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作者：Amanda L. Fuson, Peter Komlosi, Tino M. Unlap, P. Darwin Bell, and János Peti-Peterdi作者单位：Nephrology Research and Training Center, Division of Nephrology,Department of Medicine, University of Alabama at Birmingham, Birmingham,Alabama 35294 4 `0 @1 \2 Z- I5 J# l5 b
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【摘要】1 n$ M2 t5 I8 J q# K7 G% `$ S
PGE 2, the major cyclooxygenase (COX) metabolite of arachidonic acid, is an important paracrine regulator of numerous tubular and vascularfunctions in the kidney. To date, COX activity has been considered the keystep in prostaglandin synthesis and is well characterized. However, much lessis known about the recently cloned microsomal PGE 2 synthase(mPGES), the terminal enzyme of PGE 2 synthesis, which convertsCOX-derived PGH 2 to the biologically important PGE 2.Present studies provide the detailed localization of mPGES protein in therabbit kidney using immunohistochemistry. In the cortex, strong mPGES labeling was found in the macula densa (MD) and principal cells of the connectingsegment and cortical collecting tubule but not in intercalated cells. Themedulla was abundant in mPGES-positive structures, with heavy labeling in thecollecting duct system. In descending thin limbs and renal medullaryinterstitial cells, mPGES expression was less intense, and it was below thelimits of detection in the vasa recta. Expression of MD mPGES, similarly toCOX-2, was greatly increased in response to low-salt diet and angiotensinI-converting enzyme inhibition by captopril. These findings suggest autocrineregulation of renal salt and water transport by PGE 2 in descendingthin limb and collecting tubule and a paracrine effect of PGE 2 onthe glomerular and medullary vasculature. Similar to other organs, mPGES inthe kidney is an inducible enzyme and may be similarly regulated and acts inconcert with COX-2. # b p+ o" V3 j6 b8 N
【关键词】 membraneassociated prostaglandin E synthase cyclooxygenase macula densa collecting duct principal cells descending thin limb immunohistochemistry! S+ y$ p; F- g# Y$ e7 q2 L
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PGE 2 IS BY FAR the major prostanoid synthesized inthe kidney and is an important paracrine regulator of salt and waterhomeostasis ( 1 - 5, 8, 13, 14, 24 ). PGE 2 regulatestubular transport of Na and water, resulting in natriuresis anddiuresis ( 1, 24 ). As a potent vasodilator,it helps to maintain glomerular filtration and medullary blood flow inconditions associated with decreased renal perfusion( 1, 13, 24 ) and/or high renin levels( 13, 14, 24 ). Another importanttubulovascular function is PGE 2 production by macula densa (MD)cells ( 22, 23 ) in signaling low distaltubular NaCl concentration-induced renin release( 25 ). Because PGE 2 acts only in the immediate vicinity of its site of generation, it is veryimportant to know which nephron segments synthesize this autacoid. Previousenzyme immunoassay measurements, using microdissected tubule segments ( 1, 8 ) from rabbit kidney, detectedlarge amounts of PGE 2 synthesized in the descending thin limb andthe collecting duct system. However, these assays were not able to analyze short tubular segments like the MD and could not identify the exact celltype(s) of tubules, vascular or interstitial structures where PGE 2 may be synthesized. Localization of the synthetic machinery necessary forPGE 2 production could provide further insights into where thisautacoid is produced.
