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作者：Tong Wang, Hyacinth Sterling, Wei A. Shao, QingShang Yan, Matthew A. Bailey, Gerhard Giebisch, and Wen-Hui Wang作者单位：1 Department of Cellular and Molecular Physiology,Yale University School of Medicine, New Haven, Connecticut 06520; and 2 Department of Pharmacology, New York Medical College,Valhalla, New York 10595 $ B, z8 [! d' V$ A

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      【摘要】( I: Y8 \2 y& ^. L; N* Y  Z
   We previously demonstrated that carbon monoxide (CO) stimulates the apical70-pS K channel in the thick ascending limb (TAL) of the ratkidney (Liu HJ, Mount DB, Nasjletti A, and Wang WH. J Clin Invest 103: 963-970, 1999). Because the apical K channel plays a key rolein K recycling, we tested the hypothesis that heme oxygenase(HO)-dependent metabolites of heme may affect Na transport in theTAL. We used in vivo microperfusion to study the effect of chromiummesoporphyrin (CrMP), an inhibitor of HO, on fluid absorption( J v ) and Na absorption( J Na ) in the loop of Henle and renal clearance methods toexamine the effect of CrMP on renal sodium excretion. Microperfusionexperiments demonstrated that addition of CrMP to the loop of Henle decreased J v by 13% and J Na by 20% in animals onnormal rat chow and caused a decrease in J v (39%) and J Na (40%) in rats on a high-K (HK) diet. Theeffect of CrMP is the result of inhibition of HO because addition of MgPP, ananalog of CrMP that does not inhibit HO, had no effect on J v. Western blot analysis showed that HO-2 is expressed inthe kidney and that the level of HO-2 was significantly elevated in animals ona HK diet. Renal clearance studies demonstrated that the infusion of CrMPincreased the excretion of urinary Na (E Na ) and volume(UV) without changes in glomerular filtration rate. The effect of CrMP on E Na and UV was larger in HK rats than those kept on normal chow. Weconclude that HK intake increases HO-2 expression in the kidney and thatHO-dependent metabolites of heme, presumably CO, play a significant role inthe regulation of Na transport in the loop of Henle. 6 Y% X, m8 w/ S  m  |
      【关键词】 carbon monoxide sodium and potassium transport microperfusion
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HEME OXYGENASE (HO) metabolizes heme molecules to producebiliverdin, carbon monoxide (CO), and chelated iron by oxidative cleavage ( 19 ). Three isoforms of HOhave been identified: HO-1, an inducible isoform; HO-2, a constitutivelyexpressed isoform; and HO-3 ( 19, 20 ). HO-1 and HO-2 areexpressed in the kidney ( 16, 22 ), and a large body ofevidence suggests that CO plays an important role in the regulation of avariety of cell functions ( 6, 8 ). For instance, CO has beenreported to increase the production of cGMP by stimulation of guanylatecyclase ( 6, 8 ). Also, CO is involved in theactivation of Ca 2 -dependent large-conductanceK channels( 26 - 28 ),which may be responsible for CO-induced vasodilation of renal arterial vessels( 26 ).4 \( E% b5 V' ^/ i
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We previously demonstrated that inhibition of HO by chromonium mesoporphyrin (CrMP) decreases the activity of the 70-pS K channelin the thick ascending limb (TAL) of the rat kidney ( 16 ). Because the inhibitoryeffect can be reversed by CO, this suggests that CO is an HO-dependentmetabolite of heme responsible for stimulating the apical 70-pS K channel ( 16 ). Because theseK channels play a key role in K recycling across theapical membrane ( 1, 2, 5 ), their inhibition byblocking HO with CrMP is expected to decrease K recycling andsuppress the activity of the Na-K-2Cl cotransporter. This hypothesis wastested by examining the effect of inhibition of HO on transepithelial Na transport in the loop of Henle. We demonstrate that luminal perfusion of CrMP significantly decreases Na absorption and increases Na excretion in the loop of Henle. Those effects areenhanced by increasing dietary K intake.
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METHODS

