Kidney Institute, Departments of Internal Medicine, Biochemistry, and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 66160
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ABSTRACT |
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The evolution of the kidney has had a major role in the emigration of vertebrates from the sea onto dry land. The mammalian kidney has conserved to a remarkable extent many of the molecular and functional elements of primordial apocrine kidneys that regulate fluid balance and eliminate potentially toxic endogenous and xenobiotic molecules in the urine entirely by transepithelial secretion. However, these occult secretory processes in the proximal tubules and collecting ducts of mammalian kidneys have remained underappreciated in the last half of the twentieth century as investigators focused, to a large extent, on the mechanisms of glomerular filtration and tubule sodium chloride and fluid reabsorption. On the basis of evidence reviewed in this paper, we propose that transepithelial salt and fluid secretion mechanisms enable mammalian renal tubules to finely regulate extracellular fluid volume and composition day to day and maintain urine formation during the cessation of glomerular filtration.
tubule; glomerulus; fluid secretion; salt secretion; renal evolution; fluid balance
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INTRODUCTION |
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THE LIVER, PANCREAS, SALIVARY
and lacrimal glands secrete relatively large amounts of
Na+, Cl, K+, and
HCO
The urine that emerges from mammalian kidneys is widely believed to represent fluid that is left over from incomplete tubular reabsorption of glomerular filtrate (2, 17). In the renal field, "secretion" is a term that is usually reserved to describe the deposition into urine of organic anions and cations, largely by proximal tubules, and of potassium, ammonium, and protons by distal tubules and collecting ducts (45, 49, 57). However, recent evidence demonstrating that isolated nonperfused outer and inner medullary collecting ducts (OMCD and IMCD, respectively) dissected from rat kidneys secrete fluid has reopened the possibility that segmental salt and fluid secretion by mammalian renal tubules may contribute to the formation of the final urine (73, 75). In light of this new information, it is not unreasonable to suppose that the secretory transport of organic and inorganic solutes into the proximal tubules (22), coupled with the downstream secretion of salt and fluid into the collecting ducts, contributes to the formation and the modification of urine by mammalian kidneys. In this brief review, we reexamine the evolutionary basis of renal tubule secretory mechanisms that couple solute and fluid transport into the urine formed by mammalian kidneys and how this process may participate in normal and pathological states.
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EVIDENCE OF RENAL TUBULE SOLUTE AND FLUID SECRETION |
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Protovertebrates
In his brilliant treatise, From Fish to Philosopher, Homer Smith (60) considered how the kidney may have evolved in the sea from early excretory structures. The leading electrolyte constituents in seawater are (in meq/l) chloride (537), sodium (461), magnesium (53), and calcium (10) (35). Smith reasoned that, with free access to both water and salt, primordial kidneys evolved primarily to discharge potentially harmful chemicals that could not be eliminated by simple diffusion through the integument of increasingly complex multicellular animals. These waste products included polar organic compounds that, in early protovertebrates, were secreted into the lumens of simple tubular structures open to the coelom at one end and to the sea at the other. In this context, the secretory transport of solutes, including NaCl and organic molecules, coupled with the osmotic flow of water, also served to propel liquid along the tubule for eventual discharge into the sea. This primitive apocrine kidney appears to represent the framework on which additional tubular excretory processes were added in the course of evolution (Fig. 1).
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In representatives of the early life forms available for modern study, orthologs of the brush-border-laden proximal tubules exhibit mechanisms for the transepithelial secretion of organic solutes, including polar anions and cations (43). For example, in insect Malphigian tubules, which have no glomeruli attached to them, organic anions and cations are secreted into the lumens of blind-end tubules against steep concentration gradients. The fluid elaborated by these tubules appears to depend on the contemporaneous secretion of electrolyte and nonelectrolyte solutes. In recent work, it has been observed in Malphigian tubules of Aedes aegypti that hormonally regulated chloride secretion through selective anion channels has a significant role in the elimination of massive amounts of solutes and fluid (6, 47).
