Furthermore, the upper segment of the descending limb of Henle from the looped nephron of Coturnix coturnix kidneys shows zero transepithelial voltage and zero volume flux, suggesting that active transport is unlikely to be present. The descending limb is highly and nearly equally permeable to NaCl, whereas osmotic and diffusional permeability to water is low (Nishimura et al., 1989; Nishimura, 1993). Therefore, urine concentration and dilution

H. Nishimura, Z. Fan / Comparative Biochemistry and Physiology Part A 136 (2003) 479–498

appear to occur by a combination of passive diffusion and active transport and the recycling of a single solute (NaCl). This single effect may be multiplied by counterflow and the graded elongation of hairpin structures, forming an osmotic gradient along the medulla. Net NaCl flux in the thick AL is further facilitated by increased perfusion flow and NaCl concentration (Osono and Nishimura, 1994), suggesting that local factors are important for controlling the countercurrent urine concentration mechanism. To form concentrated urine, it is essential for the renal medulla to have a concentration gradient that is higher towards the papilla and for the CD to run parallel to Henle’s loop. CD cells in the cortical zone of quail Coturnix coturnix kidneys contain dark electron-dense cells that resemble intercalated cells and light mucus-secreting cells; the isolated perfused medullary CD shows nearly zero volume flux, and volume flux increases when an osmotic gradient is imposed (Nishimura et al., 1996). Also, the basal diffusional water permeability in medullary CDs from young quail, expressed as the tritiated water flux coefficient, is considerable; it is increased, however, only slightly by arginine vasotocin (AVT; avian ADH) and modestly by forskolin. In medullary cones, cAMP levels are also increased only slightly by AVT but markedly by forskolin, suggesting that the relatively low diffusional water permeability response to AVT is not due to insufficient adenylate cyclase activity (Nishimura et al., 1996). Although AVT increases cAMP accumulation in a dose-related fashion in CDs from more mature house sparrows (Goldstein et al., 1999), the cAMP production and the above-mentioned diffusional water permeability responses to AVT in birds are much smaller than the responses to ADH in rat or hamster CDs (Kondo and Imai, 1987; De Rouffignac et al., 1993). These modest responses in bird kidneys may be attributable to the limited capacity of AVT receptors or signal mechanisms downstream of cAMP, including the capacity of water channels. It is also possible that AVT-sensitive and AVTindependent water transport mechanisms exist in CDs of avian medullary cones. 3.3. Urine concentration in mammalian kidneys In mammalian kidneys, osmotic gradient along the medullary pyramids is maintained by the func-

485

tion of the loop of Henle as countercurrent multipliers and the vasa recta as countercurrent exchangers. The major structural and functional properties of renal medullas and urine-concentrating mechanisms of mammalian kidneys, as compared to avian kidneys, are briefly summarized below. The details of variations among mammalian species are beyond the scope of this article. First, the kidneys of most mammalian species possess short-looped nephrons (mainly cortical nephrons) and long-looped nephrons (mainly juxtamedullary nephrons), both of which possess loops of Henle and contribute to forming urine hyperosmotic to plasma. In mammalian kidneys, the structural heterogeneity of the thin limbs exists within the same nephrons, between short-looped and long-looped nephrons, and among species (Dieterich et al., 1975; Kriz et al., 1980; Bankir and de Rouffignac, 1985). Four types of thin limb epithelial cells are classified in accordance with the thickness of the epithelial cells, the abundance of luminal microvilli, mitochondria and interdigitation, and the depth of tight junctions (reflecting ion permeability), suggesting that ionic and water permeably also varies among thin limbs. To increase the osmotic concentration of tubular urine, as it descends along the descending limb of Henle, the distal limb should have either (or both) high permeability to water so that water is subtracted from the urine or high permeability to ions, particularly Naq and Cly, so that solutes are added to the urine. For example, the descending limb from the long-looped nephron of the hamster shows high permeability to both water and NaCl (more to Naq than to Cly) (Imai, 1984; Imai et al., 1984, 1988), whereas in human kidneys, high water permeability is a dominant force for increasing the osmotic concentration of tubular urine. The equilibration of tubular fluid with that of the interstitium can be more efficiently accomplished by subtraction of water than by simple addition of solutes; this mechanism is apparently lacking in the quail kidney, as mentioned above. It will be interesting to examine whether descending limbs from avian species that show higher urine-concentrating capacity are water permeable. Second, differing from looped nephrons of avian kidneys, long-looped nephrons in mammalian kidneys possess a thin AL that resides at the inner stripe of the outer medulla and inner medulla. Although it is a general belief that the thin AL