Animal preparation. Male Sprague-Dawley rats (from Harlan, Indianapolis, IN) weighing 200-250 g were used for the renal clearance andtubule microperfusion experiments. Animals were kept on normal rat chow, ahigh-K (HK), or a K -deficient (KD) diet (HarlanTeklad) and tap water until the experiment. The animals were anesthetized byintravenous injection of Inactin (100 mg/kg) and placed on a thermostaticallycontrolled surgical table to maintain body temperature at 37°C. The leftjugular vein and the carotid artery were cannulated for the infusion of salineand for collection of arterial blood samples, respectively. These methods havebeen described previously ( 29, 30 )." F: a( [/ _/ w8 B% R" r! K6 s
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Renal clearance studies. Renal clearance techniques were used aspreviously described ( 26, 27 ) to investigate the effects of the HO inhibitor (CrMP) on glomerular filtration rate (GFR) and on absolute(E Na, E K ) and fractional excretion rates of Na and K (FE Na, FE K ). Surgicalfluid losses were replaced with isotonic saline and a priming dose of 25µCi of [methoxy- 3 H]inulin (New England Nuclear, Boston, MA) wasgiven in 0.5 ml isotonic saline, followed by a maintenance infusion of 0.9%NaCl containing 25 µCi/h at a rate of 4.6 ml/h. Blood and urine sampleswere collected after a 60-min equilibration period. Urine collections lasted30 min, and blood samples were taken at the beginning and end of eachcollection period. After two control periods, either CrMP (3 mg/kg) or vehicle solution (control) was given intravenously as a bolus injection. Urine andplasma Na and K concentrations were measured by flamephotometry (type 480 Flame Photometer, Corning Medical and Scientific,Corning, NY) and absolute and fractional renal excretions were calculated bystandard methods ( 29, 30 ).

Microperfusion of the loop of Henle. The methods of in vivo microperfusion of superficial loops of Henle were similar to those describedpreviously ( 29, 30 ). First, a loop of Henle was selected by microperfusing a proximal tubule to locate its last loop onthe kidney surface. Then, the loop of Henle was perfused from the last loop ofthe proximal tubule with a microperfusion pump at a rate of 20 nl/min. Tubulefluid was collected from the first segment of the early distal tubule with anoil block placed distally from the collection site. The rate of fluid Na and K absorption in the loop of Henle was expressedas absorption rate per loop, because the length of individual loops of Henlein the rat has been found to vary little. Na and K concentrations in the perfusing fluid and the collected tubule fluid weremeasured with a ultramicroatomic absorption spectrophotometer as previouslydescribed ( 29, 30 ).
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The composition of the perfusion fluids was as follows (in mM): 115 NaCl,25 NaHCO 3, 4 KCl, 1 CaCl 2, 5 Na-acetate, 5 glucose, 5 L -alanine, 2.5 Na 2 HPO 4, and 0.5NaH 2 PO 4 (pH was adjusted to 7.4 and the osmolality wasat 295 mosmol/kgH 2 O).1 \# k7 W- o8 Y5 D$ f+ c& Q
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Western blot analysis. Rats were kept on different K diets: KD (

Materials and statistics. [methoxy- 3 H]inulin wasobtained from New Research Products (Boston, MA), CrMP and magnesiumprotoporphyrin (MgPP) from Porphyrin Products (Logan, UT). Data are presented as means ± SE. Control and experimental values were compared using theunpaired Student's t -test. Dunnett's test was used for comparison ofseveral treatment groups with a single control group. Differences betweengroups are reported as significant at P * Q  M7 b* k# E, G

RESULTS
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We confirmed our previous findings that HO-2 is expressed in the renalcortex and outer medulla ( 16 )and extended those studies to animals kept on different K diets.Western blot analysis revealed that the expression of HO-2 is 150 ± 10%( n = 4) higher in the kidney from rats on a HK diet than those kepton a NK or KD diet ( Fig.1 A ). HO-2 expression is significantly diminished in thekidney from rats on a KD diet compared with that observed in rats on a NKdiet. In contrast, HK intake did not significantly affect the expression ofHO-1 in the kidney ( Fig.1 B ).

Fig. 1. Western blotting shows the presence of heme oxygenase (HO) type II( A ) and type I ( B ) in the renal cortex and outer medullafrom rats on normal-K (NK), high-K (HK), andlow-K (LK) diets. PC, positive control.* b( s- V& ~+ q/ e0 L; `9 X: n