Elements of these relatively simple protovertebrate kidneys can still be found in the hagfish and lamprey (60) and are transiently represented in the pronephros of early-stage embryonic renal development in reptiles, birds, and mammals (72).
The Vertebrate Kidney
The upheaval of continents from the sea and the consequent exposure to fresh water provided "the theater of evolution of the early vertebrates" kidney (60). Herein, the simple tubular "kidney" assumed additional roles to preserve the composition of the "internal environment" in this radically different medium through the elimination of excess water and the conservation of salt. To this end, a rudimentary filtering device, the glomerulus, a latecomer in the quiet ritual of urine formation and excretion, was introduced at the blind end of the tubule (Fig. 1). The exuberant filtration of extracellular fluid (ECF) into the tubules by the newly acquired glomeruli solved the problem of getting rid of excess free water, but it created another. Mechanisms for the recapture from tubule fluid of precious filtered solutes such as NaCl were required to preserve homeostasis. Mechanisms for the avid reabsorption of Na+ and Cl
What engineer, wishing to regulate the composition of the internal environment of the body on which the function of every bone, gland, muscle, and nerve depends, would devise a scheme that operated by throwing the whole thing out sixteen times a day and rely on grabbing from it, as it fell to earth, only those precious elements which he wanted to keep?
The bony fishes fully exhibit the mesonephric agenda,
where precious solutes in the glomerular filtrate are reclaimed for the
ECF and the extraneous water is released to the sea. However, on close
inspection, the proximal tubule segments of marine and freshwater
fishes have also retained mechanisms for transepithelial net solute
secretion that can be coupled to fluid secretion. Beyenbach and
colleagues (5, 7, 8, 16) dissected proximal tubules from
marine- and freshwater-adapted fish and observed that in some, but not
all, nonperfused segments, the lumens opened in the dissecting dish
despite the absence of glomeruli. Sustained net secretion of fluid
isosmotic with the ambient medium was documented by direct measurement,
and cAMP accelerated the rate of net chloride and fluid secretion.
These studies proved that mesonephric tubules retained the capacity to
secrete solutes and water. It is not a stretch of logic to suppose that
under in situ conditions, in which glomerular filtration might be
halted, these same tubule segments would generate urine by
transepithelial secretion of solutes and water. Indeed, studies of
intact Southern Flounder in which glomerular filtration was reduced to
zero demonstrated unequivocal secretion of urine containing
Mg2+, Na+, Cl, and
SO
The Metanephric Kidney
As emphasized by Smith (60), the kidney did not finally assume full responsibility for regulating body fluid and salt balance until animals emerged permanently onto dry land (Fig. 1). Amphibians, followed by reptiles, acquired mechanisms for excreting dilute fluid created in a unique segment just beyond the proximal tubule that absorbed salt without water, which eventually became the ascending limb of Henle. In this way, the volume of dilute urine could be hormonally regulated in relation to the availability of water. Reptiles, some living away from a source of water for long periods, reduced the importance of glomerular filtration, depending once again on tubular mechanisms to regulate solute and fluid balance to a significant extent (18). But because the osmolality of urine could not be concentrated above that of the body fluids, severely limiting habitats for survival, additional mechanisms were required to conserve water and to regulate the excretion of NaCl. To this end, the collecting duct system arose from the metanephric blastema, and the loop of Henle arrangement of tubule segments and blood vessels in the medulla were interposed between the proximal and distal tubules. With the creation of the countercurrent mechanism for concentrating solutes in the renal medulla, the mammalian kidney expanded the capability of animals to live away from pools of water. For example, the desert rat concentrates urine to more than 4,000 mosmol/kgH2O, in the face of relatively high rates of glomerular filtration, subsisting only on the water derived from the metabolism of relatively dry food.An easier solution to mammalian survival under extremely arid
conditions might have been to reduce glomerular filtration to rates as
some desert reptiles and birds have done (10-12).
