National Institute of Diabetes, and Digestive and Kidney Diseases, Bethesda, Maryland 20892
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ABSTRACT |
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Experiments were performed in mice to investigate whether
cyclooxygenase-2 (COX-2) in epithelial cells near the tubulovascular contact point (macula densa and TAL cells) may regulate renin gene
expression in juxtaglomerular granular cells. Renin activity, afferent
arteriolar granularity, and renin mRNA were determined in wild-type
mice and in COX-2-knockout mice on control and low-NaCl diets. Renin
activity in microdissected glomeruli assessed as angiotensin I
formation in the presence of excess substrate and afferent arteriolar
granularity determined by direct visualization and immunostaining were
significantly reduced in COX-2 /
compared with wild-type animals.
Similarly, renal cortical mRNA levels were lower in COX-2
/
than in
wild-type mice. Maintaining mice on a low-salt diet for 14 days induced
an increase in renin mRNA, afferent arteriolar granularity, and renin
activity in wild-type mice. In contrast, renin mRNA and renin
granularity did not significantly increase in low-salt-treated COX-2
/
mice, whereas the increase in juxtaglomerular renin enzyme
activity was markedly attenuated, but not fully blocked. In additional
experiments we found that COX-2 mRNA was increased in angiotensin type
1A receptor-knockout mice compared with wild-type mice. We conclude
that COX-2 in the tubulovascular contact region is a critical
determinant of renin synthesis in granular cells under resting
conditions and that it participates in the stimulation of renin
expression caused by a low-NaCl intake.
renin activity; prostaglandins; macula densa; juxtaglomerular apparatus cyclooxygenase-2
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INTRODUCTION |
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SUBSTANTIAL EXPERIMENTAL EVIDENCE supports the concept that PGs generated in the juxtaglomerular apparatus (JGA) play an important role in the control of renin secretion (6, 22). In a number of preparations, including in primary cultures of juxtaglomerular cells, prostaglandins, specifically PGE2 and PGI2, have been shown to stimulate the release of renin (21). It is likely that this effect is the result of a direct interaction of prostaglandins with their respective Gs-coupled receptors on granular cells (2, 36). Consistent with a local regulatory effect of prostaglandins are findings demonstrating that the macula densa (MD) mechanism of renin secretion is blunted by inhibitors of cyclooxygenase, COX (12, 13). In the isolated perfused rabbit JGA in which MD control of renin release is not confounded by baroreceptor and adrenergic influences, the renin secretory response to a reduction in luminal NaCl concentration is essentially completely inhibited by anti-inflammatory nonsteroidal agents (14). Thus a functional COX in the region of the JGA is required for MD control of renin secretion.
COX, one of the rate-limiting enzymes in the formation of prostaglandins, has been shown to exist in two isoforms, the constitutive form, COX-1, and the inducible form, COX-2, (19). In the kidney, both isoforms are constitutively expressed with a predominant location in the renal medulla; however, they are also found at lower levels of expression in the renal cortex (6, 17, 41). The question, which of the two isoforms is responsible for MD control of renin secretion, has been addressed by examining the effect of inhibitors specific for COX-1 or COX-2 on NaCl-stimulated renin release in the isolated JGA preparation (37). The data show that MD control of renin secretion is inhibited by NS-398, a specific COX-2 blocker, but not by valerylsalicylate, an inhibitor of COX-1. COX-2 dependence on MD-mediated renin secretion is in accord with the demonstration of COX-2 expression in MD and surrounding thick ascending limb (TAL) cells (15, 17, 18, 41).
Because changes in renin secretion are often paralleled by changes in renal renin content, it has been suggested that, in response to prolonged alterations in MD, NaCl epithelial COX-2 not only affects renin secretion but also renin gene expression by juxtaglomerular granular cells (34). For example, a low-salt diet is known to elevate renin secretion as well as renal renin content, and this is accompanied by an increase in renal cortical COX-2 expression (17, 41). Furthermore, the increase in renal renin content in response to a low-NaCl intake was found to be attenuated by the administration of a COX-2-specific inhibitor (16). The present experiments were performed to further explore the possibility of a causal link among MD COX-2 and renin expression in mice with a knockout mutation in the COX-2 gene (9, 29). Disruption of the COX-2 gene has been verified in these mice by complete absence of COX-2 in peritoneal macrophages before and after stimulation with lipopolysaccharide (29). The specific purposes of our study were to examine 1) whether basal renin enzyme activity, renin mRNA, and glomerular renin content are suppressed in COX-2-knockout mice; and 2) whether a low-NaCl intake can activate renin enzyme activity, renin mRNA, and renin content in COX-2-knockout mice.