After it was established that HO-2 expression is affected by dietaryK intake, the role of HO in the regulation of transport in theloop of Henle was investigated. Microperfusion techniques were used to examinethe effect of CrMP on Na and K transport in the loopof Henle in rats on a NK and a HK diet.
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Figure 2 and Table 1 summarize resultsshowing the effects of 50 µM CrMP on the rate of Na ( J Na ), fluid ( J V ), and K absorption ( J K ). It is apparent that perfusion of the loop with CrMP (50 µM) inhibits Na and K absorption intubules from rats on NK and HK diets. It should be noted that the inhibitory effect of CrMP on J Na is larger in rats on a HK diet thanthose on a NK diet. In control rats, J Na decreased by 20%,from 1.54 ± 0.07 to 1.22 ± 0.05 nmol/min ( n = 11). Incontrast, CrMP decreased J Na by 40%, from 1.35 ±0.07 to 0.79 ± 0.10 nmol/min ( n = 10), in rats on a HK diet.The inhibitory effect of CrMP on J K is also enhanced inanimals on a HK diet: inhibition of HO decreased J K by 64%from 31.7 ± 3.54 to 11.2 ± 5.27 compared with a 28% decrease inthe control rats. The reason that the inhibitory effect of CrMP on J K is larger than that on J V and J Na may be due to backleak of K from theperitubular fluid into the lumen. Huang et al.( 7 ) reported that inhibition ofapical K channels significantly increases the luminalK concentration and Jamison et al.( 9 ) also observed that netK secretion takes place at low transepithelial voltage in the TAL.It has been previously shown that CrMP inhibits the apical 70-pS K channel and this could lead to attenuation of the lumen-positive potential. Moreover, because the concentrations of K in the medullary interstitial fluid may exceed that in the lumen, these two factors favorpassive influx of K from the peritubular fluid to lumen./ _  |5 U/ W% ]7 S7 b- f( \
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Fig. 2. Effects of chromium mesoporphyrin (CrMP) on Na absorption( J Na ) in the loop of Henle in rats on a NK and HK diet.Data are means ± SE. CrMP was added to the luminal perfusate at aconcentration of 50 µM.% M8 _6 b' s) Z  w+ }7 L' C

Table 1. Effects of CrMP on fluid sodium and potassium absorption in loop ofHenle of rat kidney9 c+ w3 k. [/ {* g: r

Also, J Na and J K were slightlylower under control conditions in rats on a HK diet than in rats on a NK diet.A similar observation has been reported previously( 25 ), and this modest decline of J Na and J K may be the result of adecrease in the driving force of Na and K transport inHK-adapted rats. It is possible that a high plasma K leads todepolarization of the basolateral membrane, which diminishes theelectrochemical gradient of Cl - exit across the basolateralmembrane. Because a decrease in Cl - diffusion across thebasolateral membrane leads to attenuation of the lumen-positive potential thatis the driving force for the paracellular Na and K absorption, Na and K transport is expected to slightlydecrease.
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The effect of CrMP on J V was also significantly largerin animals on a HK diet than that observed in rats on a NK diet. Thus infusion of CrMP decreased fluid reabsorption in the loop of Henle. Figure 3 and Table 1 summarize resultsdemonstrating that perfusion of the loop with CrMP decreased J V by 39% from 9.20 ± 0.48 to 5.65 ± 0.83nl/min ( n = 10) in rats on a HK diet, compared with a decrease of 13%from 9.62 ± 0.42 to 8.35 ± 0.33 nl/min ( n = 11) in ratson a NK diet.

Fig. 3. Effects of CrMP on fluid absorption ( J v ) in the loop ofHenle from rats on a NK and HK diet. Data are means ± SE. CrMP wasadded to the luminal perfusate at a concentration of 50 µM.

To exclude the possibility of unspecific inhibitory action of CrMP, weemployed MgPP, an agent that has a similar structure to CrMP but does notinhibit HO, to determine whether MgPP can mimic the effect of CrMP. Figure 4 summarizes the results from five experiments demonstrating that perfusion of the loop of Henle with50 µM MgPP did not affect J V. These results indicatethat the effect of CrMP on J Na and J V results from inhibition of HO.: b) s. t, ?. D8 w7 G0 q" a
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Fig. 4. Effects of CrMP and magnesium protoporphyrin (Mgpp) on J v in the loop of Henle from rats on a HK diet.

After establishing that inhibition of HO inhibits Na and fluid absorption in the loop of Henle, we extended our study by examining theeffects of CrMP on urinary Na and K excretion withrenal clearance techniques. After two 30-min baseline periods, a bolus intravenous infusion of CrMP (3 mg/kg) was administered and four additionalurinary collections were carried out. Application of CrMP did notsignificantly affect blood pressure (data not shown). Inspection of Table 2 and Fig. 5 shows that infusion ofHO inhibitor also did not significantly alter GFR. However, CrMP significantlyenhanced the excretion of Na (E Na ) from a mean controlvalue of 0.34 ± 0.07 to 1.27 ± 0.22 meq·min - 1 ·100 g - 1 inrats on a NK diet ( n = 5) and from 0.34 ± 0.12 to 2.42± 0.43 meq·min - 1 ·100 g - 1 in rats on a HK diet ( n = 7)( Table 2 ). It is of interest that infusion of a HO inhibitor did not significantly change urinaryK excretion (E K ) in either rats on a NK or a HK diet ( Table 2 ). Figure 5 also shows the timecourse of the effect of CrMP on urinary volume (UV) in rats on a NK or HKdiet. Inhibition of HO increases UV progressively, from 0.011 ( n = 10) to 0.047 ml/min ( n = 5) in rats on a NK diet and from 0.015 ( n = 7) to 0.042 ml/min ( n = 7) in animals on a HK diet.