However, as Smith (60) surmised, "the
filtration-reabsorption system (of mammals) is now so firmly
established that there is no easy way to overhaul it and to convert it
to a purely tubular kidney, as the marine fishes have done." He
became resigned to the filtration-reabsorption view of urine formation
in mammals but overlooked the collecting duct system in the regulation
of NaCl balance, relegating this segment to a relatively passive role
in the reabsorption of water under the control of the antidiuretic
hormone (60, 61). However, these terminal segments do much
more than reabsorb water. In the last two decades, direct studies have
established that the cortical and medullary collecting ducts
participate in the regulation of Na+, Cl,
K+, NH
Solute and Fluid Secretion in Mammalian Proximal Tubules
The capacity of mammalian proximal tubules to secrete as well as to reabsorb solutes and fluid was discovered inadvertently. My colleagues and I were surprised to find that the inclusion of p-aminohippurate (PAH) or human uremic serum containing increased levels of hippurate in the external medium bathing an isolated perfused S2 proximal tubule segment dissected from the rabbit kidney caused a sustained reversal in the net transport of fluid from absorption to secretion (28) (Fig. 2). Hippurate, a normal aryl anion metabolite, was as effective in causing fluid secretion as PAH, and probenecid, which blocked peritubular hippurate transport into the cells, inhibited fluid secretion. The net flux of hippurate was relatively low compared with net sodium transport in this segment; thus the effect of the organic anion on net fluid transport could only be seen at very low rates of tubule perfusion. A luminal PAH concentration of 40 mM had to be reached in the luminal fluid to override the active reabsorptive transport of sodium (22, 28). The peritubular mechanism for cellular uptake is powerful enough to raise intracellular hippurate to levels many-fold greater than in the external medium, thereby favoring hippurate entry into the lumen. This hyperpolarizes the transepithelial electrical potential, promoting Na+ transport through a paracellular pathway. In this way, the net reabsorption of NaCl is converted to net secretion of Na-hippurate, NaCl, and fluid. The mechanism is similar in most respects to other tissues that can either absorb or secrete Na+, owing to changes in the amount of secreted anion (58, 70, 71).
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We calculated that as much as 1 liter of secreted fluid [0.5% of glomerular filtration rate (GFR)] could be generated by hippurate transport within a 24-h period (22, 24). During periods of normal glomerular filtration, this secretory contribution of hippurate to urine formation would be masked by the robust reabsorption of 179 liters of Na+-rich glomerular filtrate. Thus it is not difficult to appreciate why fluid secretion driven by organic anion transport would be overlooked by even the best clearance methods for quantifying fractional and absolute levels of tubule fluid absorption and secretion. Indeed, an attempt to detect in humans a contribution of transtubular PAH secretion to urine formation failed because the reabsorption of glomerular filtrate was many times greater than the amount of fluid that could be secreted into the urine coupled to the transport of organic anions (4). To demonstrate fluid secretion coupled to hippurate transport by clearance methods, GFR would have to be reduced to <10% of normal to diminish the obscuring effect of competing NaCl-driven tubule fluid reabsorption, i.e., a situation more closely approximating that of the apocrine protovertebrate kidney. Thus the extent to which organic anion secretion may contribute to the entry of fluid into the lumens of mammalian proximal tubules in situ remains to be determined.
