(Hypertension. 1997;30:687.)
© 1997 American Heart Association, Inc.
Articles |
Renal Identification of Cyclooxygenase-2 in a Subset of Thick Ascending Limb Cells
From Departamento de Ciencias Fisiologicas, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago, Chile (C.P.V., C.C., P.G.), and Department of Inflammatory Diseases Research, GD Searle T3G, St Louis, Missouri (J.L.F.).
Correspondence to Carlos P. Vio, MD, Departamento de Ciencias Fisiologicas, Pontificia Universidad Catolica de Chile, Casilla 114-D, Santiago, Chile. E-mail cvio{at}genes.bio.puc.cl
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Abstract The prostaglandin G2/H2 synthase (cyclooxygenase, COX) is a key regulatory enzyme of prostanoid synthesis pathway. The message-encoding COX isoenzymes (constitutive COX-1 and inducible COX-2) have been described in the rat kidney. However, there is scarce information on the localization of COX-2 in the kidney, although it has been recently reported to be localized in the macula densa. The present study was designed to evaluate the localization of COX-2 in adult rat kidneys. Normal rat kidneys (n=10) were fixed in Bouin and were immunostained with specific antibodies against COX-2 by the peroxidase method. The cellular origin of COX-2 was assessed by the immunostaining of serial consecutive sections with antibodies against Na-K-ATPase, Tamm-Horsfall glycoprotein, H-K-ATPase, kallikrein, and macrophages. COX-2 was consistently observed in a subset of tubular cells located in the cortex and in the outer medulla. The staining of serial sections showed that the COX-2+ cells contained both Na-K-ATPase and Tamm-Horsfall, indicating that they corresponded to thick ascending limb (TAL) cells. They were observed at a considerable distance from the corresponding macula densa, although occasionally they were observed close to glomeruli. The COX-2 staining in the TAL cells was not abolished by dexamethasone treatment (1 to 20 mg/kg), suggesting its constitutive expression in normal kidneys. The presence of COX-2 in TAL (a tubular segment postulated to be devoid of COX-1) may contribute to the handling of ions through local production of prostaglandins.
Key Words: cyclooxygenase-2 • rat kidney • COX-2 immunohistochemistry • thick ascending limbs
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Introduction |
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The prostaglandins (PGs), members of the eicosanoid family, are a group of lipid substances that are synthesized in response to numerous physiological stimuli to modulate and maintain homeostasis. In the kidney, eicosanoids act as autocrine/paracrine agents that regulate several aspects of renal function: renal blood flow and hemodynamics1 and transepithelial NaCl transport in several nephron segments.2 3 PGs are synthesized in several tissues, including the kidney, by the prostaglandin G/H synthase, also known as cyclooxygenase (COX). Two isoforms of this enzyme have been described. The constitutive isoform (COX-1) is expressed in the kidney,4 and abundant immunoreactive COX-1 has been localized in arterial vascular endothelial cells, medullary and cortical collecting ducts, medullary interstitial cells, and epithelial cells lining Bowman’s capsule.5 The inducible form COX-2 is also expressed in the kidney,4 and information regarding its distribution in the kidney remains scarce, although the presence of COX-2 has been reported in thick ascending limb, medullary interstitial cells, and in a minority of macula densa cells.6 The COX-2 isoform is known to be induced in conditions such as inflammation and injury, and sensitivity to glucocorticoids.7 8 However, its expression in the kidney in normal conditions4 indicates that at least in a certain amount the enzyme is expressed constitutively, suggesting a physiological role. In a complex structure like the kidney, with several cell types highly specialized in morphology and function, the possible contribution of COX-2 to renal function can be elucidated by the knowledge of its precise cellular localization. Accordingly, the aim of this work was to assess at the cellular level the distribution of COX-2 in the rat kidney.