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lacks active solute transport, dilution of tubular urine may occur in this segment by utilization of differential permeabilities (Urea-NaCl) (Kokko and Rector, 1972) in the following manner. In human kidneys, the osmolarity of interstitial fluid at the tip of the medullary pyramid is maintained half by urea (approx. 600 mOsm) and half by NaCl (approx. 600 mOsm); whereas in tubular urine, the osmotic concentration of urea is lower than that of NaCl. Accordingly, in the thin AL, NaCl moves out of the tubule passively along a concentration gradient faster than urea moves into it. Since the thin AL is impermeable to water, tubular urine is diluted as it moves towards the thick AL (Kokko and Rector, 1972). The urinediluting function of the thick AL in mammalian kidneys is similar to that of the diluting segment of amphibians (Fig. 1; Table 1). As in avian kidneys, the diluting segment (thick AL) of mammalian kidneys provides an energy source for countercurrent urine concentration. Third, in mammalian kidneys, urea and a unique urea recirculation system significantly contribute to urine concentration. In mature rats, urea transporters (UT) are expressed in the descending limb of short-looped and long-looped nephrons (UTA2), the descending vasa recta (UT-B1), and CDs (UT-A1, vasopressin-dependent) (for review, Bankir and Trinh-Trang-Tan, 2000). Furthermore, in rodent kidneys, the descending limb of Henle from the short-looped nephron runs in parallel to the ascending vasa recta in the vascular bundle (Kriz et al., 1980; Bankir and de Rouffignac, 1985). High urea permeability in the descending limb of short-looped nephrons appears important for recapturing urea escaped from the inner medulla via the ascending vasa recta and delivering it to the distal nephron (Imai, 1984; Bankir and de Rouffignac, 1985). Urea is subsequently recycled to the inner medulla via urea-permeable CD segments. In this context, countercurrent exchange in the vasa recta is essential for maintaining the hyperosmolarity of the inner medulla. The vasa recta have low blood flow and are permeable to solutes and water. The ascending and descending vasa recta show differential permeability to sodium, urea and protein; and as the blood descends into the medulla, it becomes progressively concentrated by shunting water from the descending to the ascending vasa recta, while solutes diffusing out of the ascending vessels diffuse into the descending vessels (for

review, Pallone et al., 2003). By this exchange mechanism, the ascending vasa recta effectively removes the water from the interstitium of the inner medullaypapilla and transports it to the cortex and systemic circulation. The vasa recta exchange mechanism also lowers medullary blood flow and prevents solute washout in the inner medulla. The high osmolarity of the inner medullaypapilla is, therefore, maintained in a ‘sealed’ compartment (Bankir and de Rouffignac, 1985). Fourth, vasopressin, mammalian ADH, regulates the water permeability of CDs by evoking trafficking (acute control) of, and stimulating the synthesis of mRNA and protein (slower control) of, the AQP2 water channel (see below). The effects of ADH on water transport in mammalian kidneys (both in vivo and in vitro isolated tubules; Kondo and Imai, 1987; De Rouffignac et al., 1993) and AQP2 expression (Hayashi et al., 1994; Nielsen et al., 1995a) are far more potent than those of AVT seen in quail kidneys (Nishimura et al., 1996; Yang et al., 2003). The role of the kidney in fluid homeostasis appears to be changed during adaptation of vertebrate animals to changing environments. Fundamental transport properties of the diluting segment evolved during an early stage of vertebrate evolution, enabling the formation of dilute urine. In birds and mammals, the diluting segment that has the same transport characteristics now serves, with the development of additional architectural organization, for countercurrent urine concentration and water conservation. Table 2 summarizes transport properties of diluting segments from various species. All diluting segments show zero volume flux, low osmotic permeability and net solute flux (net fluxes of Naq and Cly are nearly equal). Interestingly, net Naq and Cly fluxes in quail kidney thick ALs are higher than those in diluting segments of other animals. This may suggest that the avian diluting segment uses more energy to operate the countercurrent multiplier system for urine concentration solely by recycling NaCl. 3.4. Renal responses to osmotic challenges Euryhaline teleosts are able to live in both hypoand hyperosmotic media by maintaining their internal osmolality relatively constant despite a large concentration gradient between the internal and external media. These osmoregulatory adjustments

