INVITED REVIEWPhysiology of the renal medullary microcirculation - 《American Journal of Physiology》美国生理学杂志干细胞之家



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发表于 2009-4-21 13:32 |只看该作者 |倒序浏览 |打印

作者：Thomas L.Pallone, ZhongZhang,  KristieRhinehart作者单位：Division of Nephrology, University of Maryland Schoolof Medicine, Baltimore, Maryland 21201-1595 - b3 d. ]* R( h8 d3 h
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      【摘要】
   Perfusion of the renal medulla plays animportant role in salt and water balance. Pericytes are smoothmuscle-like cells that impart contractile function to descending vasarecta (DVR), the arteriolar segments that supply the medulla with bloodflow. DVR contraction by ANG II is mediated by depolarization resulting from an increase in plasma membrane Cl conductance thatsecondarily gates voltage-activated Ca 2  entry. In thisrespect, DVR may differ from other parts of the efferentmicrocirculation of the kidney. Elevation of extracellular K constricts DVR to a lesser degree than ANG II orendothelin-1, implying that other events, in addition to membranedepolarization, are needed to maximize vasoconstriction. DVRendothelial cytoplasmic Ca 2  is increased by bradykinin, aresponse that is inhibited by ANG II. ANG II inhibition of endothelialCa 2  signaling might serve to regulate the site of originof vasodilatory paracrine agents generated in the vicinity of outermedullary vascular bundles. In the hydropenic kidney, DVR plasmaequilibrates with the interstitium both by diffusion and through waterefflux across aquaporin-1. That process is predicted to optimizeurinary 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 havephysiological mechanisms specific to their role in the renal medulla.
      【关键词】 vasa recta perfusion hypertension oxygenation urinaryconcentration patch clamp calcium fura
   INTRODUCTION
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THE MICROCIRCULATION OF THE kidney isregionally specialized. In the cortex, afferent and efferent arteriolesgovern the driving forces that promote glomerular filtration. A denseperitubular capillary plexus arising from efferent arterioles surroundsthe 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 ofdescending (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 tosupply 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 exertsubtle control over regional perfusion of the outer and inner medulla.The details are far from clear, but much experimental evidence pointsto the complex interactions of many autocoids and paracrine agents tomodulate vasomotor tone at various sites along the microvascularcircuit. The goal of this review is to summarize recent insights intothe control of medullary perfusion and the cell biology and mechanismsthat govern vasa recta transport and vasoactivity./ {0 Y4 @8 I- q

RENAL MEDULLARY MICROVASCULAR ANATOMY
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Studies of regional perfusion have consistently shown thatthe fraction of total renal blood flow that is distributed to the innercortex and medulla is subject to regulation ( 2, 17, 18, 28-30, 73-80, 88, 90, 110, 113, 180-185 ). Tounderstand the sites at which such regulation might occur,microvascular anatomy will be briefly reviewed (Fig. 1 ). For greater detail, the interestedreader is directed to a number of well-illustrated sources ( 6, 7, 48, 49, 55, 56, 60, 81, 85, 86, 99, 105, 110, 113, 163 ).7 g; b& T+ J2 ~
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Fig. 1. Anatomy of the medullary microcirculation. In thecortex, interlobular arteries arise from the arcuate artery and ascendtoward the cortical surface. Juxtamedullary glomeruli arise at arecurrent angle from the interlobular artery. The majority of bloodflow reaches the medulla through juxtamedullary efferent arterioles;however, some may also be from periglomerular shunt pathways. In theouter medulla, juxtamedullary efferent arterioles in the outer stripegive rise to descending vasa recta (DVR) that coalesce to form vascularbundles in the inner stripe. DVR on the periphery of vascular bundlesgive rise to the interbundle capillary plexus that perfuses nephrons(thick ascending limb, collecting duct, long looped thin descendinglimbs; not shown). DVR in the center continue across the inner-outermedullary junction to perfuse the inner medulla. Thin descending limbsof short looped nephrons may also associate with the vascular bundlesin a manner that is species dependent (not shown). Inner medulla:vascular bundles disappear in the inner medulla, and vasa recta becomedispersed with nephron segments. Ascending vasa recta (AVR) that arisefrom the sparse capillary plexus of inner medulla return to the cortexby passing through outer medullary vascular bundles. DVR have acontinuous endothelium ( inset ) and are surrounded bycontractile pericytes. The number of pericytes decreases with depth inthe medulla. AVR are highly fenestrated vessels ( inset ). Asblood flows toward the papillary tip, NaCl and urea diffuse into DVRand out of AVR. Transmural gradients of NaCl and urea abstract wateracross the DVR wall across aquaporin-1 water channels.
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The medulla of the kidney is perfused by the efferent arteriolar bloodflow that leaves juxtamedullary glomeruli. In the outer stripe of theouter medulla, juxtamedullary efferent arterioles give rise to many DVR(Fig. 1 ). There is also strong anatomic evidence that periglomerularshunt pathways give rise to some DVR ( 16 ). The innerstripe of the outer medulla is characterized by its separation intovascular bundles and the interbundle region. Vascular bundles containall DVR destined to perfuse the interbundle region and those thateventually penetrate beyond the inner-outer medullary junction to theinner medulla. DVR on the bundle periphery give rise to a capillaryplexus that perfuses the interbundle region, where metabolicallydemanding, salt-transporting epithelia of the thick ascending limb andcollecting duct are located. DVR in the bundle center traverse theinner stripe of the outer medulla to reach the inner medulla. Thelatter may be larger and more muscular than peripheral DVR. Vascularbundles contain all AVR returning from the inner medulla and, to adegree that varies with species, short looped thin descending limbs ofHenle ( 6, 7, 56, 60, 99, 110 ). Based on anatomicconsiderations alone, it seems evident that the vascular bundles placeDVR 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 inthe bundle center should enhance perfusion of the interbundle region.: j) T# Y, K3 x4 W
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DVR occupy a functional niche that is partially arteriolar andpartially capillary in nature. The DVR wall is characterized by smoothmuscle remnants that surround a continuous endothelium and impartcontractile function. The pericytes persist into the inner medulla buteventually disappear ( 111, 120 ). Near their termination,DVR become fenestrated and give rise to a sparse capillary plexus. Theplexus coalesces to form AVR that are characterized by a high degree offenestration ( 117, 138 ). The fraction of the AVR walloccupied by fenestrations is larger in the inner medulla than in theouter medulla.4 E+ X/ B1 Y) u# O5 c6 E6 R7 A" K9 K