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Methods |
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The study was carried out on adult male Sprague-Dawley rats (220 to 250 g, n=10) maintained with free access to water and fed with normal rat chow. A second group of adult rats received dexamethasone (1, 5, and 20 mg/kg; n=8) 24 hours prior to the study. The animals were maintained at the university animal care facilities, and the experimental procedures were in accordance with institutional and international guidelines for the welfare of animals. The animals were killed under pentobarbital anesthesia (60 mg/kg), and the kidneys were removed for morphological analysis. The tissue samples from both groups were coded and studied in a blinded fashion independently by two expert observers who were not aware of the codes.
The localization of COX-2 was done by immunohistochemistry with specific antibodies (see below), and the cellular origin of COX-2 was assessed by the immunostaining of serial consecutive sections with antibodies against specific cell markers: Na-K-ATPase for distal tubular segments [thick ascending limb (TAL), macula densa (MD), connecting tubule (CNT), distal convoluted tubule (DCT), and collecting ducts (CD)], Tamm-Horsfall glycoprotein for TAL, kallikrein for CNT cells, H-K-ATPase for intercalated cells (Ic), and a monoclonal antibody (ED-1) for macrophages.
Tissue Processing
Renal tissue slices, including cortex, medulla, and papilla,
were fixed by immersion in Bouin’s solution for 24 hours at room
temperature; once the tissue samples were fixed, two complementary
protocols of immunostaining were performed. A portion
of the tissue was dehydrated, embedded in Paraplast plus (Monoject
Scientific), sectioned in 7-µm thicknesses (thin sections) in a
rotary microtome, mounted on glass slides, and stored until
immunostaining. The other part of the fixed tissue was
sectioned in 40-µm thicknesses (thick sections) in a vibrating
microtome (Vibratome 1000, Tech Prod Int) without prior embedding in
Paraplast.9
Immunohistochemistry
Immunostaining was performed according to the
peroxidase- antiperoxidase (PAP) method of Sternberger10
with the modifications already described.11 12 Briefly,
the thin sections were dewaxed, rehydrated, and rinsed in 0.05
mol/L Tris-phosphate-saline buffer (TPS), pH 7.6. After
pretreatment with 3% hydrogen peroxide in absolute methanol
(vol/vol) for 15 minutes to inhibit endogenous
pseudoperoxidase activity, the tissue sections were incubated with the
primary antiserum overnight at 22°C, followed by the secondary
antibody (1:20) and the PAP complex (1:150) for 30 minutes each at
22°C. The thin sections were stained in coplin glass jars, whereas
the thick sections were immunostained as floating sections
in glass vials under gentle shaking in a rotary shaker (Penetron,
Sunkay Labs). When a monoclonal antibody was used, it was followed by
an incubation with a rabbit anti-mouse IgG antibody as a link between
the primary and secondary antibody. The peroxidase activity was
visualized by incubating the sections in 0.1% (wt/vol)
3,3'-diaminobenzidine and 0.03% (vol/vol) hydrogen peroxide.
The antisera and PAP complex were diluted in TPS containing 0.25%
(vol/vol) Triton X-100 and 0.7% (wt/vol) lambda-carrageenan.
Between each incubation the sections were rinsed with TPS buffer. The
sections were counterstained with hematoxylin and then dehydrated,
cleared with xylene, and coverslipped. The tissue sections were
observed and photographed on a Nikon Optiphot microscope with a Nikon
Microflex UFX IIA photographic system.