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To date, cyclooxygenase (COX) activity has been considered the key step inprostaglandin synthesis and the localization of two isoforms, COX-1 and COX-2,has been well characterized in the kidney( 4, 9, 10, 13, 14, 26 ). However, metabolism ofarachidonate by either COX-1 or COX-2 yields only the unstable intermediaryPGH 2 ( 2, 3, 14, 16, 18, 19 ). The subsequent fate ofPGH 2 is dictated by coexpression of a prostaglandin synthase, theother key enzyme of prostaglandin synthesis, which is capable of convertingPGH 2 to one of the prostanoid end products includingPGE 2, PGF 2a, PGD 2, PGI 2, andTxA 2 ( 2, 3, 14, 27 ). Recently, themembrane-associated PGE synthase (mPGES), a terminal enzyme of PGE 2 biosynthesis, has been cloned ( 16, 18 ). Renal mRNA expression formPGES was recently described in microdissected tubular segments of the ratkidney and in the mouse ( 12, 27 ). Also, very recent workdescribed the site-specific expression of key enzymes for prostaglandinsynthesis, including mPGES, in rodent kidney( 6 ). However, to date, there isno information on the renal regulation of mPGES protein and its localizationin the rabbit kidney. We therefore analyzed, in detail, the sites of mPGESprotein expression in the rabbit kidney and its regulation in the MD usingimmunofluorescence.8 S8 p$ `1 G( T1 y% ]
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MATERIALS AND METHODS
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Salt Diet and Captopril! c% k' z+ g0 a* W
, n+ E" Y- J) r P) d. a P$ HSeparate groups of New Zealand White rabbits (0.5-1.0 kg, Myrtle) were fedstandard (8630 Harlan Teklad, Madison, WI, 0.3% NaCl), low-salt (TD 90188,0.01% NaCl), or high-salt (TD 98164, 7.7% NaCl) rabbit chow for a minimum of 1wk. A separate group of rabbits received captopril (Sigma, St. Louis, MO) inthe drinking water (500 mg/l) for 7 days.
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Immunohistochemistry
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Fixation and preparation of tissue for immunohistochemistry. Five-hundred-gram female New Zealand White rabbits were anesthetized withpentobarbital sodium, and the kidneys were perfusion-fixed by first insertinga cannula into the descending aorta distal to the renal arteries. The kidneyswere then perfused retrograde first with PBS, pH 7.4, at 37°C to removeblood, followed by 4% paraformaldehyde in Dulbecco's modified Eagle's/F-12 medium. The kidneys were then removed, and coronal kidney sections wereincubated overnight at 4°C in 4% paraformaldehyde and then embedded inparaffin.
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Sectioning and immunolabeling. Subsequently, 4-µm-thick sections of the paraffin block were deparaffinized with toluene, washed ingraded ethanol, and rehydrated in PBS. Sections were subjected to microwaveantigen retrieval before staining and blocked with PBS-Tween for 20 mincontaining 2% goat serum to lower background fluorescence. Subsequent blockingwith goat anti-rabbit Fab IgG (1:100, Jackson ImmunoResearch Laboratories, West Grove, PA) was carried out for 40 min to reduce nonspecific binding whena rabbit polyclonal antibody (anti-mPGES) was used on rabbit tissue. Aftersubsequent washings in PBS, tissues were treated with the affinity-purifiedrabbit polyclonal mPGES antibody (1:50, Cayman Chemical, Ann Arbor, MI). Afterbeing washed, there was a 40-min incubation with Alexa Fluor 594-conjugated goat anti-rabbit IgG (1:500, Molecular Probes, Eugene, OR). Sections weremounted with Vecta-shield media, containing 4,6-diamino-2-phenylindole (DAPI)for nuclear staining (Vector Laboratories, Burlingame, CA). Tissue sectionswere examined with an Olympus IX70-inverted epifluorescence microscope using aUApo/340 x 40 objective. Images were captured using a SenSys digitalcamera and IPLab Spectrum software equipped with power microtome (SignalAnalytics).