ROLE OF DVR IN REGULATION OF MEDULLARY BLOOD FLOW: h+ b7 \4 W' ?* V7 U
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Regulation of blood flow to the renal medulla has been a subjectof interest for decades. The methods used to measure blood flow and theconclusions derived from the associated studies have been frequentlyreviewed ( 17, 73, 76, 90, 105, 110 ). Laser-Doppler is nowthe dominant method for measuring regional perfusion of the kidney.That method relies on the Doppler shift imparted to monochromatic lightby backscatter from moving red blood cells (RBCs) in a localized areaof tissue. Many regional perfusion studies have been performed inanimals that have had optical fibers acutely or chronically implantedinto the renal parenchyma ( 2, 17, 28-30, 70, 73, 76 ).Studies of the extent of autoregulation of medullary perfusion withvariation in renal perfusion pressure have produced variable results( 17, 70, 76, 90 ), but much evidence points to a possiblerole 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 asignal from a fixed volume of tissue and thus the probes are sensitiveto probe orientation. Direct measurement of DVR blood flowusing dual-slit videomicroscopy has also been performed. Cupples andMarsh ( 19 ) found that flow in a single descending vasarectum was regulated between 85 and 160 mmHg. The latter doesnot rule out the possibility that recruitment of flow might occurthrough previously unperfused DVR, as described by Roman et al. (seebelow) ( 131 ). In the latter case, single-vessel flow mightbe autoregulated while overall flow is not. Apart from the issue of regional autoregulation, a number of consistent themes haveemerged. 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 medullaryvasodilator synthesis leads to a reduction of medullary blood flow,salt retention, and hypertension. Thus, apart from the anticipated roleof medullary blood flow to contribute to urinary concentration andwater balance, a role in the regulation of sodium balance may alsoexist. The effector mechanisms that connect medullary perfusion toregulation of epithelial sodium transport are not well established, butvarious possibilities exist. It has been demonstrated that increases inperfusion pressure cause a secondary increase in renal interstitialpressure and that the latter leads to inhibition of proximalreabsorption ( 128 ). Some forms of hypertension areassociated with regulation of sodium transport pathways( 71 ), but this would not account for the immediate abilityof increased perfusion pressure to cause saliuresis. If medullaryperfusion modulates local NO release, a secondary effect on salt andwater excretion could result ( 94, 95 ).

