Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland 21201-1595
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ABSTRACT |
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Perfusion of the renal medulla plays an
important role in salt and water balance. Pericytes are smooth
muscle-like cells that impart contractile function to descending vasa
recta (DVR), the arteriolar segments that supply the medulla with blood
flow. DVR contraction by ANG II is mediated by depolarization resulting from an increase in plasma membrane Cl conductance that
secondarily gates voltage-activated Ca2+ entry. In this
respect, DVR may differ from other parts of the efferent
microcirculation of the kidney. Elevation of extracellular K+ constricts DVR to a lesser degree than ANG II or
endothelin-1, implying that other events, in addition to membrane
depolarization, are needed to maximize vasoconstriction. DVR
endothelial cytoplasmic Ca2+ is increased by bradykinin, a
response that is inhibited by ANG II. ANG II inhibition of endothelial
Ca2+ signaling might serve to regulate the site of origin
of vasodilatory paracrine agents generated in the vicinity of outer
medullary vascular bundles. In the hydropenic kidney, DVR plasma
equilibrates with the interstitium both by diffusion and through water
efflux across aquaporin-1. That process is predicted to optimize
urinary concentration by lowering blood flow to the inner medulla. To optimize urea trapping, DVR endothelia express the UT-B facilitated urea transporter. These and other features show that vasa recta have
physiological mechanisms specific to their role in the renal medulla.
vasa recta; perfusion; hypertension; oxygenation; urinary concentration; patch clamp; calcium; fura 2
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INTRODUCTION |
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THE MICROCIRCULATION OF THE kidney is regionally specialized. In the cortex, afferent and efferent arterioles govern the driving forces that promote glomerular filtration. A dense peritubular capillary plexus arising from efferent arterioles surrounds the proximal and distal convoluted tubules to accommodate enormous reabsorption of glomerular filtrate. In contrast, vasa recta serve needs specific to the medulla. Through the counterflow arrangement of descending (DVR) and ascending vasa recta (AVR), countercurrent exchange traps NaCl and urea deposited to the interstitium by collecting ducts and the loops of Henle. This is vital to maintain corticomedullary osmotic gradients but conflicts with the need to supply nutrient blood flow to medullary tissue. Metabolic substrates that enter the medulla in DVR blood diffuse to the AVR to be shunted back to the cortex. To deal with the threat of medullary hypoxia resulting from this process, the kidney has evolved a capacity to exert subtle control over regional perfusion of the outer and inner medulla. The details are far from clear, but much experimental evidence points to the complex interactions of many autocoids and paracrine agents to modulate vasomotor tone at various sites along the microvascular circuit. The goal of this review is to summarize recent insights into the control of medullary perfusion and the cell biology and mechanisms that govern vasa recta transport and vasoactivity.
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RENAL MEDULLARY MICROVASCULAR ANATOMY |
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Studies of regional perfusion have consistently shown that
the fraction of total renal blood flow that is distributed to the inner
cortex and medulla is subject to regulation (2, 17, 18,
28-30, 73-80, 88, 90, 110, 113, 180-185). To
understand the sites at which such regulation might occur,
microvascular anatomy will be briefly reviewed (Fig.
1). For greater detail, the interested
reader is directed to a number of well-illustrated sources (6, 7, 48, 49, 55, 56, 60, 81, 85, 86, 99, 105, 110, 113, 163).