Source of Antisera and Chemicals
Four rabbit polyclonal antibodies (1:200 to 800 dilution) raised
against peptides of different lengths (15 to 29 amino acids) derived
from the carboxyl terminal amino acid sequences unique to murine COX-2
were used. The specificity of these antisera have been well established
in Western blots and immunocytochemistry. One antiserum was obtained
from Monsanto Research and Development (St Louis, Mo; antibody 539,
against the peptide sequence KTATINASASHSRLD DINPTV)8 ;
and two antisera against the peptide sequences
DPQPTKTATINASASHSRLDDINPTVLIK and SHSRLD DINPTVLIK, respectively
(antibodies 160106 and 160116),13 14 were purchased from
Cayman Chemical (Ann Arbor, Mich). A fourth antiserum was obtained at
the Catholic University of Chile by immunization of rabbits against the
peptide sequence KTATINASASHSRLDDINPTV; this peptide was synthesized by
Chiron Co (Emeryville, Calif) and coupled to thyroglobulin, and the
antiserum was obtained by repeated injections in rabbits according to
standard procedures.15
Rabbit antiserum against kallikrein (1:5000) was obtained from our
laboratory,12 and goat antiserum against Tamm-Horsfall
glycoprotein (1:2000 dilution) was purchased from Organon
Teknica-Cappel (Malvern, Pa); antibodies against the H-K-ATPase (1:400
dilution) were donated by Dr A. Smolka (Medical University of South
Carolina, Charleston),16 a polyclonal antibody against
Na-K-ATPase (
1 isoform, 1:200 dilution) was purchased from Upstate
Biotechnology (Lake Placid, NY), and a monoclonal antibody against
macrophages (ED-1, 1:400 dilution) was purchased from Serotec
(Oxford, England).
As secondary antibodies, we used goat anti-rabbit IgG for COX-2, kallikrein, and H-K-ATPase and Na-K-ATPase antibodies; rabbit anti-goat IgG for Tamm-Horsfall glycoprotein antibody; and rabbit anti-mouse IgG for ED-1 antibodies. The secondary antibodies and the corresponding PAP complexes from rabbit and goat origin were purchased from Organon Teknica-Cappel (Malvern, Pa) or Sternberger-Meyer Immunochemicals (Jarretsville, Md).
Triton X-100, 3,3'-diaminobenzidine, lambda-carrageenan, and Tris were purchased from Sigma Chemicals (St Louis, Mo). Hydrogen peroxide, phosphate salts, and other chemicals were from Merck (Darmstadt, Germany). Controls for the immunostaining procedure were prepared by omission of the first antibody by its replacement with normal or preimmune rabbit serum.
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An overall examination of the immunostained renal tissue readily revealed the presence of the COX-2 in small and scattered groups of epithelial cells belonging to tubules located in the outer medulla and cortex (Figure, a). The cells were heavily stained contrasting over the unstained neighboring tubular cells and background. The COX-2 subcellular immunostaining pattern was diffuse in the cytoplasm and concentrated in the perinuclear cytoplasmic region (Figure, b). The study of serial consecutive sections showed that COX-2 immunostaining was present on cells containing both Na-K-ATPase and Tamm-Horsfall, indicating that they corresponded to thick ascending limb (TAL) cells (Figure, c and d). Furthermore, the tubules containing COX-2 were devoid of kallikrein and H-K-ATPase, indicating that the enzyme was absent from connecting tubules and collecting ducts. The analysis of axially sectioned TAL revealed that the COX-2 positive cells were observed at a considerable distance from the corresponding macula densa, although occasionally they were observed close to glomeruli (Figure, a, c, e). Upon close examination, the COX-2 positive cells were present in the site of unstained cells opposite the macula densa (Figure, b). The use of 40-µm-thick sections confirmed and extended the observations obtained with thin sections (7 µm thickness). This method, complementary to the standard 7-µm-thick sections, has several useful features: owing to its thickness, in the same preparation several planes of the structure under study can be seen, allowing (1) the study on the face of cells from tubules axially sectioned and (2) the study of the spatial relationship between tubules and the glomeruli and corresponding afferent arteriole, efferent arteriole, and macula densa. With this technique, we observed that many of the COX-2 positive cells unequivocally located close to glomeruli corresponded to cells belonging to TAL passing by in the proximity of the glomeruli and not macula densa cells (Figure, g). In addition, the observation on face of the immunostained TAL revealed that the COX-2 positive cells were often in groups of 5 to 10 (or more) cells along its axis (Figure, f). We also studied the presence of COX-2 in the very few and scattered macrophages present in the renal tissue as identified by the ED-1 positive immunostaining. The macrophages exhibited no immunoreactivity to COX-2 (not shown).