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are the consequence of the integrative work of gills, skin, intestines and kidneys. When euryhaline fish are transferred from one medium to the other, transient increases or decreases occur in the solute concentrations of their body fluid due to osmosis and diffusion of salts, and restoration is achieved during the next few days. Firstly, GFR immediately changes (primary adjustment): a sharp initial increase (FW adaptation) or decrease (SW adaptation) followed by a slow component. Secondly, the water permeability of the renal tubules appears to change within a few days after transfer (secondary adjustment), and urine flow changes accordingly. Prolactin and interrenal steroids play important roles in the control of epithelial water permeability (for review, see Nishimura, 1985; Henderson, 1997). The cellular and molecular mechanisms of this adaptation with respect to iony water channels and the signaling mechanism remain to be determined. Non-mammalian terrestrial vertebrates handle an excess or a depletion of salt or water by the combined efforts of the kidney and gut, including the cloaca, skin and salt glands in some species. Reptiles, such as the FW turtle, Pseudemys scripta, and snake, Natrix sipedon, that live in both terrestrial and aquatic environments, can excrete a wide range of hypoosmotic urine or isoosmotic urine; whereas reptiles that live in desert areas have little ability to dilute urine (Dantzler and SchmidtNielsen, 1966; Dantzler and Braun, 1980), and urine flow primarily depends on GFR. Although it is difficult to generalize because of the numerous variations among species, there seem to be two patterns of avian renal response to osmotic challenges (Dantzler and Braun, 1980): (1) acute reduction in GFR and urine flow to retain water and prevent an increase in plasma osmolality; this pattern of response is seen in desert quail; and (2) excretion of excess salt at the expense of water, as seen in starlings. Similarly, excess water may be excreted at the expense of salt (Skadhauge and Schmidt-Nielsen, 1967), or it may perhaps be retained in the body to prevent acute salt loss. During dehydration or salt loading, the inulin Uy P ratio or creatinine UyP ratio increases in reptiles and birds (Table 1), indicating that renal tubules effectively absorb water. In contrast, significant tubular water absorption continues during water loading in desert quail; only 79% of the loaded water is excreted, despite the increase in single nephron GFR and the number of filtering nephrons

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(Braun and Dantzler, 1975). This may suggest that avian kidneys cannot efficiently turn on and off the control mechanism for renal tubule permeability, unlike the case in mammalian CDs in which ADH effectively serves this function. However, birds have, in general, higher tolerance and adaptability to a wide range of plasma osmolarity than mammals. Furthermore, some avian species such as domestic fowl are able to shift tissue fluid to the vascular compartment when their blood volumeyblood pressure is acutely reduced; thus, blood volumeyblood pressure is promptly restored (Wyse and Nickerson, 1971; Nishimura and Bailey, 1982; Ploucha and Fink, 1986). Such a unique compensatory mechanism may help in the maintenance of avian cardiovascular homeostasis. There is no large difference in GFR when compared on a weight basis between birds and mammals, but the percentage of filtered water excreted after water deprivation is higher in birds. A larger urine flow may be required for birds to excrete uric acid and other metabolic products. It is necessary to examine the affinityyconcentration of AVT receptors in avian CDs and to investigate whether AVT effectively increases or decreases trafficking or expression of AQP2 (or equivalent water channel) during osmotic challenges. Non-mammalian vertebrates have variable GFR and a remarkable ability to adapt to a wide range of plasma osmolalities. In this context, when seeking indices of urine concentration and dilution, caution is needed in interpreting the percentage of filtered water excretedyreabsorbed and the osmolal UyP ratio. In general, mammalian kidneys have an amazing capacity to excrete or conserve water and ions matching their variable intakes, which can range from as low as one-tenth normal to as high as 10 times normal. As a result, fluid and ion homeostasis is maintained within a narrow normal range (for review, Jamison, 1981; Guyton and Hall, 1996; Vander, 1985). This adaptive capability of the kidney may be accomplished by the following factors, more noticeable in mammalian than in non-mammalian kidneys: (1) the complex nephrons and vascular organization of the medulla that help effective urine concentration and dilution; (2) countercurrent multiplier and exchanger systems among the renal tubular and renal vasa recta systems; and (3) sensitive and effective (turns on and off promptly) and, in some aspects, redundant regulatory mechanisms. For example, an increase of only 2 mOsmyl in plasma osmolarity due to

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water deprivation is sufficient to evoke ADH secretion that reabsorbs water from CDs as well as to stimulate the thirst mechanism. In contrast, a large excess of water in the human body stimulates the kidney to excrete as much as 20 lyday of dilute urine with a concentration as low as 50 mOsmyl by completely shutting off the ADH mechanism and by increasing medullary blood flow and thus reducing (washing out) the hyperosmolarity of the renal medulla. During formation of dilute urine, the kidney continues to reabsorb solutes, however; thus, the excretion of excess water can be accomplished without significant loss of solute. When a large acute blood loss (such as hemorrhage) occurs, the body tries to restore blood volumeyblood pressure via various defense mechanisms, including the baroreceptor reflex evoking sympathetic activation, the volumeylow-pressure receptor reflex originating in the right atriumygreat veins (reduction of volume stimulates ADH release), the release of various vasoconstrictive hormones, and the fluid shift from the interstitial tissue space to the vascular compartment. These acute–intermediate time–period responses are followed by more chronic volume adjustment by the kidney. When sodium intake is increased, a slight increase in extracellular fluid volume triggers various mechanisms that increase sodium excretion, including (1) the above-mentioned atrial volumey low pressure receptor that reflexly inhibits renal sympathetic nerve activity, leading to the decreased tubular Na reabsorption; (2) pressure natriuresis via an increase in arterial pressure; (3) inhibition of angiotensin and the resultant reduction of tubular Na reabsorption; and (4) the possible stimulation of natriuretic factor (Guyton and Hall, 1996). 4. Aquaporins 4.1. Structure and function of aquaporins Aquaporins (AQPs) are a family of small, hydrophobic proteins (major intrinsic proteins, MIP) that were originally cloned in mammalian lens as MIP26 (for review, see Yamamoto and Sasaki, 1998; Borgnia et al., 1999; Agre, 2000; Verkman and Mitra, 2000; Nishimura and Fan, 2002). Eleven major mammalian AQPs, many isoforms, and two subgroups (AQP and aquaglyceroporin) have been identified (Yamamoto and