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The medulla of the kidney is perfused by the efferent arteriolar blood flow that leaves juxtamedullary glomeruli. In the outer stripe of the outer medulla, juxtamedullary efferent arterioles give rise to many DVR (Fig. 1). There is also strong anatomic evidence that periglomerular shunt pathways give rise to some DVR (16). The inner stripe of the outer medulla is characterized by its separation into vascular bundles and the interbundle region. Vascular bundles contain all DVR destined to perfuse the interbundle region and those that eventually penetrate beyond the inner-outer medullary junction to the inner medulla. DVR on the bundle periphery give rise to a capillary plexus that perfuses the interbundle region, where metabolically demanding, salt-transporting epithelia of the thick ascending limb and collecting duct are located. DVR in the bundle center traverse the inner stripe of the outer medulla to reach the inner medulla. The latter may be larger and more muscular than peripheral DVR. Vascular bundles contain all AVR returning from the inner medulla and, to a degree that varies with species, short looped thin descending limbs of Henle (6, 7, 56, 60, 99, 110). Based on anatomic considerations alone, it seems evident that the vascular bundles place DVR and AVR into close apposition to favor efficient equilibration. They are also likely to be an important site for regulation of the regional perfusion of the outer and inner medulla because preferential vasodilation of DVR on the bundle periphery or constriction of DVR in the bundle center should enhance perfusion of the interbundle region.
DVR occupy a functional niche that is partially arteriolar and partially capillary in nature. The DVR wall is characterized by smooth muscle remnants that surround a continuous endothelium and impart contractile function. The pericytes persist into the inner medulla but eventually disappear (111, 120). Near their termination, DVR become fenestrated and give rise to a sparse capillary plexus. The plexus coalesces to form AVR that are characterized by a high degree of fenestration (117, 138). The fraction of the AVR wall occupied by fenestrations is larger in the inner medulla than in the outer medulla.
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ROLE OF DVR IN REGULATION OF MEDULLARY BLOOD FLOW |
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Regulation of blood flow to the renal medulla has been a subject of interest for decades. The methods used to measure blood flow and the conclusions derived from the associated studies have been frequently reviewed (17, 73, 76, 90, 105, 110). Laser-Doppler is now the dominant method for measuring regional perfusion of the kidney. That method relies on the Doppler shift imparted to monochromatic light by backscatter from moving red blood cells (RBCs) in a localized area of tissue. Many regional perfusion studies have been performed in animals that have had optical fibers acutely or chronically implanted into the renal parenchyma (2, 17, 28-30, 70, 73, 76). Studies of the extent of autoregulation of medullary perfusion with variation in renal perfusion pressure have produced variable results (17, 70, 76, 90), but much evidence points to a possible role for variation of medullary autoregulation with extracellular fluid volume status to regulate "pressure natriuresis" (17, 76, 78, 131). Laser-Doppler studies with implanted flow probes yield a signal from a fixed volume of tissue and thus the probes are sensitive to probe orientation. Direct measurement of DVR blood flow using dual-slit videomicroscopy has also been performed. Cupples and Marsh (19) found that flow in a single descending vasa rectum was regulated between 85 and 160 mmHg. The latter does not rule out the possibility that recruitment of flow might occur through previously unperfused DVR, as described by Roman et al. (see below) (131). In the latter case, single-vessel flow might be autoregulated while overall flow is not. Apart from the issue of regional autoregulation, a number of consistent themes have emerged. Blood flow to the medulla is dependent on the tonic vasodilatory influence of prostaglandins and nitric oxide (NO) (74, 75, 79, 83, 84, 88, 119). Blockade of renal medullary vasodilator synthesis leads to a reduction of medullary blood flow, salt retention, and hypertension. Thus, apart from the anticipated role of medullary blood flow to contribute to urinary concentration and water balance, a role in the regulation of sodium balance may also exist. The effector mechanisms that connect medullary perfusion to regulation of epithelial sodium transport are not well established, but various possibilities exist. It has been demonstrated that increases in perfusion pressure cause a secondary increase in renal interstitial pressure and that the latter leads to inhibition of proximal reabsorption (128). Some forms of hypertension are associated with regulation of sodium transport pathways (71), but this would not account for the immediate ability of increased perfusion pressure to cause saliuresis. If medullary perfusion modulates local NO release, a secondary effect on salt and water excretion could result (94, 95).
Given the importance of medullary perfusion in influencing salt and
water balance, we were motivated to determine which location(s) along
the microvascular circuit provides control of medullary blood flow.