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& R2 P; b6 x6 P3 a3 ~- Y# _6 N3 jDouble labeling mPGES with aquaporin-1 or -2. Some of the kidney sections were double labeled with anti-mPGES and anti-aquaporin (AQP)-1 orAQP2 antibodies. After blocking for 20 min with 2% donkey serum in PBS-Tween,there was a subsequent blocking with goat anti-rabbit Fab IgG (1:100, JacksonImmunoResearch Laboratories) for 40 min to reduce nonspecific binding. After being subsequently washed with PBS-Tween, tissues were treated with either agoat polyclonal AQP1 or AQP2 antibody (L-19 and C-17, respectively, 1:100,Santa Cruz Biotechnology, Santa Cruz, CA) for 1 h. The tissue was then washedand subsequently incubated with an Alexa Fluor 594-conjugated donkey anti-goat IgG (1:500, Molecular Probes) for 40 min. Sections were then washed andsubsequently incubated with affinity-purified mPGES polyclonal antibody (1:50,Cayman Chemical) for 1 h. After being washed, sections were incubated for 40min with Alexa Fluor 488-conjugated goat anti-rabbit IgG (1:500, Molecular Probes). Sections were washed and mounted with Vecta-shield media, containingDAPI for nuclear staining (Vector Laboratories). Tissue sections were examinedas described earlier.
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& N* s H7 n" [& ]0 r- ICOX-2 immunofluorescence. Rabbit kidney sections were prepared asdescribed above. For labeling, tissues were treated with either a goatpolyclonal COX-2 antibody (C-20, 1:100, Santa Cruz Biotechnology) overnight orwith the affinity-purified rabbit polyclonal mPGES antibody (1:50, CaymanChemical). After being washed, there was a 40-min incubation with Alexa594-conjugated donkey anti-goat IgG (1:500, Molecular Probes) for COX-2sections or with Alexa 488-conjugated goat anti-rabbit IgG (1:500, Molecular Probes) for mPGES sections.; y/ Z; b! D) k, R
, u9 m. E/ a1 v `: a2 Y- ^+ iImmunolabeling controls. The following controls were performed: 1 ) adsorption controls made by incubation with affinity-purified mPGES polyclonal antibody (10 µg/ml) previously reacted with purified mPGESprotein (100 µg/ml) that was used for immunization (Cayman Chemical) and 2 ) incubation without the use of primary antibodies. All controlsrevealed an absence of labeling.
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RESULTS
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Localization of mPGES in the Renal Cortex) a7 h& R5 {$ ~
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Overall expression of the mPGES protein in the cortex( Fig. 1 A ) was muchlower than in the medulla ( Fig.1 B ) and was confined to only short or isolated tubulesegments in the distal nephron. Fluorescence labeling was specific, becauseomitting or blocking the primary antibody with the mPGES protein (data notshown) resulted in no staining. Also, labeling was present throughout thecytoplasm and was confined to small granules, consistent with microsomallocalization. Strong labeling for mPGES was found in the macula densa( Fig. 2 A ), surroundingcortical thick ascending limb cells, in the connecting segment (CNT), and inthe cortical collecting duct (CCD; Fig.2 B ). No staining was detected in the proximal or distalconvoluted tubules, in the glomerulus, or in vascular structures. Carefulanalysis revealed that only a subpopulation of cells in the CNT and CCD ( Fig. 2 B ) wasimmunoreactive. Double labeling with an AQP2 antibody that selectively bindsto mainly the apical membrane of principal cells (PC) found that mPGES proteinwas localized only in PC of CNT and CCD( Fig. 2 C ) and labelingwas below the limits of detection in intercalated (IC) cells.
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# J# @. A6 o) _% w( p: L/ DFig. 1. Overview of microsomal PGE 2 synthase (mPGES) immunofluorescencestaining (red) in the renal cortex ( A ) and medulla ( B ).Magnification x 200; nuclei are blue.% r5 n8 n) w8 @% n
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Fig. 2. Immunohistochemical localization of mPGES (red) in the renal cortex. A : macula densa (arrowhead) region with surrounding cortical thinascending limb (cTAL) and glomerulus (G). B : connecting segment (CNT)and cortical collecting duct (CCD; arrowheads point at individual cells devoidof staining). C : double labeling of mPGES (green) and aquaporin(AQP)2 (red) in CCD. Intercalated cells (arrowheads) were not immunoreactive,whereas principal cells were labeled with both the mPGES antibody (green,throughout the cells) and AQP2 (red, mainly at the apical membrane).Magnification x 400 ( A - C ) and x 1,000( D ); nuclei are blue.