Sasaki, 1998; Verkman and Mitra, 2000). AQPs are phylogenetically old molecules and are present in insects, microbial organisms and plants (for review, see Chrispeels and Agre, 1994; Borgnia et al., 1999). The three-dimensional structure of AQPs reveals four homotetramers in which each monomer (26–34 kDa in size) contains six membrane-spanning alpha-helical segments (Mitra, 2001). Each molecule has two internal repeats oriented at 1808 to each other in the membrane. Both repeats contain a highly conserved short sequence, the NPA motif (asparagine– proline–alanine) between transmembrane domains 2–3 (loop B) and 5–6 (loop E). Loops B and E are highly hydrophobic. The two NPA motifs are juxtaposed and form a single aqueous channel spanning the bilayer (hourglass model) to comprise a single water-selective channel. Mutation of this region reduces water permeability (Jung et al., 1994). AQPs 1, 2, 3, 4, 6 and 7 are expressed in mammalian kidneys (Yamamoto and Sasaki, 1998). AQP1 is a mercury-sensitive, channel-forming integral protein (CHIP) of 28 kDa (CHIP28; Preston and Agre, 1991) and is expressed widely in mammalian water-permeable tissues, including proximal tubules (microvilli of the apical brush border and less intensely in the basolateral membrane), the thin descending limb of Henle’s loop, the descending vasa recta of the kidney (Nielsen et al., 1995b), gall bladder, red blood cells, eye, respiratory tract and alveoli. AQP2 has been cloned from kidneys of rats (Fushimi et al., 1993), humans, mice and other species (Yamamoto and Sasaki, 1998). The AQP2-specific region (198–205) differs significantly from that of other renal AQPs. AQP2 is selectively expressed in connecting tubules and cortical and medullary CDs and is localized at the apical membrane and subapical regions of the principal cells (Fushimi et al., 1994). Both AQP1 (cys-189) and AQP2 (cyc-181) have a mercury-sensitive site; the inhibition of water permeability may occur by an interaction between cysteine and mercury. AQP3 shows modest permeability to urea and glycerol in addition to water and is expressed in the basolateral membrane of the cortical and outer medullary CDs and in the epithelial cells of the gastrointestinal tract, trachea and other tissues (Echevarria et al., 1994). AQP4 has been cloned independently as a mercury-insensitive water channel by two groups

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(for review, see Yamamoto and Sasaki, 1998) from the rat lung and brain cDNA library and is expressed in the basolateral side of the principal cells of the inner medulla (Terris et al., 1995), bronchial epithelia, eye epithelia and other tissues. While AQP2 is inducible, AQP1, 3 and 4 are constitutively expressed and not regulated through trafficking between the intracellular vesicles and cell membrane. AQP6 was isolated from rat and human kidneys as a unique intracellular water channel (King et al., 2000); its gene sequence locus is similar to that of AQP2, suggesting that their evolution may be closely related. AQP6 is expressed in vesicles of the epithelial cells of the proximal tubules and in acid-secreting intercalated cells of the CDs (Yasui et al., 1999a,b) and may be important for the regulation of anion permeability and acid–base balance (Yasui et al., 1999a,b). 4.2. Cellular mechanism and regulation AQP2 is primarily regulated by a vasopressiny cAMP-dependent vesicular trafficking mechanism, attributed to the so-called ‘Shuttle hypothesis’ (for review, see Laycock and Hanoune, 1998; Verkman and Mitra, 2000) via V2 receptors, whereas the factors regulating AQP1, 3 and 4 are not known. Upon AVP binding to basolateral membrane receptors and activation of the adenylate cyclaseycAMP and protein kinase A system, vesicles containing AQP are translocated to the apical membrane, where AQPs are inserted and act as a water channel. When inactivated, AQPs are returned to the endosomes via protein kinase C activation (Deen and Van Os, 1998). Furthermore, vesicleassociated membrane proteins colocalized with AQP2 facilitate the vesicle trafficking process (King et al., 2000). Wild-type AQP is expressed on the apical membrane of oocytes upon stimulation, whereas non-phosphorylated mutant AQPs remain in the cytosolic compartment (Kamsteeg et al., 2000). Recently, stoichiometric studies indicate that in principal cells of CDs, three out of four monomers of AQP2 must be phosphorylated prior to initiation of trafficking from the subapical endosomes to the apical membrane (Kamsteeg et al., 2000). Although the precise mechanisms by which phosphorylation induces vesicle trafficking are unclear, cytoskeletal structures such as microtubules appear important (Brown et al., 1998).