Afferent and efferent arterioles of juxtamedullary glomeruli could
constrict and dilate to serve this purpose, but that hypothesis
conceivably conflicts with the need for them to simultaneously control
juxtamedullary glomerular filtration pressures. The possibility that
periglomerular pathways for perfusing the medulla are important in this
scheme has been proposed (16, 17). Based on anatomic
considerations (Fig. 1), it seems probable that DVR are an important
site of regulation. The latter has been impossible to test directly
because the outer medulla and most of the inner medulla are
inaccessible to observation in vivo. When DVR are isolated from rats
and examined in vitro, contractile pericytes are observed and the
vessels exhibit vasoreactivity, responding to numerous constrictors and
dilators (Fig. 2). Vasoactive agonists
include many paracrine agents that are synthesized within the medulla
(104, 111-113, 129, 144-146). Because DVR are
branches of efferent arterioles, it seems logical to conclude that
their vasomotion could affect glomerular filtration pressures; however, compensatory changes in afferent arteriolar tone could hypothetically offset that effect with the response to signals arising from
tubuloglomerular feedback and myogenic response. The details are
uncertain, but it is likely that DVR are an important regulator of
medullary perfusion.
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The parallel arrangement of DVR within outer medullary vascular bundles raises two questions. First, does global constriction of DVR regulate the rate at which blood crosses from the cortex to the medulla, i.e., influence total medullary perfusion? Second, does DVR vasomotion within vascular bundles regulate distribution of blood flow between the interbundle region of the outer medullary inner stripe and the inner medulla? Those actions are not mutually exclusive. Some quantitative and qualitative observations are germane. Roman and colleagues (131) reported that variation in inner medullary tissue perfusion is related both to changes in blood flow through single vessels and to the recruitment of blood flow into previously nonperfused DVR. Given that the luminal diameter of DVR is similar to that of RBCs, it seems plausible that flow through them could be stopped by intense foci of constriction in the outer medulla. If that occurs, excessive back-pressure might not result because blood from the efferent arteriole could still traverse adjacent vessels that lie in parallel within the vascular bundles (Fig. 1). This possibility is qualitatively supported by the observation that bolus spurting of RBCs through the lumen of DVR can sometimes be seen on the surface of the papilla (inner one-third of the inner medulla) when the papilla is exposed for micropuncture (Pallone, unpublished observations). Goligorsky and colleagues (34, 61) have postulated that membrane fluidity changes related to local production of NO contribute to such processes. Finally, differential regulation of outer vs. inner medullary perfusion by vasopressin has been observed when optical laser-Doppler probes were inserted into the medulla at various depths (28).
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VASOACTIVITY OF DVR |
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When DVR are isolated from outer medullary vascular bundles,
perfused in vitro, and exposed to contractile agonists, they constrict
at various foci along their length (Fig. 2). Of the various agents thus
far examined, endothelin-1 and -2 yield the most intense and durable
constriction (146). They have threshold effects at
1014 M and most often obliterate the vessel lumen at
higher concentrations (100% constriction, Fig. 2). These agents induce
durable constriction that does not wane and is only slowly reversible
after washout. ANG II is also a consistent constrictor that, on
average, reduces luminal diameter of microperfused vessels by 40- 60%
(104, 114, 129). As in cortical vessels, thromboxanes are
partially responsible for mediation of ANG II DVR constriction
(140, 143, 164, 165). In contrast to endothelins,
vasoconstriction by ANG II tends to maximize 5-10 min after
application and then slowly wane toward a stable baseline (Fig. 2).
Microperfused DVR seem to exhibit a minimum of intrinsic tone and to
show no myogenic activity when pressurized (104). It must
be recognized, however, that these observations are obtained from
isolated vessels placed into artificial buffers without supporting
interstitum, often hours after the death of the rat.
Pericytes are the smooth muscle remnants that surround DVR and
presumably impart contractile function. Recently, the mechanisms by
which ANG II induces vasoconstriction have been evaluated using fluorescent probes of intracellular Ca2+ concentration
([Ca2+]i) and membrane potential and by
electrophysiological recording. As expected for signaling via the ANG
II AT1 receptor, a classic peak-and-plateau intracellular
Ca2+ response is elicited in fura 2-loaded pericytes (Fig.