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Localization of mPGES in the Renal Medulla
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The medulla was abundant in mPGES-immunoreactive structures. In the outermedulla, descending thin limbs (DTL; Fig.3, A - E ) and medullary collecting ducts (MCD; Fig. 3, C - E )displayed strong labeling. Similar to the distinct localization of mPGEs inthe CCD, only a subpopulation of cells in the outer MCD ( Fig. 3 E ) wasimmunoreactive. mPGES-positive cells, similar to CCD, also labeled with AQP-2,indicated a PC phenotype (not shown). No evidence for mPGES was found indescending vasa recta (DVR; Fig. 3, B and E ). Vasa recta was identified by red bloodcells in the lumen and also based on their expression of the AQP1 waterchannel. Double labeling with an AQP1 antibody that selectively binds to DTLsegments and vasa recta revealed that mPGES protein was localized only in DTLsand not in DVR or ascending thin limbs( Fig. 3 E ). In theinner medulla, heavy labeling of mPGES in MCD continued to the papilla. Inaddition to MCD, numerous thin-walled tubular structures were immunoreactive ( Fig. 3 D ), resemblingthe terminal part of long DTLs. mPGES was also localized to renal medullaryinterstitial cells (RMIC; Fig.3 D ).5 X. P" y; }# h( p0 \" i9 ?/ X; b
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Fig. 3. Immunohistochemical localization of mPGES (red) in the renal medulla. A : transition of a straight proximal tubule (S3), devoid of staininginto the strongly labeled outer medullary descending thin limb (DTL). B : mPGES expression in the vasa recta next to DTL (arrow indicatesmPGES-positive red blood cells in the lumen) was below the limits ofdetection. C : CCDs next to DTLs. D : renal medullaryinterstitial cells (RMIC) near the papilla, around heavily labeled medullarycollecting ducts (MCD) and numerous thin-walled tubular structures (DTL). E : double labeling of mPGES (green) and AQP1 (red) in the medullademonstrates colocalization in DTLs (yellow), whereas descending vasa recta(DVR) was positive only for AQP1 (red) and CCD only for mPGES (green).Magnification x 400; nuclei are blue.
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0 b& d; I/ X: z5 W# L4 B: `Regulation of MD mPGES Protein Expression by Salt Diet andCaptopril
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: i! J2 M% z' tBecause mPGES is considered as an inducible enzyme similar to COX-2, wetested whether well-defined stimuli for COX-2, such as changes in salt intakeand angiotensin I-converting enzyme (ACE) inhibition by captopril, would alsoregulate mPGES expression in the MD segment of renal cortex. Figure 4 demonstrates that mPGES and COX-2 were colocalized in the MD segment. A low-salt dietsignificantly increased the number of both COX-2- and mPGES-immunoreactive MDcells per MD plaque ( 5.5- and 3-fold, respectively, n = 6 MDplaques in each group, P
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4 X4 L. A2 p5 |$ M BFig. 4. Immunohistochemical localization of cyclooxygenase (COX)-2 (red) and mPGES(green) in the macula densa (arrowhead) on normal-, low-salt (LS), andhigh-salt (HS) diets and after captopril (Cap) treatment ( A ). B : statistical summary of the number of immunoreactive MD cells perMD plaque in the same groups ( n = 6 each).4 c8 a& U) ~) } a