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Serine 256 of the AQP2 is critical for triggering vasopressinycAMP-induced translocation (Fushimi et al., 1997). Furthermore, a series of amino acid mutations of the 6th transmembrane domain in the rat revealed that the dileucine motif (217– 218, 222–223) plays an important role in the vasopressin-induced translocation of AQP2 (Yamashita et al., 2000). In mammalian kidneys, vasopressin regulates AQP2 expression in two stages: first, short-term (minutes) regulation of CD water transport via enhancement of AQP trafficking and, second, longer-term (hours–days) modulation of CD water permeability via upregulation of AQP2 mRNA and protein (Hayashi et al., 1994; Knepper, 1997; Van Os and Deen, 1998). In addition, AQP expression appears to be modulated by various physiological and pathological conditions of the kidney (Marples et al., 1999; Knepper, 1998) independent of vasopressin (Nielsen et al., 1999). Hereditary nephrogenic diabetes insipidus (NDI) occurs by mutations of the genes encoding either the vasopressin V2 receptor or AQP2 (Kamsteeg et al., 1999; Agre, 2000). In human hereditary (familial) NDI, water uptake by the renal tubules and urineconcentrating ability are impaired, and the kidneys excrete a large amount of hypotonic urine. Although NDI is most commonly caused by impaired ADH receptors, mutation of the AQP2 water channel gene (such as premature termination of translation) evokes autosomal recessive NDI (Deen et al., 1994; Mulders et al., 1998). In contrast, the renal phenotype of the AQP1 null family and the appearance and survival of AQP1 knockout mice are grossly normal (Preston et al., 1994; Ashcroft, 2000), suggesting that a paracellular water pathway independent of the transcellular water channel compensates for the defect. Water-deprived AQP1 knockout mice (Verkman, 1999) or AQP1-deficient humans (King et al., 2000), however, cannot conserve water sufficiently in response to water deprivation. Similarly, although the basal urine osmolarity of AQP4 knockout mice is similar to that of wild-type mice, urine osmolarity of the former does not increase as much as in wild-type mice after water deprivation. 4.3. Aquaporins in non-mammalian vertebrates AQP homologues known as ‘green AQPs’ have

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been cloned from plants; and AQP homologues that structurally resemble AQP1 and aquaglyceroporin homologues have also been found in bacteria, yeast and unicellular algae (for review, see Chrispeels and Agre, 1994; Borgnia et al., 1999). In invertebrates, it has been shown that AQP homologues in insects permit transfer of water from the midgut to the Malpighian tubules (Beuron et al., 1995). Although it is anticipated that all vertebrate kidneys possess AQPs, much work is needed in this area; AQP isoforms have been cloned from only a few species of fish, amphibians and birds. Studies on the expression, function and regulation of AQPs in animals that live in different salinities and during osmotic challenges will elucidate fundamental mechanisms of water homeostasis in vertebrates. Teleost fish and amphibians: AQP3-homologue mRNA is expressed in the gill, esophagus and rectal tissues of European eels (Lignot et al., 2001; Cutler and Cramb, 2000). Expression is high in the gill of FW eels, whereas the mRNA levels decrease after the eels are transferred to SW. Also, killifish AQP (Virkki et al., 2001) homologous to MIP26 has been cloned from the eye lens, and a 59 cDNA similar to AQP3 has been found from the cDNA library of channel catfish skin (Karsi et al., 2002). Four AQP homologue cDNAs have been cloned from amphibians: (1) AQP-toad bladder (AQP-TB), from the urinary bladder of a toad, Bufo marinus (Siner et al., 1996); (2) frog AQP (FA)-CHIP from the urinary bladder of a frog, Rana esculenta (Abrami et al., 1994); (3) fMIP, MIP from frog lens (Austin et al., 1993); and (4) aquaglyceroporin from Xenopus laevis oocytes (AQPxlo, Virkki et al., 2002). AQP-TB has overall amino acid identity with FA-CHIP (76%), human AQP1 (61%) and rat AQP2 (44%). Differing from AQP2, however, AQP-TB is expressed abundantly in various tissues, including kidney, skin, lung, skeletal muscles, brain and urinary bladder. Dehydration increases AQP-TB expression in the toad urinary bladder. Expression of AQP-TB protein in X. laevis oocytes, however, failed to increase oocyte membrane water permeability (Siner et al., 1996). In contrast, in vitro transcribed cRNAs encoding FA-CHIP injected into Xenopus oocytes evoked a marked increase in osmotic water permeability (Abrami et al., 1994, 1995). FA-CHIP has 78% identity with rat and human AQP1, suggesting that the amphibian AQP homologue may resemble AQP1. AQPxlo is strongly