Given the importance of medullary perfusion in influencing salt andwater balance, we were motivated to determine which location(s) alongthe microvascular circuit provides control of medullary blood flow.Afferent and efferent arterioles of juxtamedullary glomeruli couldconstrict and dilate to serve this purpose, but that hypothesisconceivably conflicts with the need for them to simultaneously controljuxtamedullary glomerular filtration pressures. The possibility thatperiglomerular pathways for perfusing the medulla are important in thisscheme has been proposed ( 16, 17 ). Based on anatomicconsiderations (Fig. 1 ), it seems probable that DVR are an importantsite of regulation. The latter has been impossible to test directlybecause the outer medulla and most of the inner medulla areinaccessible to observation in vivo. When DVR are isolated from ratsand examined in vitro, contractile pericytes are observed and thevessels exhibit vasoreactivity, responding to numerous constrictors anddilators (Fig. 2 ). Vasoactive agonistsinclude many paracrine agents that are synthesized within the medulla( 104, 111-113, 129, 144-146 ). Because DVR arebranches of efferent arterioles, it seems logical to conclude thattheir vasomotion could affect glomerular filtration pressures; however, compensatory changes in afferent arteriolar tone could hypothetically offset that effect with the response to signals arising fromtubuloglomerular feedback and myogenic response. The details areuncertain, but it is likely that DVR are an important regulator ofmedullary perfusion.
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Fig. 2. Vasoconstriction of isolated, microperfused outermedullary DVR. A : DVR isolated and microperfused in vitro isexposed to ANG II (10 nM) by abluminal application from the bath. a andb, Vessel before and after constriction, respectively. Two cell typescan be seen. Pericyte cell bodies project from the abluminal surface,and endothelia line the lumen. B : quantification of DVRconstriction through measurement of luminal diameter. Results areexpressed as %constriction = 100 × ( D o D )/ D o, where D o is basal diameter and D isdiameter after constriction. The mean luminal diameter of perfused DVRis ~14 µm. Constriction has been induced by abluminal exposure toendothelin 1 (0.1 nM, n = 6), ANG II (10 nM, n = 15) or by raising of extracellular K concentration from 5 to 100 mM by isosmotic substitution for NaCl( n = 6). Data are reproduced from Refs. 104, 146, and 176.
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The parallel arrangement of DVR within outer medullary vascular bundlesraises two questions. First, does global constriction of DVR regulatethe rate at which blood crosses from the cortex to the medulla, i.e.,influence total medullary perfusion? Second, does DVR vasomotion withinvascular bundles regulate distribution of blood flow between theinterbundle region of the outer medullary inner stripe and the innermedulla? Those actions are not mutually exclusive. Some quantitativeand qualitative observations are germane. Roman and colleagues( 131 ) reported that variation in inner medullary tissueperfusion is related both to changes in blood flow through singlevessels and to the recruitment of blood flow into previouslynonperfused DVR. Given that the luminal diameter of DVR is similar tothat of RBCs, it seems plausible that flow through them could bestopped by intense foci of constriction in the outer medulla. If thatoccurs, excessive back-pressure might not result because blood from theefferent arteriole could still traverse adjacent vessels that lie inparallel within the vascular bundles (Fig. 1 ). This possibility isqualitatively supported by the observation that bolus spurting of RBCsthrough the lumen of DVR can sometimes be seen on the surface of thepapilla (inner one-third of the inner medulla) when the papilla isexposed for micropuncture (Pallone, unpublished observations).Goligorsky and colleagues ( 34, 61 ) have postulated thatmembrane fluidity changes related to local production of NO contributeto such processes. Finally, differential regulation of outer vs. innermedullary perfusion by vasopressin has been observed when opticallaser-Doppler probes were inserted into the medulla at various depths( 28 ).
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VASOACTIVITY OF DVR6 [  E/ ^# B0 V& K, r

When DVR are isolated from outer medullary vascular bundles,perfused in vitro, and exposed to contractile agonists, they constrictat various foci along their length (Fig. 2 ). Of the various agents thusfar examined, endothelin-1 and -2 yield the most intense and durableconstriction ( 146 ). They have threshold effects at10 14 M and most often obliterate the vessel lumen athigher concentrations (100% constriction, Fig. 2 ). These agents inducedurable constriction that does not wane and is only slowly reversibleafter washout. ANG II is also a consistent constrictor that, onaverage, reduces luminal diameter of microperfused vessels by 40- 60%( 104, 114, 129 ). As in cortical vessels, thromboxanes arepartially 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 afterapplication and then slowly wane toward a stable baseline (Fig. 2 ).Microperfused DVR seem to exhibit a minimum of intrinsic tone and toshow no myogenic activity when pressurized ( 104 ). It mustbe recognized, however, that these observations are obtained fromisolated vessels placed into artificial buffers without supportinginterstitum, often hours after the death of the rat.. V2 O# l0 a9 [) o- T% x7 Z8 V0 z
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Pericytes are the smooth muscle remnants that surround DVR andpresumably impart contractile function. Recently, the mechanisms bywhich ANG II induces vasoconstriction have been evaluated using fluorescent probes of intracellular Ca 2  concentration([Ca 2  ] i ) and membrane potential and byelectrophysiological recording. As expected for signaling via the ANGII AT 1 receptor, a classic peak-and-plateau intracellularCa 2  response is elicited in fura 2-loaded pericytes (Fig. 3 ) ( 130, 176 ). Both wholecell electrophysiological recording and measurements with apotentially sensitive fluorescent probe showed that ANG IIdepolarizes the pericyte cell membrane (Fig. 4 ) ( 107, 130, 175, 176 ).This seems to occur through activation of a Ca 2  -sensitiveCl conductance that shifts membrane potential away fromthe equilibrium potential of the K ion toward that ofCl ( 107, 175 ). An 11-pS Cl channel has been identified in the pericyte cell membrane. This channelhas low basal open probability but is activated by ANG II or excisioninto high-Ca 2  buffers (Fig. 5 ). Membrane potential of ANG II-treatedpericytes often oscillates, and voltage-clamped cells held at 70 mVexhibit classic spontaneous transient inward currents typical ofvarious smooth muscle preparations (Fig. 4 C ) ( 35, 43, 46, 91 ).
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Fig. 3. Measurement of intracellular Ca 2  transientsin DVR pericytes. A : appearance of an isolated DVR afterexposure to collagenase. B : isolated collagenase-treatedvessel has been drawn into a glass micropipette with a heat-polishedopening of ~6 µm diameter, stripping pericytes from the abluminalsurface. This process can be continued to isolate a group of pericytesfor loading with the Ca 2  -sensitive fluorescent indicatorfura 2 ( 130 ). Bar = ~10 µm. C :intracellular Ca 2  concentration([Ca 2  ] i ) response of fura 2-loaded DVRpericytes to ANG II (10 nM) is shown in the presence and absence ofdiltiazem, n = 6 and 7, respectively. In the controlgroup, diltiazem was added to the bath for 11-16 min. Diltiazeminhibits the plateau phase of the pericyte Ca 2  response.Data are reproduced from Refs. 130 and 176.