Table 2. Effects of CrMP on GFR, urinary volume, and Na andK excretion in normal- and high-K diet

Fig. 5. Effects of HO inhibitor CrMP on urinary volume and glomerular filtrationrate (GFR). Data are means ± SE. CrMP was given by intravenous (iv)bolus injection at a concentration of 3 mg/kg in rats on NK or HK diets. * Significantly different from control values ( P + g: R7 H, f1 T6 g8 ~9 W* v

Data summarized in Fig. 6 demonstrate the effects of intravenous injection of CrMP on FE Na and FE K. It is apparent that the effect of CrMP on FE Na is larger in rats on a HK diet than that observed in rats on a NK diet. Thusinhibition of HO increased FE Na from 0.012 to 2.44% in rats on a HKdiet but only from 0.031 to 1.34% in rats on a NK diet. Inspection of Fig. 6 shows that CrMP has noeffect on FE K in rats on a NK or HK diet, although rats on a HKdiet had a higher basal level of FE K.

Fig. 6. Effects of CrMP on fractional excretion of Na (FE Na; top ) and K (FE K; bottom ). CrMP wasgiven by iv bolus at a concentration of 3 mg/kg in rats on NK or HK diets. * Significantly different from control values ( P 7 A5 l9 K; E- d

DISCUSSION8 ]# H- o2 l  U0 A& m
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Previous studies showed that dietary K intake affects ion transport in the TAL ( 15, 17, 18 ). However, the mechanism bywhich dietary K intake alters membrane transport in the TAL isincompletely defined. We previously demonstrated that a high dietaryK intake increases the expression of inducible nitric oxidesynthase in the renal cortex and outer medulla and attenuates the inhibitoryeffect of external Ca 2 on the apical 70-pSK channel in the TAL( 3 ). In the present study, wereport that HO-2 expression is also augmented in the kidney from rats on a HKdiet. Because HO-2 is also expressed in the TAL( 22 ), the finding that a HKintake increases HO-2 expression suggests that, like nitric oxide,HO-dependent metabolites of heme are also involved in regulating ion transportin the TAL from K -adapted animals. This suggestion is supported by the finding that infusion of CrMP, a known inhibitor of HO, lowersNa reabsorption along the loop of Henle. Two lines of evidencesuggest that the effect of CrMP results from inhibition of HO-dependentmetabolism: 1 ) perfusion of the loop of Henle with MgPP, a CrMPanalog and weak inhibitor of HO, did not inhibit Na absorption inthe loop; and 2 ) the inhibitory effect of CrMP on Na andfluid absorption was enhanced in rats on a HK diet. This is consistent withour observation that the renal expression of HO-2 was also significantlyelevated in these animals.
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The mechanism by which inhibition of HO inhibits Na and fluid absorption in the loop of Henle is not fully understood. The loop of Henleincludes the late proximal tubule, the thin descending limb, the TAL, and theearly distal convoluted tubule. Immunocytochemical studies show that HO-1 andHO-2 are expressed in the proximal tubule, TAL, and distal tubule( 22 ). Accordingly, theinhibitory effect of CrMP on Na transport could be the result ofinhibition of Na transport in the late proximal tubule, TAL, ordistal convoluted tubule. The observation that CrMP significantly decreases J v suggests that inhibition of HO decreases the transportin the S3 segment and descending limb, because the TAL has very low waterpermeability. However, the observation that high dietary K intakesignificantly augmented the expression of HO-2 in the renal outer medulla,consisting mainly of the TAL, strongly suggests that this nephron segment isan important site for the regulation of transport by HO-dependent metabolites. One interesting observation in the present study was that the inhibitoryeffect of CrMP on Na was greater in HK than control, despite thefact that J Na and J K were slightlylower in HK rats. The reduction in J Na and J K in HK has been reported previously ( 25 ); this modest decline of J Na and J K may be the result of adecrease in the driving force of Na and K transportfrom lumen to cell in HK-adapted rats. The increased inhibitory action of CrMPon J Na may be explained by our recent observation that theratio of 35- and 70-pS K channels in the TAL is significantly modulated by HK intake. The 35-pS K channel was reduced from 57 to26%, but the 70-pS channel was increased from 2 to 23% by HK. Because the35-pS K channel is not regulated by HO-dependent CO production( 16 ), the inhibitory effect ofCrMP on Na absorption would be the result of inhibition of theincreased total 70-pS K channel activity in HK-treated rats.