expressed in X. laevis oocytes and X. laevis fat bodies, but only weak expression is seen in the kidney. AQPxlo-expressed oocytes show increased osmotic permeability and increased uptake of glycerol and urea (Virkki et al., 2002). Birds. The diffusional water permeability of quail Coturnix coturnix CDs is considerable and is only modestly increased by AVT, whereas adenylate cyclase activity exists abundantly (Nishimura et al., 1996), suggesting that AVT-dependent and AVT-independent components of water transport may exist in quail CDs. Using a cloning method based on reverse transcription–polymerase chain reaction (RT–PCR), we cloned two AQPs from medullary cones of water-deprived Japanese quail, Coturnix coturnix: an AQP2 homologue (referred to as qAQP2) and an AQP4 homologue (qAQP4) (Cui et al., 2001; Yang et al., 2002, 2003 and GenBank lt439990, AF465730). qAQP2 (274 amino acids) has two NPA water-selective motifs and six putative transmembrane domains and shows 78% amino acid identity and 85% homology to rat AQP2. qAQP2 has a possibly mercury-sensitive cysteine residue (position 182), and serine at position 256 of the cytoplasmic carboxyl terminus. The osmotic water permeability (Pf) of Xenopus oocytes-expressed qAQP2 is more than 20-times higher than control and Pf was reduced by HgCl2 (Yang et al., 2003). Immunoreactive AQP2 is recognized at the apical and subapical regions of medullary CDs (Fig. 3). Interestingly, CDs from normally hydrated quails exhibit considerable immunoreactive AQP2, although the intensity and area of staining increases in water-deprived quail and water-deprivedyvasotocin-treated quail. This agrees with our previous study in perfused CDs, indicating that medullary CDs have considerable basal water permeability and that vasotocin only modestly increases water flux from the luminal to the basolateral side (Nishimura et al., 1996). Furthermore, the AQP2 antibody recognized proteins of ;29 kDa (predicted molecular size) and ;38 kDa (possible glycosylated form) extracted from the medullary cones, suggesting that quail kidney CDs possess AQP2-homologue water channels regulated by AVT. qAQP4 consists of 335 amino acids, and the deduced protein shows )70% overall amino acid identity with human and rat AQP4; identity is highest in the six putative transmembrane domains. At 72 h after injection of AQP4 cRNA, the rate of swelling of Xenopus oocytes in hypoosmotic Barth’s solution, however,

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Fig. 3. (A) A cross section of the medullary cone from a 16-week-old, water-deprived, vasotocin-treated quail Coturnix coturnix. Medullary cone sections were incubated with anti-rat AQP2 rabbit serum (gift from Dr Sei Sasaki, Tokyo Medical and Dental University, Japan) and visualized with FITC-conjugated goat anti-rabbit IgG. Fluorescent signals are seen in collecting duct cells by a laser scanning confocal microscope. (B and C) Higher magnification of the medullary cone section. Fluorescent staining is localized at the apical side of collecting duct epithelial cells. Bar, 50 mm. Reproduced from Nishimura et al. (2001), with permission from Monduzzi Editore.

did not increase significantly, whereas oocytes injected with rat AQP1 cRNA swelled remarkably. Bird kidneys provide excellent models for examining interactions between renal function and AVT, specifically, for elucidating the transition from vascular action to the tubular effect of AVT. Regulation of AQP2 by AVT, however, particularly regarding rapid turn-onyoff mechanisms, may not be well developed in avian tubules. 5. Hormones controlling renal handling of water In non-mammalian vertebrate kidneys, GFR is intermittently controlled and is an important determinant of urine flow, which is discussed in detail in another section of these proceedings. In fishes, amphibians and reptiles, there is no clear evidence that GFR or renal blood flow is autoregulated. Rather, GFR depends on renal perfusion pressure regulated by systemic blood pressure and preglomerular arterial resistance. Water movement across renal tubules is determined by osmotic gradients formed by osmotically active solutes and the permeability of tubular epithelia via paracellular and transcellular pathways. Details of the cellular mechanism of these physical controls of water movement are beyond the scope of this review. Several hormones regulate renal handling of water directly and indirectly (for review, see Nishimura, 1985, 1987; Henderson, 1997; Bentley, 1998). First, AVT controls renal ion and fluid