Fig. 4. Nystatin-perforated-patch whole cell electrophysiologicalrecordings from DVR pericytes. A : membrane potentialrecorded from pericytes as they are exposed to ANG II (10 nM) for2-10, 2-3, or 20-25 min. Data were sampled at 10 Hz,averaged to 1 Hz, and then averaged for n = 6 cells/group. ANG II depolarizes the cells but cannot be reversed afterprolonged exposure. B : membrane potential oscillations in apericyte exposed to 10 nM ANG II. C : spontaneous transientinward currents in a DVR pericyte exposed to ANG II. The cell is heldat 70 mV and then exposed to ANG II (10 nM, arrow). Data arereproduced from Ref. 107.$ ~# p. M# V1 M  Z) g" z2 T7 q! @
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Fig. 5. 11-pS Cl channel recorded from DVR pericyte. A : recording showing channel activity in excised patch heldat potentials shown on the right. O and C, open and closed,respectively. B : excision of patch into 1 mMCa 2  buffer activates the channel. ANG II activates thischannel in cell-attached patches (data not shown). Data are reproducedfrom Ref. 175.9 o2 u3 |: i0 R6 q2 D1 y

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 Ca 2  entry( 14, 15, 64 ). Until recently, however, the existence ofvoltage-gated Ca 2  entry pathways in the efferentcirculation has been uncertain. Rigorous examination of this issue withRT-PCR, immunochemistry, and the assessment of vasoreactivity inisolated arterioles has been reported by Hansen and colleagues( 38 ). T-type subunits, Ca(V)3.1 and Ca(V)3.2, andan L-type subunit, Ca(V)1.2, were found in efferent arterioles ofjuxtamedullary glomeruli but not superficial glomeruli. These subunitswere also identified in DVR ( 38 ). Based on this finding,membrane potential of DVR pericytes is expected to controlvoltage-gated Ca 2  entry and modulate[Ca 2  ] i, a prediction that received recentexperimental support. The L-type channel blocker diltiazem vasodilatesANG II-constricted DVR and reduces [Ca 2  ] i ofANG 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, areeffective vasodilators (Fig. 6 ) ( 176 ). The many downstream effects of pericyte ANG IIreceptor activation remain unknown; however, there are hints thatimportant effects result from actions independent of[Ca 2  ] i elevation. Principally,depolarization in the absence of agonist induces far less intenseconstriction than does ANG II or endothelins (Fig. 2 ). Phosphorylationevents that sensitize the intracellular contractile machinery to theeffects of Ca 2  are likely to be implicated( 133 ).& {6 B6 A/ R& p- U( k

Fig. 6. Repolarization of ANG II-depolarized pericytes byvasodilators. A : recording of membrane potential from a DVRpericyte successively exposed to ANG II (10 nM) and bradykinin (100 nM). Resting membrane potential of 48 mV depolarizes after ANG II. Abiphasic repolarization occurs after exposure to bradykinin. B : similar recording from a DVR pericyte exposed to ANG II(10 nM) and then the ATP-sensitive K channel openerpinacidil (10 µm). Both bradykinin and pinacidil repolarize pericytesand vasodilate preconstricted DVR ( 109, 176 ). Data arereproduced from Ref. 176.0 v# z3 B; u) r2 `* d1 N
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ROLE OF DVR ENDOTHELIA IN THE REGULATION OF VASOACTIVITY