Solute and Fluid Secretion in Mammalian Collecting Ducts
Collecting ducts, the last intrarenal tubular segments through which urine flows, were also the last tubular segments in which transepithelial NaCl transport was rigorously quantified. The potential role of collecting ducts in the regulation of NaCl balance was hotly debated in the 1970s (20, 36, 41, 48, 64, 65, 67, 68). The majority view, which holds to this day, supposes that collecting ducts reabsorb, under the control of aldosterone, an amount of NaCl equivalent to ~3-5% of the filtered load (45, 76-78). Na+ reabsorption, linked to the epithelial sodium channel (ENaC) (54), has been demonstrated in the cortical collecting ducts (CCD) (2, 26, 27); however, OMCD and IMCD have not been found in in vitro perfused tubule experiments to transport much NaCl one way or the other, with some notable exceptions. Rocha and Kudo (52) reported that rat IMCD absorbed NaCl under normal perfusion conditions, but this could be reversed to net secretion on the addition of cGMP to the external medium or the addition of atrial natriuretic peptide, which stimulates the intracellular production of cGMP. However, efforts in other laboratories to reproduce these results have not been successful. On the other hand, in support of Rocha and Kudo's findings, cultured rat CCD and IMCD appear to absorb Na+ under basal conditions but can be induced to secrete ClSonnenberg and colleagues (62-64) used a retrograde catheterization technique to measure NaCl and fluid transport in rat IMCD in situ and found that massive ECF volume expansion with saline converted net NaCl and fluid absorption to net secretion. Results consistent with bidirectional Na+ transport in the IMCD have been reported by using classic in situ micropuncture methods (3); however, there is a concern that admixture of urine from juxtamedullary long-looped nephrons and superficial nephrons may have complicated the interpretation of these results (20, 36, 41). Net NaCl secretion in IMCD is further obfuscated by the relatively low rates of net solute transport, together with the fact that renal pelvic contraction (56) and the concentration of interstitial solutes are disturbed by in situ microcatheterization and micropuncture and in vitro microperfusion methods.
Wallace and colleagues (75) have recently addressed the
issue of collecting duct solute and fluid transport using a novel strategy to quantify net absorption and secretion. IMCD were dissected from the renal medullas of rats and maintained in vitro at 37°C for
several hours. With the use of methods developed for the study of net
fluid secretion in proximal tubules, the lumens of nonperfused collecting ducts were examined after addition to the incubation media
of substances that had been shown in a variety of secretory tissues,
including human renal cyst epithelial cells, to promote the net
secretion of Cl and fluid (Fig. 2). The results were
striking and unambiguous. The addition of cAMP to the collecting ducts
caused previously collapsed lumens to open widely with fluid, albeit at
a relatively low rate. Inclusion of benzamil, a high-affinity amiloride
derivative that inhibits ENaC channels in IMCD, potentiated the net
secretion of fluid caused by cAMP, indicating that reduction of
competing Na+ absorption unmasked a significant degree of
solute and fluid secretion. After inhibition with benzamil, a small
amount of residual absorption implicated nonspecific solute transport
mechanisms in addition to ENaC. The solutes secreted into the lumens
were osmometrically active and, more than likely, principally comprised Na+ and Cl
, although contributions of
K+, NH
secretion
[bumetanide, diphenylamino-2-carboxylic acid (DPC), and DIDS]
significantly reduced net fluid secretion promoted by cAMP. In
preliminary studies, epinephrine was found to be a potent agonist of
Cl
-dependent fluid secretion, working through
-adrenergic receptor stimulation of adenylate cyclase
(74).
Evidence of cAMP-mediated Cl secretion has been observed
in cultured monolayers enriched in IMCD cells obtained from rat and mouse (39, 40, 66). In preliminary studies
(74), cultured cell monolayers enriched in human IMCD
cells from the initial region of the inner medulla generated an
apically negative transepithelial potential difference averaging 5 mV
and positive short-circuit current (SCC). This basal SCC was diminished
by the apical application of benzamil, implicating ENaC-dependent
cation absorption as a contributor to the basal SCC. The addition of
cAMP to benzamil-treated membranes strikingly increased positive SCC,
consistent with the stimulation of anion transport. Bumetanide, DPC,
and DIDS inhibited the cAMP-mediated current, further implicating net
secretory Cl
transport by these cells. These preliminary
studies in cultured human cells support the view that IMCD have the
intrinsic capacity to secrete Cl
and Na+ and
thereby osmotically drive water into the tubule lumen.