3) (130, 176). Both whole
cell electrophysiological recording and measurements with a
potentially sensitive fluorescent probe showed that ANG II
depolarizes the pericyte cell membrane (Fig.
4) (107, 130, 175, 176).
This seems to occur through activation of a Ca2+-sensitive
Cl conductance that shifts membrane potential away from
the equilibrium potential of the K+ ion toward that of
Cl
(107, 175). An 11-pS Cl
channel has been identified in the pericyte cell membrane. This channel
has low basal open probability but is activated by ANG II or excision
into high-Ca2+ buffers (Fig.
5). Membrane potential of ANG II-treated
pericytes often oscillates, and voltage-clamped cells held at
70 mV
exhibit classic spontaneous transient inward currents typical of
various smooth muscle preparations (Fig. 4C) (35, 43,
46, 91).
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The role of membrane depolarization and changes in Cl
conductance are well established in the afferent arteriole (13,
39, 47, 63) as a means of gating Ca2+ entry
(14, 15, 64). Until recently, however, the existence of
voltage-gated Ca2+ entry pathways in the efferent
circulation has been uncertain. Rigorous examination of this issue with
RT-PCR, immunochemistry, and the assessment of vasoreactivity in
isolated arterioles has been reported by Hansen and colleagues
(38). T-type subunits, Ca(V)3.1 and Ca(V)3.2, and
an L-type subunit, Ca(V)1.2, were found in efferent arterioles of
juxtamedullary glomeruli but not superficial glomeruli. These subunits
were also identified in DVR (38). Based on this finding,
membrane potential of DVR pericytes is expected to control
voltage-gated Ca2+ entry and modulate
[Ca2+]i, a prediction that received recent
experimental support. The L-type channel blocker diltiazem vasodilates
ANG II-constricted DVR and reduces [Ca2+]i of
ANG II-treated pericytes. Both high external K+
concentration and the L-channel agonist BAY K 8644 are weak DVR vasoconstrictors. Finally, agents that repolarize pericytes, bradykinin (BK) and the ATP-sensitive K+ channel opener pinacidil, are
effective vasodilators (Fig. 6) (176). The many downstream effects of pericyte ANG II
receptor activation remain unknown; however, there are hints that
important effects result from actions independent of
[Ca2+]i elevation. Principally,
depolarization in the absence of agonist induces far less intense
constriction than does ANG II or endothelins (Fig. 2). Phosphorylation
events that sensitize the intracellular contractile machinery to the
effects of Ca2+ are likely to be implicated
(133).
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ROLE OF DVR ENDOTHELIA IN THE REGULATION OF VASOACTIVITY |
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As a fortuitous consequence of the fact that the
Ca2+-sensitive fluorophore fura 2 loads almost exclusively
into DVR endothelia (to the near exclusion of pericytes), it has been
relatively easy to examine global Ca2+ transients generated
by endothelium-dependent vasodilators (Fig. 7). As expected, BK generates a
peak-and-plateau Ca2+ response, enhances NO generation
(Fig. 8), and induces vasodilation (112, 129, 130). An unexpected finding is that the
vasoconstrictor ANG II suppresses basal Ca2+ and inhibits
BK-, acetylcholine-, thapsigargin-, and cyclopiazonic acid-induced
Ca2+ responses in DVR endothelia (Fig. 7, B and
C) (114, 130). This is surprising for several
reasons. First, AT1 receptors, which mediate the vast
majority of the effects of ANG II, signal through inositol
3,4,5-trisphosphate generation and Ca2+ mobilization.