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Dexamethasone was used to determine the level of regulation of COX-2 in the TAL. Kidney sections obtained from rats treated with the steroid (1 to 20 mg/kg) showed qualitatively similar results on the cellular distribution of COX-2 as well as in the intensity of the cellular staining (Figure, h). No staining for COX-2 was observed in other cortical or outer medullary tubular segments; papillary tubules; and glomerular, vascular or interstitial cells including papillary interstitial cells.
To improve the reliability of our immunohistochemical detection method we used four different antisera against the carboxyl terminal amino acid sequences unique to murine COX-2. They yielded identical localization in rat kidneys, with only minor differences in background staining. No staining was observed when the primary antisera were omitted or replaced by normal or preimmune serum.
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The distal tubule is a very complex structure formed by different segments, some of them composed of various highly differentiated cell types17 with specific roles in the overall renal function. These cells can be distinguished with the use of specific probes and sensitive immunohistochemical techniques. The cell types forming medullary and cortical TAL, DCT, CNT, and CCD, except the Ic, contain high levels of activity of Na,K-ATPase.18 Furthermore, these high levels of activity correlate well with high levels of expression of
1 isoform of Na-K-ATPase as detected with in situ
hybridization histochemistry.19 The thick ascending limb
can specifically be distinguished by the presence of the Tamm-Horsfall
glycoprotein,17 the connecting tubule by the
presence of kallikrein,20 the cortical and medullary
collecting duct by the presence of H-K-ATPase in intercalated
cells,16 and macrophages with ED-1 monoclonal
antibodies.21 Thus, colocalization of these proteins as
markers with COX-2 immunoreactivity provided useful information about
the cellular origin of COX-2.
The results reported here demonstrate the presence of COX-2 in a subset
of TAL cells present in the outer medulla, medullary rays of the
cortex, and cortical labyrinths. The colocalization of COX-2
immunoreactivity with the Tamm-Horsfall glycoprotein
immunoreactivity characterized the TAL as the cellular origin of COX-2,
since this protein is expressed only in this segment and is absent in
macula densa cells.17 Furthermore, COX-2 was colocalized
with the 1 isoform of Na-K-ATPase, already mentioned to be abundant
in the TAL segment. The localization of COX-2 seems to be restricted to
TAL cells since there was no colocalization with markers of the distal
nephron like kallikrein, which is produced by the connecting
tubule20 or with H-K-ATPase, a marker of intercalated
cells.16
Recently, it was reported that COX-2 immunoreactivity is associated with the macula densa cells, although as stated by the authors, "The majority of identified glomeruli sectioned through the juxtaglomerular apparatus did not have COX-2 positive in the macula densa."6 We did not find immunoreactivity in cells that can be positively identified as macula densa cells. Although small groups of cells showing COX-2 were found close to few glomeruli that could be interpreted as cells of the macula densa, they also contained Tamm-Horsfall glycoprotein, indicating that its origin was the TAL cells rather than macula densa cells. Besides, in many of the cases the COX-2 positive cells were located on the side opposite to the macula densa. Additional information was obtained with the use of 40-µm-thick sections. This method, complementary to the standard 7-µm-thick sections, has several useful features: owing to its thickness, in the same preparation several planes of the structure under study can be focused, allowing the study on face of cells from tubules axially sectioned and making feasible the study of the spatial relationship between tubules and the glomeruli and its corresponding afferent arteriole, efferent arteriole, and macula densa. With this technique, we observed that many of the COX-2 positive cells unequivocally located close to glomeruli corresponded to cells belonging to TAL passing by in the proximity of the glomeruli and not macula densa cells. In addition the observation on face of the immunostained TAL revealed that the COX-2 positive cells were often in groups of 5 to 10 (or more) cells, in contrast to the previous report where only one (and rarely two) COX-2 positive cells were observed per site.6
Thus, in agreement with a previous report,6 we found that the predominant cell type where COX-2 is present is the thick ascending limb cell, and while there may also be more rare expression of COX-2 in the macula densa and in papillary interstitial cells, this was not detected in our study. This discrepancy can be related to the presence of COX-2 in low amounts below the level of detection of our immunohistochemical protocol. In addition, our study was performed in normal rats without stimulation of the expression of COX-2 by a low sodium diet. Previously it has been reported that in rats on a normal sodium diet, 5% of macula densa cells contained COX-2, whereas in rats on a low sodium diet the percentage of macula densa cells increased to 16%.6