As a fortuitous consequence of the fact that theCa 2  -sensitive fluorophore fura 2 loads almost exclusivelyinto DVR endothelia (to the near exclusion of pericytes), it has beenrelatively easy to examine global Ca 2  transients generatedby endothelium-dependent vasodilators (Fig. 7 ). As expected, BK generates apeak-and-plateau Ca 2  response, enhances NO generation(Fig. 8 ), and induces vasodilation ( 112, 129, 130 ). An unexpected finding is that thevasoconstrictor ANG II suppresses basal Ca 2  and inhibitsBK-, acetylcholine-, thapsigargin-, and cyclopiazonic acid-inducedCa 2  responses in DVR endothelia (Fig. 7, B and C ) ( 114, 130 ). This is surprising for severalreasons. First, AT 1 receptors, which mediate the vastmajority of the effects of ANG II, signal through inositol3,4,5-trisphosphate generation and Ca 2  mobilization.Second, infusion of ANG II has been observed to lead to secondaryenhancement of NO levels within the medulla ( 182, 185 ) andin isolated cortical microvessels ( 153, 154 ). Given thatendothelial nitric oxide synthase (eNOS)/NOS3 is a Ca 2  -dependent isoform of NOS, suppression ofCa 2  would be expected to block rather than enhanceendothelial NO generation. As a possible answer to this paradox, wepointed out that adjacent nephrons also express NOS isoforms, so thatANG II elevation of Ca 2  in those structures would favor NOgeneration on the vascular bundle periphery. Hypothetically, this couldprovide a feedback loop (in addition to adenosine) through which themedullary thick ascending limb (mTAL) can regulate its own perfusion.As previously discussed, ANG II might suppress DVR endothelialCa 2  signaling as a means of turning regulation of DVRvasomotion away from the endothelium to the mTAL ( 114, 130 ).2 h; M: W% G$ ~/ g

Fig. 7. Measurement of [Ca 2  ] i transients in DVR endothelia. A : white light and fluorescentimages from an isolated DVR loaded with fura 2. Abluminal pericytes(arrows, left ) are not visible in the fluorescent image( right ). In contrast, endothelial cells load fura 2 and emita strong fluorescent signal. B : example of DVR endothelial[Ca 2  ] i response after exposure to bradykinin(BK; 100 nM). C : means ± SE of n = 7 DVR exposed to ANG II (10 nM). Slight suppression of[Ca 2  ] i is seen. D : suppression ofDVR endothelial [Ca 2  ] i after exposure to ANGII (10 nM) is dramatic when [Ca 2  ] i has beenpreviously increased by exposure to the sarcoplasmic endoplasmicreticulum Ca 2  ATPase inhibitor cyclopiazonic acid (CPA; 10 µm). Data are reproduced from Refs. 112, 114, and 130.

Fig. 8. Measurement of nitric oxide (NO) generation in isolated DVR using4,5-diaminofluorescein (DAF)-2. A : white light andfluorescent image shows that DAF-2 loads into both endothelia andpericytes. B : fluorescent emission at 535 nm duringexcitation at various wavelengths (abscissa). Successive recordings areobtained at 1-min intervals from DVR exposed to 2.5 mM sodiumnitroprusside (SNP) as a NO donor. Fluorescence increases without ashift in spectra. C : DAF-2 emission reflecting endogenous NOproduction in isolated DVR. In the control group, fluorescence declinesdue to leakage of DAF-2 from the cytoplasm. Fluorescence is greater onexposure to BK (100 nM) and increases further when the bath containsthe superoxide dismutase mimetic tempol (1 mM). Data are reproducedfrom Ref. 129. ** P P
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The concentrations of ANG II required to influence endothelialCa 2  signaling or to maximally constrict DVR in vitro(nanomolar) exceed circulating levels (picomolar). Compartmental ANG IIconcentrations within the kidney can be as high as 10 9 to10 10 M ( 89, 142 ). The renal outer medulla isinaccessible to micropuncture, so that direct sampling of outermedullary DVR plasma directly downstream of juxtamedullary glomerulicannot be performed. Seikaly and colleagues ( 142 ) foundthat ANG II concentrations in star vessel plasma sampled downstream ofsuperficial glomeruli exceed circulating levels by as much as1,000-fold. On this basis, it seems possible that DVR could be exposedto nanomolar ANG II in vivo.* ]4 L+ l( W  C" W; P) d" o

The vasodilatory influence of NO cannot be completely understoodwithout considering its interaction with O 2 free radicals. These are generated by one-electron reductions of O 2 togenerate superoxide (O 2 − ·), hydrogen peroxide (H 2 O 2 ), hypochlorous acid, and hydroxyl radical(·OH), the "reactive oxygen species" (ROS). ROS favorvasoconstriction and have been implicated in various forms ofhypertension ( 53 ). Mechanistically, this is at least inpart because O 2 − · reacts with NO to formperoxynitrite (ONOO ), a product that, compared with NO,is a weak vasodilator. ROS are generated by the "leak" of electronsfrom the mitochondrial electron transport chain as well as a variety ofenzymatic processes. Intrinsic mechanisms limit cellular levels of ROS.Several isoforms of superoxide dismutase (SOD) convertO 2 − · to O 2 andH 2 O 2. In turn, H 2 O 2 isdecomposed to O 2 and H 2 O by catalase and otherperoxidases. By limiting reaction of NO with O 2 − ·, the extracellular isoform of SOD found in plasma and endothelia hasbeen identified as a principal regulator of NO bioavailability ( 62, 96 ). Endogenous antioxidants are also responsible for scavenging ROS. For example, hemeoxygenase (HO) is a microsomal enzymethat degrades heme. In the process, it forms CO, a vasodilator, andbiliverdin, an antioxidant ( 27, 180 ). Both HO-1 and HO-2 isoforms are expressed in renal smooth muscle and nephrons ( 4, 40, 45 ).