Second, infusion of ANG II has been observed to lead to secondary
enhancement of NO levels within the medulla (182, 185) and
in isolated cortical microvessels (153, 154). Given that
endothelial nitric oxide synthase (eNOS)/NOS3 is a Ca2+-dependent isoform of NOS, suppression of
Ca2+ would be expected to block rather than enhance
endothelial NO generation. As a possible answer to this paradox, we
pointed out that adjacent nephrons also express NOS isoforms, so that
ANG II elevation of Ca2+ in those structures would favor NO
generation on the vascular bundle periphery. Hypothetically, this could
provide a feedback loop (in addition to adenosine) through which the
medullary thick ascending limb (mTAL) can regulate its own perfusion.
As previously discussed, ANG II might suppress DVR endothelial
Ca2+ signaling as a means of turning regulation of DVR
vasomotion away from the endothelium to the mTAL (114,
130).
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The concentrations of ANG II required to influence endothelial
Ca2+ signaling or to maximally constrict DVR in vitro
(nanomolar) exceed circulating levels (picomolar). Compartmental ANG II
concentrations within the kidney can be as high as 109 to
10
10 M (89, 142). The renal outer medulla is
inaccessible to micropuncture, so that direct sampling of outer
medullary DVR plasma directly downstream of juxtamedullary glomeruli
cannot be performed. Seikaly and colleagues (142) found
that ANG II concentrations in star vessel plasma sampled downstream of
superficial glomeruli exceed circulating levels by as much as
1,000-fold. On this basis, it seems possible that DVR could be exposed
to nanomolar ANG II in vivo.
The vasodilatory influence of NO cannot be completely understood
without considering its interaction with O2 free radicals. These are generated by one-electron reductions of O2 to
generate superoxide (O), a product that, compared with NO,
is a weak vasodilator. ROS are generated by the "leak" of electrons
from the mitochondrial electron transport chain as well as a variety of
enzymatic processes. Intrinsic mechanisms limit cellular levels of ROS.
Several isoforms of superoxide dismutase (SOD) convert
O
Renal generation of ROS favors vasoconstriction and may contribute to
some forms of hypertension. Tempol is a cell-permeant SOD mimetic that
reduces hypertension in the spontaneously hypertensive rat (139,
141). Of the several sources of O. Interestingly,
PO2 values are lower in the SHR, and this too
is normalized by ARB therapy or treatment with the SOD mimetic tempol
(1, 164). Tempol also has been shown to enhance medullary
perfusion (183). NO production by isolated DVR and the
mTAL is enhanced by tempol, and this agent blunts ANG II-induced DVR
vasoconstriction (94, 129). Given the importance of
medullary blood flow in the regulation of blood pressure, it is
inviting to speculate that some forms of hypertension might be related
to an increase in "oxidative stress" in the renal medulla.
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MEDULLARY PO2 AND PERFUSION OF THE MEDULLA |
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PO2 in the medulla of the kidney is low,
in the range of 10-25 mmHg (11, 12, 22). This is
predicted to be a consequence of the countercurrent arrangement of vasa
recta (173) because O2 in DVR blood diffuses
to AVR to be shunted back to the cortex. Evidence supports the notion
that O2 consumption by the salt-transporting mTAL makes it
vulnerable to ischemia (12). Several hormonal systems play a role in the protection of the medulla from
ischemic insult. Each shares the ability to enhance medullary
blood flow and inhibit salt reabsorption along the nephron.
Hypothetically, this should have a dual effect of enhancing the supply
of O2 and simultaneously reducing the demand for its
consumption. A first example is the generation of vasodilatory
prostaglandins through activation of cyclooxygenase (COX)
(58). It has been observed that perfusion of the renal
medulla is sensitive to COX inhibition (110, 113, 119).
Furthermore, renomedullary interstitial cells have receptors for ANG II
and BK and release PGE2 in response to these agents
(21, 72, 178, 179, 186). Recently, Qi et al.
(127) have shown that the COX-2 isoform is expressed in
those cells and is responsible for this action. In their study, ANG II
reduced medullary blood flow in COX-2-, but not COX-1-, deficient mice
(127). The ability of PGE2 to promote
natriuresis may be explained in part by the ability of PGE2
to inhibit Cl reabsorption by the mTAL (41,
146). PGE2 is a vasodilator of in vitro perfused DVR
(104, 146).