Several findings arise from our work. First, only a subset and not all of the cells of TAL exhibit COX-2 immunoreactivity. This cannot be explained in terms of cell heterogeneity because the TAL is considered to be formed of only one cell type with very well-defined features, with the obvious exception of the macula densa, which is situated within and functionally belongs to the TAL.17 Although subtle structural differences have been observed between medullary and cortical TAL, they develop gradually, the most obvious change being a gradual decrease in cell height toward the cortex; in the medullary ray of the cortex, the total height further decreases.17 Also there is a decrease in mitochondrial density and a decrease in basolateral membrane area. The axial changes in the structure of TAL cells along the segment are associated with parallel changes in Na-K-ATPase activity and transport capacity.18 Again, the structural changes in TAL cells are gradual and cannot account for the described distribution of COX-2. Ongoing studies in our laboratory toward the ultrastructural characterization of this subset of cells will establish whether they correspond to a different phenotype of TAL cells or the presence of COX-2 corresponds merely to a different functional state of conventional TAL cells. In addition, useful information will be obtained by assessing whether different functional or pathological states are associated with a differential distribution of COX-2 containing cells within the thick ascending limbs.
A second finding is that COX-2 immunoreactivity is present in normal renal tissue in the absence of any sign of inflammation, which suggests that COX-2 is expressed constitutively in a subset of TAL cells. This is sustained by the fact that COX-2 is still detected in kidneys from rats that were treated with dexamethasone, which is known to suppress COX-2 expression.7 This glucocorticoid was the first agent discovered that selectively suppresses COX-2; agents like cytokines and bacterial lipopolysaccharide stimulate COX-2 expression, which can be inhibited by dexamethasone. Besides these, it is known that glucocorticoids such as dexamethasone do not alter basal production of renal prostaglandins.22 23 This suggests that the glucocorticoids are not affecting the constitutive synthesis of renal prostaglandins, classically considered to be mediated by COX-1. Nevertheless, the presence of a constitutive pool of COX-2, insensitive to glucocorticoids, suggests that they also may be involved in the basal production of prostaglandins. Also, there were very few and scattered macrophages present in the tissue; as revealed by the ED-1 immunoreactivity, they were located in the intertubular interstitium, and these macrophages exhibited no immunoreactivity to COX-2, indicating that they were not activated. As is already known, COX-2 is induced in macrophages during inflammation, and glucocorticoids, in addition to blocking the induction of COX-2 message, exert posttranscriptional inhibitory effects on COX-2 expression.8 This pool of constitutive COX-2 observed in TAL does not seems to coexist with COX-1 in the kidney, since the latter has been described to be restricted to arterial vascular endothelial cells, epithelial cells lining Bowman’s capsule, medullary and cortical collecting ducts, and medullary interstitial cells.5 6
As mentioned before, COX-2 is expressed at low levels in the kidney, 2000 molecules of mRNA/100 ng of poly(A)+ RNA4 ; such a low level detected in an RNA sample from an entire organ may represent a high message in a small subpopulation of cells in which its presence can be indeed physiologically relevant. COX-2 was observed exclusively in a very restricted subset of TAL cells; furthermore, these cells were heavily immunostained for COX-2, suggesting high levels of the enzyme. Interestingly, the subcellular distribution of COX-2 in TAL cells—cytoplasm and perinuclear staining—was similar to that reported with confocal fluorescent microscopy in human umbilical endothelial cells, bovine aortic endothelial cells, and the murine 3T3-cPGHS-2 cell line.24
The physiological role for COX-2 in TAL is still unknown. Nevertheless, the importance of COX-2 in renal structure and function is highlighted by the fact that mice with COX-2 gene disruption develop mild to severe nephropathy at 3 to 6 weeks after birth.14
Regarding the possible contribution of COX-2 to TAL physiology in adults, it should be stressed that this nephron segment has a crucial role in salt and water homeostasis. First, it reabsorbs an important fraction of the NaCl filtered load through the combination of activities of the apically located Na-K-2Cl cotransporter and basolateral Na-K-ATPase. Second, the reabsorption of NaCl without water is the single effect in the generation of hyperosmolarity in the medullary interstitium, which is required for the operation of the countercurrent mechanism.25 Third, TAL is the target of furosemide, the prototype of the most potent class of diuretics.