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PHYSIOLOGICAL IMPLICATIONS OF RENAL TUBULAR SOLUTE AND FLUID SECRETION IN TERRESTRIAL MAMMALS |
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Regulation of NaCl and Fluid Balance
Under normal conditions in which there is free access to water and salt, the kidneys of a normal person filter ~125 ml/min of plasma containing 140 and 105 meq/l (25,200 and 18,900 meq/day) of Na+ and ClAssuming for the moment that certain renal tubule segments do secrete
NaCl under normal conditions, how might this have a role in the
formation of the final urine and the regulation of salt and
extracellular fluid balance? Salt secretion by tubules distal to
segments with high Na+ absorptive capacity would seem to
have the greatest impact on the economy of salt and water balance. Were
collecting ducts to add NaCl to the tubule fluid, it is likely that
this contribution would be reflected in the solute content of the final
urine. For the purpose of illustration, an extreme example of this
hypothesis is shown in Fig. 3, where it
is assumed that all of the filtered NaCl is reabsorbed before the urine
enters the medullary collecting ducts. In this case, the NaCl in the
final urine would be derived entirely from collecting duct secretion.
Alternatively, salt absorptive and secretory processes may be
distributed to varying degrees along the collecting duct system from
cortex to papilla.
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How then might we assess the possible contribution of salt secretion to urine formation? Clinicians have observed for decades that an imbalance between the intake and the excretion of salt and fluid often occurs insidiously, although eventually leading to massive edema. For example, the daily retention of salt and water equal to 100 ml of ECF (equivalent to only 0.055% of the GFR) could in 1 mo lead to the accumulation of 3 liters of fluid. In other words, changes in net tubule reabsorption equal to <1% of the filtered NaCl load would be sufficient to cause large changes in ECF volume over extended periods of time. Similarly, a decrease in NaCl secretion equal to <1% of the filtered load could have an effect as important as an increase in the fractional reabsorption of a similar magnitude, and we would be unable to tell one mechanism from the other. Conversely, were renal tubules to secrete each day an additional amount of NaCl equal to 100 ml of glomerular filtrate, neglecting compensatory responses, in 1 mo there would be a decrease in ECF volume of 3 liters and, more than likely, a lowering of the blood pressure. Thus seemingly inconsequential changes in tubule salt secretion could ultimately be reflected by changes in ECF volume manifested as edema or conversely as orthostatic hypotension.
Vasoactive intestinal peptide, a powerful Cl secretogogue
in the rat that activates adenylyl cyclase (59), increased
the renal excretion of NaCl in isolated perfused rat kidneys without causing changes in renal hemodynamics or GFR (53). This
finding is consistent with a contribution of net NaCl secretion to the final urine. Luke (42) reported in 1973 that restricting
drinking water for 24 h with a constant intake of salt caused rats
to increase the net excretion of NaCl, an effect that was mimicked by
the administration of vasopressin to euvolemic animals. The authors suggested that the increased excretion of NaCl, which seemed
paradoxical at the time, may reflect a mechanism the kidneys use to
maintain the tonicity of ECF during dehydration. In this regard, it is important to note that net NaCl secretion in the IMCD would most likely
be downhill, in which case salt excretion could be regulated in part by
hormonal effects on the permeability of collecting duct segments to
Na+ and Cl
(55). It is
conceivable that simple dehydration unmasks a cAMP-mediated salt
secretory mechanism in rat renal tubules that contributes to the
regulation of ECF tonicity, a process in the protovertebrate era that
was reinstated several million years ago in Lophius, a fish
that unloaded its glomeruli on returning to live in the sea (44,
60) (Fig. 1).
Perhaps it is time to reexamine, in those patients with mysterious
forms of chronic edema or ECF contraction, the possibility that tubule
NaCl secretion might have a role to play. Could the impaired renal
tubular functions in some idiopathic edema states, e.g., congestive
heart failure and hepatic insufficiency, reflect to some extent a
diminution in the tubular secretion of NaCl? And, conversely, could
excessive tubule NaCl secretion aggravate the salt wastage of certain
renal diseases and orthostatic states associated with ECF contraction?