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* A H, F% W8 X/ XThe present study provides a detailed description of the localization ofmPGES protein in the rabbit kidney ( Fig.5 ). In contrast to the renal cortex, a high level of mPGESexpression was found in the medulla, the major site of PGE 2 synthesis ( 1, 24 ). Strong labeling in thecollecting duct system and DTL is also consistent with earlier enzymeimmunoassay measurements ( 1, 8 ), demonstrating that thesenephron segments are the major sites of PGE 2 synthesis in thekidney. However, this enzyme immunoassay( 8 ) used isolated nephronsegments microdissected from rabbits, the same species we used forimmunohistochemistry, so there was no information obtained from vascularstructures and the interstitium. Also, the use of dissected tubules( 8, 27 ) or cell cultures withmixed phenotype ( 7, 9 ) did not allow comparisonbetween different cell types within the individual segments. Presentimmunolocalization data are similar to findings of a very recent report( 6 ) that described thesite-specific expression of key enzymes for renal prostaglandin synthesis inrodent kidney. The only exception seems to be the significant mPGES expressionin the DTL in rabbit kidney that was apparently not present in rat andmouse.3 L! q! T) {% n+ R# r; A3 v) F7 V
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Fig. 5. Schematic representation of mPGES expressing renal structures (dark areas)in rabbit kidney. DT, distal tubule; PT, proximal tubule; TAL, thick ascendinglimb.
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This study is an extension of our recent work that detected PGE 2 release from MD cells and first described, in preliminary form, thelocalization of mPGES in MD cells( 22, 23 ). Expression of mPGES inthe MD is consistent with the presence of COX-2 in these cells( 4, 13, 23, 25, 28 ) and also withPGE 2 production and release from MD cells( 22, 23 ). However, a recent reportfailed to detect mPGES mRNA in MD cells from the rat kidney( 27 ). These conflictingresults may represent different sensitivities of methods used. Identificationof PC in the collecting tubule was based on double labelingimmunohistochemistry using an AQP2 antibody that selectively binds to mainlythe apical membrane of PC in various species( 17, 20 ). Consistent with this, wefound strong AQP2 labeling of PC at the apical membrane( Fig. 2 C ).( T$ g" W" q2 Y0 i6 E) b& t5 U4 M
, l6 ^0 K, W$ N6 m0 U |. p( w( {Distinct localization of mPGES in PC but not in IC cells has not beenreported previously. Each of the PGH 2 -producing COX isoforms, butparticularly COX-1, is expressed in the collecting duct system; however, thelocalization seems to be species, cell type, and physiological statusdependent ( 4, 9, 13, 14, 26 ). A high level ofPGE 2 synthesis was detected in both isolated CCD and MCD( 8 ), and there arewell-established inhibitory effects of PGE 2 on PC Na and water transport ( 1 ).However, there are no known specific effects of PGE 2 on IC cells,except that a recent report suggested, indirectly, the presence of a PGEreceptor [most likely E prostanoid (EP) receptor EP 3 ] in thesecells ( 15 ). At present, thefunctional importance of this distinct mPGES localization in the CCD and OMCDis not known. It is possible that other as yet to be localized PGE synthaseisoforms ( 18 ) are alsoexpressed in the collecting tubule and participate in PGE 2 biosynthesis. Understanding the role of PC-specific, mPGES-derivedPGE 2 synthesis on collecting tubule function will require knowledgeof cell-specific expression of different EP receptors in this nephron segment.PGE 2 interacts with four different G protein-coupled EP receptorsdesignated EP 1, EP 2, EP 3, and EP 4 ( 2, 3 ), and all of these receptors appear to be expressed in the collecting tubule( 3, 11 ). Thus PGE 2 synthesis by COX and PGES isoforms may exert local autocrine or paracrineactions in the collecting tubule via one or more of these receptors, and thiscomplex interaction needs to be further investigated.