In most vascular beds, ischemia favors generation of adenosine, a paracrine agent that enhances blood flow through local vasodilation. The actions of adenosine in the renal cortex are unusual because it induces vasoconstriction, accompanied by a reduction of glomerular filtration rate (2, 90). Within the medulla, however, adenosine acts as a vasodilator and inhibits salt reabsorption by the mTAL (2, 184). This presumably serves to reduce O2 consumption while enhancing O2 delivery (2, 22). It is a reasonable hypothesis that adenosine produced by the mTAL diffuses to and dilates outer medullary DVR on the periphery of vascular bundles. Outer medullary DVR on the bundle periphery supply the mTAL with blood flow, so such a mechanism represents a feedback system that would protect the mTAL from hypoxia. The mTAL has the capacity to produce adenosine (9) and that A1 and A2 receptor mRNA is expressed in DVR (54). Adenosine A1 and A2 receptor stimulation favors DVR vasoconstriction and vasodilation, respectively (144, 145).
Studies have shown that renal medullary NOS activity and NO production exceed that in the cortex (74, 75, 79, 80, 87, 166, 167, 182). Evidence is accumulating that NO acts in an autocrine and paracrine fashion to modulate both vasomotor tone and epithelial NaCl reabsorption. Inhibition of NOS in the renal medulla has isoform-specific effects. NOS1 inhibition reduces NO levels in the medulla and induces salt-sensitive hypertension but fails to alter medullary perfusion (50, 74, 77). Global inhibition of NOS1, NOS2, and NOS3 isoforms with nonselective blockers decreases medullary NO levels and induces salt retention and hypertension. In addition, global NOS inhibition reduces medullary blood flow and tissue oxygenation (11, 42, 78, 124). NO generation may be important to abrogate tissue hypoxia that would otherwise arise from release of vasoconstrictors. ANG II, norepinephrine, and vasopressin stimulate release of NO in the medulla (121, 150, 151, 181, 185). Subpressor infusion of NG-nitro-L-arginine methyl ester into the renal interstitium does not affect medullary blood flow or PO2 but enables otherwise ineffective doses of ANG II (185) norepinephrine (151, 181), or vasopressin (150) to induce a fall in these parameters. Taken together, the data support the conclusion that medullary NO production has a tonic effect in maintaining perfusion and protecting the medulla from ischemic injury. In addition to vascular effects, NO inhibits solute and water reabsorption in the collecting duct and thick ascending limb (31-33, 95, 122, 123, 148, 149). Studies in knockout mice implicated NOS3 as the isoform responsible for autocrine stimulation of NO in the thick ascending limb (122). Thus, like prostaglandins and adenosine, NO is a vasodilator that also inhibits salt reabsorption and therefore O2 consumption in the thick ascending limb.
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TRANSPORT OF SOLUTES AND WATER ACROSS VASA RECTA |
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DVR occupy a functional niche that is partially that of a vasoactive arteriole and partially that of a transporting microvessel. As such, it is not surprising that evidence has emerged to show that DVR endothelia have specialized characteristics that reflect the requirements endowed by their anatomic location and dual role. DVR have a continuous endothelial lining and zona occludens. It is expected that the paracellular pathway conducts diffusive transport of NaCl and other small hydrophilic solutes (82, 109, 158). In addition to this, transcellular pathways have been identified that conduct transport of urea and water (51, 52, 92, 93, 97-99, 106, 108, 117, 118). The principal transport functions of vasa recta will be briefly discussed. For a detailed explanation and historical perspective, the reader is referred to other reviews (25, 110).