Nephrologists may recall that it was not until indomethacin, a
cyclooxygenase inhibitor, was administered to intact animals that roles
for endogenous eicosanoids were appreciated as determinants of water
and salt balance (1). Furthermore, in this regard,
inhibition of prostaglandin synthesis in normal rats enhanced
Cl reabsorption in collecting duct segments
(37), a possible clue that eicosanoids regulate salt
transport in these segments through their capacity to stimulate the
formation of cAMP and, thereby, stimulate Cl
secretion
pathways. As we come to better understand the cellular mechanisms of
renal tubule NaCl secretion, it may be possible to find more selective
inhibitors or promoters of tubule solute and fluid secretion that will
make it possible to examine the potential impact of this occult
mechanism on long-term ECF balance.
Potential Role of Tubule NaCl and Fluid Secretion in Acute Renal Failure
The sudden reduction of blood volume through external hemorrhage or plasma sequestration leads to changes in renal hemodynamics that ultimately lead to the renal conservation of ECF. Similar effects on the kidney can be produced by the intravascular infusion of powerful renal vasoconstricting agents, or in some animals such as the diving seal, by a combination of neural and humoral mediated factors. The net effect is to reduce renal blood flow, decrease GFR, and minimize the renal loss of NaCl and water. Were glomerular filtration to cease, tubular lumens would collapse as fluid was completely reabsorbed. However, do the tubule lumens remain completely collapsed under such extreme circumstances? Most human plasma contains sufficient hippurate to promote net fluid secretion in isolated proximal tubules (28, 50). A similar secretory mechanism has been suggested as a means to maintain tubular excretory function in lower animals in which glomerular filtration is intermittent (7, 13, 15).It is conceivable that, under conditions of markedly reduced or
complete cessation of glomerular filtration, mammalian proximal tubules
could secrete hippurate and similar substances in amounts sufficient to
maintain patent tubule lumens and to propel urine through the nephron,
albeit at markedly reduced rates of flow (Fig. 4). In the collecting
duct segments, the net addition of NaCl and water by secretion could
contribute further to urine formation. In this way, elimination of some
of the potentially toxic products normally excreted by the kidneys, as
well as NaCl and water, would serve a useful survival function, which
mirrors to a large extent the formation of urine in aglomerular
teleosts.
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The extent to which proximal tubule fluid secretion may occur in intact
kidneys under conditions defined as acute renal failure is unknown.
Widely dilated renal tubules, commonly seen in photomicrographs of
renal biopsy sections, are consistent with a secretory process. Robust
secretion of hippurate in patients destined to recover from acute renal
failure has been well established and is a reliable indicator of
prognosis (30). Whether the scant amount of urine formed
under such circumstances is a product of incomplete reabsorption of
markedly reduced glomerular filtrate or a product of tubule solute and
fluid secretion is a question worth consideration. It is generally held
that the relatively high fractional excretion of Na+ and
Cl in urine with a markedly reduced urine-to-plasma
creatinine ratio is secondary to reduced tubular reabsorption of scant
glomerular filtrate attributable to tubule cell mispolarization of
transport proteins and cellular necrosis (46). The
possibility that the urine may also reflect the secretion of organic
and inorganic solutes and fluid by the proximal tubules and the
dilution of this fluid by downstream secretion of NaCl and water by the
collecting ducts has not been seriously considered. Perhaps it should.
Could it be that the favorable effect of aminophylline, a
phosphodiesterase inhibitor, on the outcome of acute renal failure may
have as much to do with the stimulation of tubule salt and fluid
secretion as with the blockade of adenosine receptors (9,
31)?