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Expression of mPGES in the DTL is consistent with earlier work ( 8 ) that detected significantPGE 2 synthesis in individual DTLs microdissected from the rabbitkidney. It has been suggested that PGE 2, synthesized in thissegment, may regulate tubular transport( 1, 8 ), but it may also influencemedullary blood flow by acting on nearby pericytes of DVR( Fig. 2 E ).Identification of DVR was based on the presence of red blood cells in the lumen ( Fig. 3 B ) anddouble labeling immunohistochemistry using an AQP1 antibody that selectivelybinds to DTL and DVR ( 21 ). Consistent with this, we found strong AQP1 labeling in these structures( Fig. 3 D ). Absence ofmPGES in DVR ( Fig. 3, B and E ) suggests that this vascular segment cannot synthesizePGE 2; however, it does not rule out that PGE 2 productionby DTL, MCD, and medullary interstitial cells may cause DVR vasodilation andan increase in medullary blood flow. Indeed, mPGES labeling was intense inRMIC ( Fig. 3 D ), aspecial cell type in the medulla that expresses COX-2( 10 ) and interconnects tubular structures with each other and with vasa recta. The absence of mPGES labelingin both cortical and medullary vascular structures, but its presence inadjacent tubular segments and cell types, suggests a paracrine effect forPGE 2 on renal hemodynamics.7 |; r' S1 o- G! u5 W
% B) v z2 S# M7 ZThe present studies also demonstrated that mPGES, an enzyme capable ofconverting COX-2-derived PGH 2 to PGE 2, was not only present in the rabbit MD ( Fig.2 A ) but that it colocalizes with COX-2 in these cells( Fig. 4 ). In addition, weexamined if well-established stimuli for COX-2 (i.e., changes in salt intakeand ACE inhibition) would also induce mPGES expression. We found that MDexpression of both COX-2 and mPGES was greatly upregulated in response tolow-salt intake and ACE inhibition by captopril( Fig. 4 ). Also, high-saltintake caused a small reduction in COX-2 and mPGES staining in the MD. Thesefindings indicate that, consistent with other cell types( 16, 18, 19 ), mPGES in the MD is aninducible enzyme, similar to COX-2. Low-salt intake upregulates cortical COX-2expression in various species including rabbit( 14, 28 ). Colocalization of COX-2 and mPGES in the MD and their upregulation by a low-salt diet support thenotion that these enzymes share a common gene-regulatory mechanism( 16, 18, 19 ) and may contribute to theincrease in PGE 2 synthesis associated with stress, inflammatory,and pyretic responses. Consistent with these immunofluorescence findings,recent functional experiments using a biosensor technique ( 22, 23 ) demonstrated significantlyincreased PGE 2 release from MD cells on a low-salt diet, comparedwith normal-salt intake. Further work is needed to characterize the regulation of mPGES expression in response to various other stimuli and in the renalmedulla.' B1 F. ^( k* I1 C. {. p3 }
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In summary, the present studies localized a PGES in DTL, MD, and PC of thecollecting duct system and medullary interstitial cells in the rabbit kidney.Regulation of the mPGES protein expression by various salt diets and ACEinhibition suggests that mPGES is an inducible enzyme, similar to COX-2.Understanding the importance and complex effects of PGE 2 synthesized by mPGES at these sites of the nephron requires furtherstudies.
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" g3 Z$ Y K1 p4 y; lDISCLOSURES
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This work was supported by grants from National Institute of Diabetes andDigestive and Kidney Diseases (32032) to P. D. Bell and American HeartAssociation SDG (0230074N) and ASN Carl W. Gottschalk Research Scholar Grantto J. Peti-Peterdi.
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ACKNOWLEDGMENTS6 F: s9 A9 |$ T: o* M4 y
6 x6 p! C8 M* g6 S2 zWe thank J. Hosmer, University of Alabama at Birmingham (UAB) AnimalResources Program, Histology Division, for excellent technical assistance withtissue processing and sectioning. Also, the authors thank A. Tousson and S.Williams at UAB High Resolution Imaging Facility for help with fluorescenceimaging.
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发表于 2009-4-21 13:43