The TAL is responsible for absorption of 25% filtered NaCl load and plays akey role in the urinary concentrating ability ( 1 ). The absorption of NaClinvolves two steps: 1 ) NaCl enters the cells across the apicalmembrane through the Na-K-2Cl cotransporter; and 2 ) Na isextruded across the basolateral membrane via Na-K-ATPase and Cl - leaves the cell by diffusion along a favorable electrochemical gradient.K recycling is important to maintain the activity of the Na-K-2Clcotransporter because it provides an adequate K supply for thecotransporter ( 1, 2 ). Therefore, inhibition ofeither apical K channels( 24 ) or Na-K-2Cl cotransporters ( 4 ) could blocktransepithelial NaCl absorption. In addition, if CrMP inhibits basolateralCl - channels, it can also lead to a decrease in transepithelialNaCl absorption ( 23 ). However,it is safe to conclude that the diuretic effect of CrMP results at leastpartially from inhibition of apical K recycling by decreasingHO-dependent metabolites such as CO, because it was previously shown that COcan reverse the inhibitory effect of CrMP on the apical 70-pS K channel ( 16 ). It is mostlikely that the effect of CrMP is caused by decreasing CO generation. A largebody of evidence indicates that CO plays an important role in the regulationof several cell functions. CO has been reported to regulate blood pressure( 10 - 12, 14 ). This effect is possiblymediated by stimulation of Ca 2 -activated large-conductance K channels( 27, 28 ). CO has also been suggested to be involved in energy metabolism and synaptic transmission ( 21 ). Our present data suggestthat CO may be involved in the regulation of NaCl transport in the loop ofHenle.- v6 r0 J- g6 A' S" X1 }

Three observations support the suggestion that the effect of CrMP ismediated by inhibition of HO-2. First, the expression level of HO-1 wassignificantly lower than that of HO-2 under control conditions( 22 ). Second, the expressionof HO-1 was not altered by a high dietary K intake. Third, HKintake significantly increased the expression of HO-2 and enhanced theinhibitory effect of CrMP on Na absorption in the loop of Henle.However, the role of HO-1 in the regulation of NaCl transport in the loopcould not be completely excluded. The mechanism by which HK intake increasesHO-2 expression is not clear. High dietary K intake has beendemonstrated to increase plasma aldosterone levels. However, it is unlikelythat a large increase in HO-2 levels results from an increase in plasmaaldosterone levels, because low-Na intake did not increase HO-2expression in renal cortex and outer medulla (unpublished observation)." G( c" v7 u3 x9 L; F# e( H

Inhibition of Na absorption in the loop of Henle is expected toincrease Na delivery in the collecting tubule( 13 ), and this should lead tostimulation of Na absorption and K secretion in theinitial cortical collecting tubule. However, our clearance studiesdemonstrated that infusion of CrMP did not alter K excretion,although Na excretion increased significantly. It is possible thatCrMP inhibits apical Na channels, apical small-conductancesecretory K channels, or the Ca 2 -dependent large-conductance K channel. CO has been shown to activate theCa 2 -dependent large-conductance K channelin smooth muscle cells( 26 - 28 ).If inhibition of HO with CrMP would similarly block theCa 2 -dependent large-conductance K channel in principal cells, CrMP should also attenuate flow-dependent K secretion that is mediated by Ca 2 -dependentlarge-conductance K channels( 31 ). Alternatively,inhibition of HO may stimulate K absorption in the medullary collecting ductvia H-K-ATPase ( 32 ). Furtherexperiments are needed to examine these possibilities.
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In conclusion, HO-2 expression is regulated by K intake and HO-dependent metabolites of heme such as CO regulate Na  ,K  , and fluid absorption in the loop of Henle.& m. q5 t9 w1 r3 r& D
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DISCLOSURES
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This work is supported by National Institutes of Health Grants HL-34300 (toW. H. Wang) and DK-17433 (to G. Giebisch).

ACKNOWLEDGMENTS
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The authors thank M. Steinberg for editorial assistance.
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