The first evidence that DVR endothelia express a carrier for urea was that individual vessels, perfused simultaneously with [22Na]- and [14C]urea, often exhibited low or moderate Na+ permeability but always had very high permeability to urea (117). This was surprising because the diffusivities of Na+ and urea in water are nearly identical, so that transport via diffusion in an aqueous pore predicts identical permeabilities to these tracers. The ability of phloretin and urea analogs to reduce DVR urea permeability supported the existence of a carrier in DVR endothelia, implying a major contribution of transcellular, facilitated diffusion to overall urea transport (97, 117). That urea carrier was eventually identified as the one expressed by the RBC (UTB), a form that is distinct from the vasopressin-sensitive and -insensitive splice variants of the epithelial carrier (UTA1-UTA4) (5, 8, 44, 51, 52, 125, 134, 135, 155-157, 168, 170). Taken together, the expression of epithelial, endothelial, and RBC-facilitated carriers seems to ensure that urea diffusing from AVR plasma will be efficiently recycled by diffusing into thin descending limbs and DVR. Yang and Verkman (171, 172) have shown that UTB exhibits water channel activity and that UTB conducts water across the aquaporin-1 (AQP1)-deficient RBC membrane. A role for UTB in the transport of water across DVR has not been established; however, it is notable that urea, glucose, and raffinose can drive substantial water flux across AQP1-deficient DVR (106).
It has long been known that DVR plasma protein concentration increases
with distance into the renal medulla due to water efflux from the DVR
lumen to the papillary interstitium. That transport proceeds in a
direction opposite to inwardly directed Starling forces (hydraulic and
oncotic pressure), thus implicating transmural small-solute osmotic
gradients as the responsible driving force (98, 118, 137,
138). For NaCl and urea gradients generated by the lag in
equilibration between DVR plasma and medullary interstitium to induce
water efflux, the water must traverse a pathway of sufficiently small
pore size for these solutes to be osmotically active. The missing piece
of that puzzle was provided by the cloning of the AQP1 water channel,
followed by the demonstration that it is expressed in DVR and other
endothelia (3, 92, 93, 132). When AQP1 was blocked by
p-chloromercuribenzenesulfonate in the rat
(108) or deleted in the mouse (66, 106), the
water flux driven by transmural NaCl (but not albumin) gradients was
nearly eliminated, such that osmotic water permeability fell from
~1,100 µm/s to nearly 0. Another surprising finding was
that AQP1 deletion was accompanied by a marked increase
in DVR diameter, the first demonstration of the capacity of
vasa recta to remodel (Fig. 9). The
question remained, How does the efflux of water from DVR to the
medullary interstitium benefit urinary concentration? Insight derived
from mathematical simulations showed that shunting of water from DVR to
AVR in the superficial medulla reduced blood flow to the deep medulla, secondarily improving plasma-interstitial equilibration. This
was predicted to improve the efficiency of inner medullary countercurrent exchange and enhance interstitial osmolality (23, 24, 106, 152).
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Nephrons, collecting ducts, and DVR deposit water to the medullary interstitium. Thus, for mass balance, removal is delegated to AVR. The latter are highly fenestrated (110, 138) and have very high hydraulic conductivity and solute permeability that exceeds that of DVR (68, 69, 102, 103, 116). AVR are less well characterized than DVR because they cannot be isolated for in vitro perfusion. AVR have been postulated to serve an unusual role in the clearance of macromolecules from the medullary interstitium. The renal medulla is devoid of lymphatics, so albumin must be removed from the interstitium into AVR (10, 20). The reflection coefficient of AVR to albumin is relatively low (0.58-0.78) (66-68, 101). Based on this and the ability of AVR to withstand a hydraulic pressure gradient without collapsing, it has been postulated that albumin is cleared from the interstitium by convective solvent drag across the AVR wall (67-69, 100, 160-162). A detailed simulation by Zhang and Edwards (174) verified the feasibility of that mechanism and predicted the presence of an axial gradient of albumin concentration in the medullary interstitium.