Renal generation of ROS favors vasoconstriction and may contribute tosome forms of hypertension. Tempol is a cell-permeant SOD mimetic thatreduces hypertension in the spontaneously hypertensive rat ( 139, 141 ). Of the several sources of O 2 − ·, NADPHoxidase appears to be important. Some NADPH oxidase subunit isoformsare upregulated and activated by vasoconstrictors ( 36, 57, 126, 159, 165, 177 ). It has been shown that both ANG II receptorblockers (ARBs) and the combination of hydrochlorothiazide, hydralazine, and reserpine (triple therapy) can normalize blood pressure in the SHR rat; however, only ARBs reduce excretion of ROSreaction product 8-iso-PGF 2. Interestingly,P O 2 values are lower in the SHR, and this toois normalized by ARB therapy or treatment with the SOD mimetic tempol( 1, 164 ). Tempol also has been shown to enhance medullaryperfusion ( 183 ). NO production by isolated DVR and themTAL is enhanced by tempol, and this agent blunts ANG II-induced DVRvasoconstriction ( 94, 129 ). Given the importance ofmedullary blood flow in the regulation of blood pressure, it isinviting to speculate that some forms of hypertension might be relatedto an increase in "oxidative stress" in the renal medulla.
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P O 2 in the medulla of the kidney is low,in the range of 10-25 mmHg ( 11, 12, 22 ). This ispredicted to be a consequence of the countercurrent arrangement of vasarecta ( 173 ) because O 2 in DVR blood diffusesto AVR to be shunted back to the cortex. Evidence supports the notionthat O 2 consumption by the salt-transporting mTAL makes itvulnerable to ischemia ( 12 ). Several hormonal systems play a role in the protection of the medulla fromischemic insult. Each shares the ability to enhance medullaryblood flow and inhibit salt reabsorption along the nephron.Hypothetically, this should have a dual effect of enhancing the supplyof O 2 and simultaneously reducing the demand for itsconsumption. A first example is the generation of vasodilatoryprostaglandins through activation of cyclooxygenase (COX)( 58 ). It has been observed that perfusion of the renalmedulla is sensitive to COX inhibition ( 110, 113, 119 ).Furthermore, renomedullary interstitial cells have receptors for ANG IIand BK and release PGE 2 in response to these agents( 21, 72, 178, 179, 186 ). Recently, Qi et al.( 127 ) have shown that the COX-2 isoform is expressed inthose cells and is responsible for this action. In their study, ANG IIreduced medullary blood flow in COX-2-, but not COX-1-, deficient mice( 127 ). The ability of PGE 2 to promotenatriuresis may be explained in part by the ability of PGE 2 to inhibit Cl reabsorption by the mTAL ( 41, 146 ). PGE 2 is a vasodilator of in vitro perfused DVR( 104, 146 ).
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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 itinduces 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 themTAL ( 2, 184 ). This presumably serves to reduceO 2 consumption while enhancing O 2 delivery( 2, 22 ). It is a reasonable hypothesis that adenosineproduced by the mTAL diffuses to and dilates outer medullary DVR on theperiphery of vascular bundles. Outer medullary DVR on the bundleperiphery supply the mTAL with blood flow, so such a mechanismrepresents a feedback system that would protect the mTAL from hypoxia.The mTAL has the capacity to produce adenosine ( 9 ) andthat A 1 and A 2 receptor mRNA is expressed inDVR ( 54 ). Adenosine A 1 and A 2 receptor stimulation favors DVR vasoconstriction and vasodilation,respectively ( 144, 145 )./ L* x+ Y! m  _% U

Studies have shown that renal medullary NOS activity and NO productionexceed that in the cortex ( 74, 75, 79, 80, 87, 166, 167, 182 ). Evidence is accumulating that NO acts in an autocrine andparacrine fashion to modulate both vasomotor tone and epithelial NaClreabsorption. Inhibition of NOS in the renal medulla hasisoform-specific effects. NOS1 inhibition reduces NO levels in themedulla and induces salt-sensitive hypertension but fails to altermedullary perfusion ( 50, 74, 77 ). Global inhibition ofNOS1, NOS2, and NOS3 isoforms with nonselective blockers decreasesmedullary NO levels and induces salt retention and hypertension. Inaddition, global NOS inhibition reduces medullary blood flow and tissueoxygenation ( 11, 42, 78, 124 ). NO generation may beimportant to abrogate tissue hypoxia that would otherwise arise fromrelease of vasoconstrictors. ANG II, norepinephrine, and vasopressinstimulate release of NO in the medulla ( 121, 150, 151, 181, 185 ). Subpressor infusion of N G -nitro- L -arginine methyl esterinto the renal interstitium does not affect medullary blood flow orP O 2 but enables otherwise ineffective doses ofANG II ( 185 ) norepinephrine ( 151, 181 ), orvasopressin ( 150 ) to induce a fall in these parameters.Taken together, the data support the conclusion that medullary NOproduction has a tonic effect in maintaining perfusion and protectingthe medulla from ischemic injury. In addition tovascular effects, NO inhibits solute and water reabsorption in thecollecting duct and thick ascending limb ( 31-33, 95, 122, 123, 148, 149 ). Studies in knockout mice implicated NOS3as the isoform responsible for autocrine stimulation of NO in the thickascending limb ( 122 ). Thus, like prostaglandins andadenosine, NO is a vasodilator that also inhibits salt reabsorption andtherefore O 2 consumption in the thick ascending limb.+ [# u( W) \1 b! D1 X1 s( d