balance via its vascular actions (dorsal aortic pressure andyor preglomerular resistance); this varies depending on species, doses and habitats. In general, AVT causes antidiuresis by constricting preglomerular arteries in anuran amphibians, reptiles and birds; whereas in teleosts, lungfish and urodeles, AVT tends to cause diuresis via increases in dorsal aortic pressure (Sawyer, 1972; Pang et al., 1982). It has been well established that AVT increases osmotic permeability of the frog skin and toad bladder. Stimulation of tubular water transport by direct action of AVT is discussed in Section 3.2 and Section 4.3. In mammalian kidneys, vasopressin stimulates Cl transport (reabsorption) across the thick AL (Hall and Varney, 1980; Hebert et al., 1981), whereas AVT increases neither transepithelial voltage nor lumen-to-bath Cl transport in isolated and perfused thick ALs from young quail (Miwa and Nishimura, 1986). AVT slightly increases cAMP production in the thick AL from the medulla of the house sparrow, Passer domesticus (Goldstein et al., 1999). An AVT receptor and isotocin receptor have been cloned from a bony fish, Catastomus commersoni (Mahlmann et al., 1994; Hausmann et al., 1995), and a mesotocin receptor has been identified in the toad bladder (Akhundova et al., 1996). These receptors are expressed in the kidney, urinary bladder, brain, gut, etc. and, differing from the vasopressin V2 receptor, they are mediated via the inositol–calcium signal pathway. In contrast,

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AVT stimulates cAMP production in avian CDs; and forskolin, but not its inactive analogue, increases CD water permeability (Nishimura et al., 1996; Goldstein et al., 1999), suggesting that the signal pathway may be similar to the V2 receptor. It has been shown that angiotensin (Ang) alters GFR in various species of non-mammalian vertebrates either by controlling systemic blood pressure or directly by constricting renal arteriesyarterioles; thus, Ang plays a role in fluid balance (Nishimura, 1985, 1987). Direct action of Ang on renal tubule transport of Na and water has been suggested but not established in fishes. In fowl, Ang causes endothelium-dependent relaxation, and Ang receptor (AT1-homologue, cAT1) mRNA is expressed in the endothelia of renal arteriesyarterioles (Kempf et al., 1996; Nishimura et al., 2003). cAT1 mRNA is abundantly expressed in glomeruli, particularly in those of embryonic kidneys, suggesting that Ang may have a role in glomerular filtration via mesangial growth or control of renal blood flow. Prolactin plays an important role in osmoregulation in hypoosmotic media by decreasing the epithelial water permeability of the gills, kidney, urinary bladder and intestines, whereas adrenocorticosteroid is essential for SW adaptation (for review, see Nishimura, 1985; Bentley, 1998). It has been suggested that prolactin causes chloride cell dedifferentiation by reducing Naq –Kq –ATPase activity and leak pathway, whereas cortisol stimulates chloride cell proliferation and differentiation, in the gill in fishes (Foskett et al., 1983; Bentley, 1998) and that it causes thickening of amphibian skin (Brown and Brown, 1987) and thus decreases water permeability. The cellulary molecular mechanism of prolactin action and the site of prolactin’s water permeability effect in the kidney and whether AQPs are involved in prolactin’s role in FW adaptation remain to be examined.

Fig. 4. A dendrogram for vertebrate AQP (including aquaglyceroporin) phylogeny calculated with Clustal X and based on similarity scores. Although many AQP isoforms have been reported, the structures of vertebrate AQPs reported by Agre’s group and Sasaki’s group are used. AQPs 1, 2, 5 and 6 are water-selective aquaporins, whereas AQPs 3, 7, 8 and 9 are aquaglyceroporins. AQPs in the box frame indicate those cloned from non-mammalian vertebrate species. Selectivity for glycerol has not been tested in non-mammalian AQPs. AQPs from invertebrates, plants and microorganisms are excluded from this figure, as are aquaglyceroporins from plants and microorganisms. Reproduced with modification from Nishimura and Fan (2002) with permission from BIOS Scientific Publishers Ltd. Aquaglyceroporin (AQPxlo) from Xenopus laevis oocyte (Virkki et al., 2002) has not yet been accommodated in this figure.