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SUMMARY AND CONCLUSIONS |
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The microcirculation of the renal medulla serves several roles. The classic depiction of vasa recta as passive filters that provide countercurrent exchange and solute trapping belies the complexity of their structure and function. DVR are arterioles that respond to an array of vasoactive agents (111). They are also transporting microvessels that express specific transporters for water (AQP1) and urea (UTB) (92, 93, 168). The ability to isolate and study these vessels has made it possible to examine transport properties, pericyte contractile mechanisms, and endothelial interactions. The physiology of AVR is less well characterized because they have only been studied on the surface of the exposed papilla in vivo.
We have recently learned that DVR pericytes behave in ways that are
typical of smooth muscle from the afferent arteriole and other
microvascular beds. When exposed to ANG II, pericytes depolarize by
activating a Cl conductance, a process that gates
voltage-activated Ca2+ entry pathways (38, 107, 130,
176). It is surprising is that this process apparently occurs in
the juxtamedullary efferent circulation that supplies the renal medulla
with blood flow but not in smooth muscle of superficial efferent
arterioles (13-15, 63, 64). The physiological purpose
of this axial heterogeneity is uncertain, but prior observations that
L-channel antagonists enhance medullary blood flow seem better
explained (26, 37, 65, 169). The ability to access DVR
pericytes for electrophysiological examination and measurement of
intracellular Ca2+ transients is a recent development
(107, 130, 175, 176). Only cells from outer medullary
vessels have been studied, and it remains possible that those from the
inner medulla will be found to have unique properties. In the inner
medulla, extracellular Na+, K+,
Cl
, urea, and osmolyte concentrations are high, and this
might have forced the evolution of unusual mechanisms to control and
gate membrane potential and Ca2+ entry.
It is clear that DVR endothelia are unusual. These cells express the AQP1 water channel that is responsible for small-solute-driven efflux of water to the medullary interstitium (118, 137). Thus, in opposition to the classic view of purely diffusive countercurrent exchange, water abstraction is an important mode of DVR equilibration. Furthermore, it has been predicted that the latter serves to lower blood flow and optimize interstitial solute concentrations in the deep medulla, where axial gradients are largest (106). In addition to AQP1, DVR endothelia express the same urea carrier as red blood cells, UTB (125, 168, 170-172). Presumably, this provides for rapid equilibration of urea in DVR plasma, RBC interior, and medullary interstitium. As expected, DVR endothelia generate NO, cellular levels of which may be regulated in part through generation of superoxide anion (129). What has been more surprising is that an elevation of endothelial [Ca2+]i , expected to stimulate the NOS3 isoform, does not occur on ANG II stimulation. In fact, ANG II is found to reduce endothelial [Ca2+]i and suppress [Ca2+]i responses to endothelium-dependent vasodilators. It has been hypothesized that this turns modulation of pericyte constriction away from the endothelium to NO diffusion from adjacent mTALs of the outer medullary interbundle region (114, 130). Because NOS3 is subject to regulation by a variety of influences, confirmation of this hypothesis awaits sensitive measurement of DVR NO generation.
Although isolation of DVR for in vitro study has provided the key technique for delineation of the cell biology of these vessels, barriers to our understanding remain. It is uncertain how well observations translate to the in situ condition, where vessels are supported by interstitium and lie in close proximity to paracrine influences arising from adjacent interstitial cells and epithelia (59). The notion that DVR play a role in the modulation of total and regional perfusion of the medulla remains a matter of anatomic inference. Until methods specifically enable observation of blood flow redistribution within vascular bundles in response to specific agonists, uncertainty concerning their precise role will continue. Given the importance of medullary perfusion to salt and water balance, tissue oxygenation, and the pathophysiology of analgesic nephropathy and acute renal failure, the motivation to resolve the details of pericyte-endothelial interactions will be substantial.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institutes of Health Grants DK-42495, HL-62220, and HL-68686.
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FOOTNOTES |
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Address for reprint requests and other correspondence: T. L. Pallone, Div. of Nephrology, N3W143, Univ. of Maryland at Baltimore, Baltimore, MD 21201-1595 (E-mail: tpallone{at}medicine.umaryland.edu).
10.1152/ajprenal.00304.2002
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