TRANSPORT OF SOLUTES AND WATER ACROSS VASA RECTA

DVR occupy a functional niche that is partially that of avasoactive arteriole and partially that of a transportingmicrovessel. As such, it is not surprising that evidence hasemerged to show that DVR endothelia have specialized characteristicsthat reflect the requirements endowed by their anatomic location anddual role. DVR have a continuous endothelial lining and zona occludens.It is expected that the paracellular pathway conducts diffusivetransport of NaCl and other small hydrophilic solutes ( 82, 109, 158 ). In addition to this, transcellular pathways have beenidentified that conduct transport of urea and water ( 51, 52, 92, 93, 97-99, 106, 108, 117, 118 ). The principal transport functions ofvasa recta will be briefly discussed. For a detailed explanation andhistorical perspective, the reader is referred to other reviews ( 25, 110 ).
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The first evidence that DVR endothelia express a carrier for urea wasthat individual vessels, perfused simultaneously with [ 22 Na]- and [ 14 C]urea, often exhibited lowor moderate Na permeability but always had very highpermeability to urea ( 117 ). This was surprising becausethe diffusivities of Na and urea in water are nearlyidentical, so that transport via diffusion in an aqueous pore predictsidentical permeabilities to these tracers. The ability of phloretin andurea analogs to reduce DVR urea permeability supported the existence ofa carrier in DVR endothelia, implying a major contribution oftranscellular, facilitated diffusion to overall urea transport( 97, 117 ). That urea carrier was eventually identified asthe one expressed by the RBC (UTB), a form that is distinct from thevasopressin-sensitive and -insensitive splice variants of theepithelial carrier (UTA1-UTA4) ( 5, 8, 44, 51, 52, 125, 134, 135, 155-157, 168, 170 ). Taken together, the expression ofepithelial, endothelial, and RBC-facilitated carriers seems to ensurethat urea diffusing from AVR plasma will be efficiently recycled bydiffusing into thin descending limbs and DVR. Yang and Verkman( 171, 172 ) have shown that UTB exhibits water channelactivity and that UTB conducts water across the aquaporin-1(AQP1)-deficient RBC membrane. A role for UTB in the transport of wateracross DVR has not been established; however, it is notable that urea,glucose, and raffinose can drive substantial water flux acrossAQP1-deficient DVR ( 106 ).

It has long been known that DVR plasma protein concentration increaseswith distance into the renal medulla due to water efflux from the DVRlumen to the papillary interstitium. That transport proceeds in adirection opposite to inwardly directed Starling forces (hydraulic andoncotic pressure), thus implicating transmural small-solute osmoticgradients as the responsible driving force ( 98, 118, 137, 138 ). For NaCl and urea gradients generated by the lag inequilibration between DVR plasma and medullary interstitium to inducewater efflux, the water must traverse a pathway of sufficiently smallpore size for these solutes to be osmotically active. The missing pieceof that puzzle was provided by the cloning of the AQP1 water channel,followed by the demonstration that it is expressed in DVR and otherendothelia ( 3, 92, 93, 132 ). When AQP1 was blocked by p -chloromercuribenzenesulfonate in the rat( 108 ) or deleted in the mouse ( 66, 106 ), thewater flux driven by transmural NaCl (but not albumin) gradients wasnearly eliminated, such that osmotic water permeability fell from~1,100 µm/s to nearly 0. Another surprising finding wasthat AQP1 deletion was accompanied by a marked increasein DVR diameter, the first demonstration of the capacity ofvasa recta to remodel (Fig. 9 ). Thequestion remained, How does the efflux of water from DVR to themedullary interstitium benefit urinary concentration? Insight derivedfrom mathematical simulations showed that shunting of water from DVR toAVR in the superficial medulla reduced blood flow to the deep medulla, secondarily improving plasma-interstitial equilibration. Thiswas predicted to improve the efficiency of inner medullary countercurrent exchange and enhance interstitial osmolality ( 23, 24, 106, 152 ).