6. Perspectives and questions Fig. 4 shows a dendrogram for AQP phylogeny, calculated by the Clustal=program, based on similarity scores. The top part of the figure represents aquaglyceroporins, and the lower half indicates AQPs. Much information is needed to determine AQP phylogeny in non-mammalian vertebrates. It appears that amphibian AQPs are closely related to human or rat AQP1 and that qAQP4 and rAQP4,

and rat AQP2 and qAQP2 are closely related, as expected. It is interesting that the branch leading to AQP1 and AQP4 and the branch leading to AQP2 diverged at an early evolutionary stage. The discovery of AQP1 and AQP3 homologues in primitive vertebrates suggests that these AQPs (or aquaglyceroporins) may be evolutionarily fundamental, whereas AQP2 may have coevolved with the renal tubule action of AVT. There may be VT-

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Fig. 5. Comparison of transport properties among looped nephron of quail (left), long-looped nephron of neonatal rat kidney (middle) and long-looped nephron of mature rat kidney (right), showing similarities between bird and neonatal rat nephron. Water permeability of distal segments of loopless nephron of avian kidneys has not been studied. See text (Section 6) for details. AQP, aquaporin; AVT, arginine vasotocin; AVP, arginine vasopressin. Slightly modified and reproduced with permission from Liu et al. (2001). Transport properties of avian-type nephron are based on the studies reported by Nishimura and coworkers (see Sections 3.2 and 4.3).

independent water movement, however, in the medulla of the avian kidney. Indeed, during the development of the rat kidney, AQP1, AQP3 and AQP4 mature earlier than AQP2 (Yamamoto et al., 1997), whereas the expression of AQP2 mRNA continues to increase after birth. In this context, a comparison of phylogeny and ontogeny provides useful information. Liu and coworkers (Liu et al., 2001) compared medullary nephrons from the kidneys of (1) quail (looped nephron); (2) neonatal rats (long-looped nephron); and (3) mature adult rats (long-looped nephron) and found several structural and functional similarities between the first two (Fig. 5). 1. Both lack the thin AL, and the entire thick limb shows characteristics of diluting segments. During maturation of rat kidneys, apoptosis occurs in the lower segment of the AL, where the

Naq –Kq –2Cly cotransporter is replaced by a thin AL-specific Cl channel. 2. The descending limbs from quail and neonatal rat show low water permeability; AQP1 expression is absent in the descending limb of the neonatal kidney. In contrast, both show high Na and Cl permeability, suggesting that the increase in osmotic concentration of tubular urine in the descending limbs of Henle is likely to occur by addition of solute, but not subtraction of water. 3. AQP2 is present in the CD of both neonatal rat and quail kidneys, but the AQP2 responses (increases in water permeability, AQP2 protein level, etc.) to vasopressin (rat)yAVT (quail) are only modest. 4. The thin AL and CD of neonatal rats (and presumably quail kidney) lack urea permeability and urea transporters (UT), whereas UTA1 mRNA is expressed in mature rat kidneys.

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Hence, the contribution of urea to a urine– concentrating mechanism is unlikely in neonatal rats. As discussed in Section 3.3, urea recirculation utilizing exchange mechanisms between the vasa recta and tubule segments contributes to the development of an osmotic gradient, and this mechanism may not have developed in maturing kidneys. In addition, in mature kidneys, effective removal of water from the inner medulla by the ascending vasa recta helps to maintain high osmolality in the inner medulla. Water handling by the kidney is essential for both aquatic and terrestrial life. The role of the kidney, however, differs depending on habitats, phylogenetical stage of vertebrates and species. However, when we compare kidney functions among vertebrate animals that belong to various stages of phylogeny, we realize that many fundamental cellularymolecular mechanisms of glomerular filtration, ion pumps and channels, including cotransporters and exchangers, water channels, and membrane channelyreceptor proteins, are similar. The factors that make the kidney functions diverse are: (1) architectural organization, such as increases in complexity in nephron segments, development of the vasa recta, and their interaction with tubules; and (2) intrarenal and systemic regulatory systems involving hemodynamic, humoral and neural mechanisms. Furthermore, communication between preglomerularyglomerular structures and tubules, such as glomerulo-tubular balance or tubuloglomerular feedback, and the integration of systemic and intrarenal structures by autoregulation make the entire fluid-ion balance more complex. It is, therefore, very important to investigate the role of the kidney in body fluid homeostasis from two aspects: (1) elucidation of cellulary molecular mechanisms; and (2) integration at the in vivo level as to how the various systems work in concert. References Abrami, L., Capurro, C., Ibarra, C., Parisi, M., Buhler, J.-M., Ripoche, P., 1995. Distribution of mRNA encoding the FACHIP water channel in amphibian tissues: effects of salt adaptation. J. Membrane Biol. 143, 199–205. Abrami, L., Simon, M., Rousselet, G., Berthonaud, V., Buhler, J.-M., Ripoche, P., 1994. Sequence and functional expression of an amphibian water channel, FA-CHIP: a new member of the MIP family. Biochim. Biophys. Acta 1192, 147–151. Agre, P., 2000. Aquaporin water channels in kidney. J. Am. Soc. Nephrol. 11, 764–777.

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