Role of NaCl and Fluid Secretion in Tubule Cyst Formation and Enlargement
Autosomal dominant polycystic kidney disease (ADPKD) (14) and acquired cystic kidney disease (23) have provided important clues to the existence within tubular epithelial cells of mechanisms for the secretion of solutes and fluid. In ADPKD, cysts develop in proximal, distal, and collecting tubules as a consequence of the mutation of either of two genes, PKD1 or PKD2. The cysts begin as focal outgrowths of individual tubule segments and in a sense represent benign neoplastic tumors that are full of liquid rather than cells. In the early stages of cyst formation, the fluid within them derives from the afferent tubule segment in which the cyst arose. Unreabsorbed glomerular filtrate enters the cysts and collects there as the segment expands, owing to the growth of mural epithelial cells. Interestingly, when the cysts reach a diameter of ~200 µm, most of them separate from the parent tubule and become isolated sacs of liquid. In this circumstance, net transepithelial fluid secretion is the only mechanism for the sustained addition of liquid to the expanding cyst.The mechanisms of fluid secretion in human renal cysts of ADPKD
patients have recently been elucidated (70, 71). The mural cells appear somewhat less mature that the proximal and distal epithelium from which they derived, and the capacity to absorb solutes
and water is greatly reduced. On the other hand, the epithelial cells
derived from both proximal and distal tubule elements retain the
capacity to secrete NaCl and fluid, as was demonstrated in tubules from
normal individuals. This fluid secretion process is regulated by
intracellular cAMP, which increases the permeability of cystic fibrosis
transmembrane conductance regulator-like Cl channels in
apical membranes. This, together with the entry of Cl
from the basolateral side of the cells through a
Na+-K+-2Cl
cotransporter in
conjunction with basolateral K+ channels for recycling this
ion, leads to the net secretion of Cl
into the urine and
an increase in lumen negativity. The negative transepithelial potential
increases the movement of peritubular Na+ into the lumen
through paracellular pathways.
The amount of fluid secretion into cysts can be increased by substances
that activate adenylate cyclase, including arginine vasopressin,
prostaglandin E2, secretin, vasoactive intestinal polypeptide, phosphodiesterase inhibitors, and an anonymous neutral lipid that has been detected in cyst fluids of patients with ADPKD (25, 29). Fluid secretion can be inhibited by blocking the Na+ pump with ouabain, inhibiting the
Na+-K+-2Cl cotransporter with
bumetanide, inhibiting a basolateral K+ channel with
glybenclamide, blocking the apical cystic fibrosis transmembrane
conductance regulator with DPC, and blocking the action of protein
kinase A with H-89 and RpcAMP. Fluid secretion in renal cysts,
therefore, resembles in most respects the secretion of NaCl and fluid
by mammalian renal collecting ducts.
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SUMMARY AND CONCLUSIONS |
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The mammalian kidney reflects its evolutionary precursors to a remarkable extent. It retains many of the molecular and energy-efficient functional features of simple primordial kidneys that regulate fluid balance and eliminate potentially toxic molecules entirely by secretion. However, the modern kidney must deal with an exuberant glomerulus that was fused to the proximal tubule during the adaptive journey in a freshwater environment, where radical expulsion of free water was necessary for survival. Terrestrial reptiles and desert birds have suppressed the impact of the glomerulus, but it has stubbornly flourished even in mammals that prefer to live in arid climates. In the face of avid solute and fluid reabsorption imposed by glomeruli, occult secretory processes in the proximal and collecting tubules of the mammalian kidney, carried forward during the evolution of vertebrates from the sea to dry land, have persisted as mechanisms for the fine regulation of ECF volume and composition day to day, and possibly for the continuance of a small stream of urine even during the failure of glomerular filtration.
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ACKNOWLEDGEMENTS |
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The authors thank Drs. Lawrence Sullivan and Thomas DuBose for helpful discussions.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants (P01-DK-53763 and P50-DK-57301 from the Department of Health and Human Services to J. J. Grantham), a National Research Service Award (to D. P. Wallace), and the Polycystic Kidney Foundation.
Address for reprint requests and other correspondence: J. J. Grantham, Kidney Institute, Univ. of Kansas Medical Ctr., 3901 Rainbow Blvd., Kansas City, KS 66160 (E-mail: jgrantha{at}kumc.edu).
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