Fig. 9. Osmotic water permeability ( P f ) of DVR fromaquaporin-1 (AQP1)-deficient ( / ) and wild-type ( / ) mice. A : photomicrographs show the increase in diameter ofAQP1-deficient ( / ) murine DVR. B : P f measurements obtained from in vitro perfusedDVR of wild-type ( / ), heterozygous ( / ) and AQP1 null ( / ) mice. P f was measured by imposing transmural gradientsof NaCl to drive water flux across the DVR wall. Data are reproducedfrom Ref. 106 with permission.3 b# Q, }; U3 F. e

Nephrons, collecting ducts, and DVR deposit water to the medullaryinterstitium. Thus, for mass balance, removal is delegated to AVR. Thelatter are highly fenestrated ( 110, 138 ) and have veryhigh hydraulic conductivity and solute permeability that exceeds thatof DVR ( 68, 69, 102, 103, 116 ). AVR are less wellcharacterized than DVR because they cannot be isolated for in vitroperfusion. AVR have been postulated to serve an unusual role in theclearance of macromolecules from the medullary interstitium. The renalmedulla is devoid of lymphatics, so albumin must be removed from theinterstitium into AVR ( 10, 20 ). The reflection coefficientof AVR to albumin is relatively low (0.58-0.78) ( 66-68, 101 ). Based on this and the ability of AVR to withstand ahydraulic pressure gradient without collapsing, it has been postulatedthat 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 ) verifiedthe feasibility of that mechanism and predicted the presence of anaxial gradient of albumin concentration in the medullary interstitium.

SUMMARY AND CONCLUSIONS

The microcirculation of the renal medulla serves several roles.The classic depiction of vasa recta as passive filters that providecountercurrent exchange and solute trapping belies the complexity oftheir structure and function. DVR are arterioles that respond to anarray of vasoactive agents ( 111 ). They are alsotransporting microvessels that express specific transporters for water(AQP1) and urea (UTB) ( 92, 93, 168 ). The ability toisolate 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 becausethey have only been studied on the surface of the exposed papilla in vivo.

We have recently learned that DVR pericytes behave in ways that aretypical of smooth muscle from the afferent arteriole and othermicrovascular beds. When exposed to ANG II, pericytes depolarize byactivating a Cl conductance, a process that gatesvoltage-activated Ca 2  entry pathways ( 38, 107, 130, 176 ). It is surprising is that this process apparently occurs inthe juxtamedullary efferent circulation that supplies the renal medullawith blood flow but not in smooth muscle of superficial efferentarterioles ( 13-15, 63, 64 ). The physiological purposeof this axial heterogeneity is uncertain, but prior observations thatL-channel antagonists enhance medullary blood flow seem betterexplained ( 26, 37, 65, 169 ). The ability to access DVRpericytes for electrophysiological examination and measurement ofintracellular Ca 2  transients is a recent development( 107, 130, 175, 176 ). Only cells from outer medullaryvessels have been studied, and it remains possible that those from theinner medulla will be found to have unique properties. In the innermedulla, extracellular Na  , K  ,Cl, urea, and osmolyte concentrations are high, and thismight have forced the evolution of unusual mechanisms to control andgate membrane potential and Ca 2  entry.% o+ Q* Z9 J0 i9 I) f

It is clear that DVR endothelia are unusual. These cells express theAQP1 water channel that is responsible for small-solute-driven effluxof 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 deepmedulla, where axial gradients are largest ( 106 ). In addition to AQP1, DVR endothelia express the same urea carrier as redblood cells, UTB ( 125, 168, 170-172 ). Presumably,this provides for rapid equilibration of urea in DVR plasma, RBCinterior, and medullary interstitium. As expected, DVR endotheliagenerate NO, cellular levels of which may be regulated in part throughgeneration of superoxide anion ( 129 ). What has been moresurprising is that an elevation of endothelial[Ca 2  ] i, expected to stimulate the NOS3isoform, does not occur on ANG II stimulation. In fact, ANG II is foundto reduce endothelial [Ca 2  ] i and suppress[Ca 2  ] i responses to endothelium-dependentvasodilators. It has been hypothesized that this turns modulation ofpericyte constriction away from the endothelium to NO diffusion fromadjacent mTALs of the outer medullary interbundle region ( 114, 130 ). Because NOS3 is subject to regulation by a variety ofinfluences, confirmation of this hypothesis awaits sensitivemeasurement of DVR NO generation.7 Q! M( j( i$ z3 p; i

Although isolation of DVR for in vitro study has provided the keytechnique 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 aresupported 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 oftotal and regional perfusion of the medulla remains a matter ofanatomic inference. Until methods specifically enable observation ofblood flow redistribution within vascular bundles in response tospecific agonists, uncertainty concerning their precise role willcontinue. 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 thedetails of pericyte-endothelial interactions will be substantial.

ACKNOWLEDGEMENTS0 b1 B7 z- r1 d' z: H, C5 A
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This work was supported by National Institutes of Health GrantsDK-42495, HL-62220, and HL-68686.; y' c* @+ C: ^- u$ {" }( V0 G3 D
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