The importance of arachidonic acid metabolites derived from cytochrome P-450 monooxygenases have been precisely demonstrated in TAL cells26 27 ; they exert a furosemide-like effect in medullary TAL cells inhibiting the Na-K-2Cl cotransporter.28 Classic arachidonic acid metabolites such as PGE2 can also be important also since TAL synthesizes PGE229 and this affects the NaCl transport of ions by medullary TAL,30 which as mentioned before seems to be devoid of COX-1.5 6 One of the products of COX activity is PGE2, whose synthesis has been demonstrated in cortical and medullary TAL.29 Also, there is evidence for the presence of PGE2 receptors in rat kidney, most of which are found in the outer medulla with a similar distribution to the Tamm-Horsfall glycoprotein, indicating that they are located in TAL cells.31 Cumulative evidence indicates that PGE2 inhibits NaCl reabsorption, and this effect is mediated by an inhibition of Na-K-ATPase activity in this segment.30 32 33 The physiological context in which PGE2 inhibits the TAL Na-K-ATPase is not completely established but could be related in part to ADH or angiotensin II action in this segment. It is known that ADH stimulates NaCl reabsorption in this segment through V2 receptors coupled to adenylyl cyclase,34 and also it has been demonstrated that PGE2 inhibits this ADH action. Both the inhibition of TAL Na-K-ATPase activity and the blunting of ADH action contributes to natriuresis. Similarly, angiotensin II also has receptors in TAL,35 stimulates PGE2 production, and affects sodium transport in renal epithelial cells.36
The inhibitory effect of PGE2 can be expressed also in pathological conditions such as inflammatory diseases which decrease glomerular filtration rate, renal blood flow, and modify tubular function. Tumor necrosis factor (TNF), a cytokine secreted by medullary TAL cells in response to LPS and IL-1, decreased ouabain-sensitive 86Rb flux in isolated medullary TAL cells, reflecting an inhibition in Na-K-ATPase activity. Moreover, this inhibition is reverted by indomethacin, but not by SKF-525-A, an inhibitor of the cytochrome P450 monooxygenase pathway. Besides, TNF stimulates PGE2 production in medullary TAL cells.37 All of this evidence indicates that TNF inhibits Na-K-ATPase activity through a PGE2-mediated mechanism.
The present study provides an anatomic basis for biochemical and functional studies on the contribution of eicosanoids to salt handling by the thick ascending limb. Additional studies are required for a better understanding of the presence of COX-2 in this segment of the nephron, such as the structural and functional characteristics of the subset of TAL cells exhibiting COX-2, as well as the regulation of the expression of COX-2 in these cells.
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Acknowledgments |
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This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (Fondecyt, Chile) grant 1951010. Pedro Gallardo is a graduate student of the PhD Program in Biological Sciences and is supported in part by a fellowship from the Dirección de Investigacion y Postgrado from the Pontificia Universidad Católica de Chile. The expert technical assistance in the routine tissue processing of Maria Alcoholado is gratefully acknowledged.
Received March 15, 1997; first decision April 15, 1997; accepted April 30, 1997.
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