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METHODS |
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Animals.
Breeder pairs of COX-2-knockout mice, originally generated by Dinchuk
et al. (9), were obtained from Jackson Laboratories and
bred in the National Institutes of Health animal facility. At weaning,
animals were ear tagged and a short piece of the tail was clipped off.
Genomic DNA was extracted from the tails after digestion with
proteinase K and purification of DNA with ethanol. The genotype of each
DNA sample was determined by testing for the presence of wild-type or
modified COX-2 sequence by using PCR. COX-2 gene-specific primers were
selected in the targeted exon 1 region to amplify a 142-bp PCR product
in DNA from wild-type, however, not from COX-2 /
mice. The mutant
COX-2 gene was detected with the neomycin resistance gene
(Neor)-specific primers amplifying a 280-bp
product of Neor in COX-2
/
, however, not in
COX-2 +/+. The sequence of the oligonucleotide primers and
their location in the published sequence is as follows: COX-2 sense
5'-GCAGCCAGTTGTCAAACTGC-3' (bp 961-980); COX-2 antisense 5'-CTCG
GAAGAGCATCGCAGAGG -3' (bp 1081-1112) (11); Neor sense 5'-CTTGGGT GGAGAGGCTATTC-3' (bp
191-210 ); and Neor, antisense
5'-AGGTGAGATGACA GGAGATC-3' (bp 451-470) (1).
Amplification was carried out for 30 cycles (denaturation at 94°C for
40 s, annealing at 58°C for 40 s, and extension at 72°C
for 40 s, followed by a final extension at 72°C for 8 min).
After genotyping, animals were separated according to genotype and
gender. Angiotensin type 1A receptor (AT1A)-knockout mice
were provided by Dr. T. Coffman (Duke University) and genotyped as
previously described (35).
Northern blots. Total RNA was isolated from the mouse cortex by using RNeasy Mini Kit (Qiagen, Valencia CA). Ten micrograms of total RNA were separated on 1% agarose gels and transferred to a nylon membrane. A 601-bp fragment derived from mouse renin cDNA (24) was labeled with [32P]-dCTP by using a random prime-labeling system (Amersham, Arlington Heights IL). Hybridization was carried out at 43°C overnight in the presence of 106 cpm/ml of the renin probe according to NorthernMax-Gly protocol (Ambion, Austin TX). The membrane was stripped by boiling for 10 min in 0.1% SDS and rehybridized with glyceraldehyde-3-phosphate dehydrogenase probe (Ambion).
Direct renin granule visualization. Dissection of renal vessel trees was performed as previously described by Casellas et al. (3). Briefly, kidneys were treated with 5 N HCl at 37°C for 60 min, rinsed and kept in distilled H2O for 2 days. Vessel trees were dissected in acidified distilled water (pH 2.5) under a stereomicroscope by gently freeing them from surrounding tubules. Small vessel trees were transferred to microscopic slides and covered with coverslips on a rim of silicone glue to bring arterioles into one plane. As has been noted previously (3), renin-containing granules can be directly visualized under the microscope due to the greater refraction of granular cells. The number of renin-positive and renin-negative arterioles was counted in 5-6 vessel trees per kidney.
Immunohistochemistry. The dissected vessel trees were permeabilized with 5% Triton X-100 in distilled water for 20 min and then fixed with 10% formaldehyde. The endogenous peroxidase activity was quenched by treatment with 3% hydrogen peroxide for 5 min. After blocking for 30 min, the vessel specimens were incubated with a rabbit polyclonal antiserum to mouse renin at a dilution of 1:1,000 (gift from Dr. T. Inagami, Vanderbilt University, Nashville TN), washed with PBS, and incubated with biotin-conjugated secondary antibody. Vascular trees were then treated with an avidin-biotinylated horseradish peroxidase and immunoreactivity was generated with diaminobenzidine tetrahydrochloride peroxidase substrate (Vectastain ABC kit; Vector Laboratories, Burlingame CA).
Glomerular renin activity. Glomeruli were dissected from untreated nonperfused kidneys and freed from adherent arterioles and tubules as much as possible. In each animal 10-20 glomeruli were dissected from all regions of the cortex. Glomeruli were transferred to a dish containing fresh dissection medium for washing. Single glomeruli were picked up in 5 µl medium with an Eppendorf pipette, transferred into 100 µl of phosphate buffer and frozen in liquid nitrogen until renin analysis. Five microliters of the wash medium were treated in parallel to assess the renin background activity. Renin content of single glomeruli was liberated by freezing and thawing 4 times and measured by radioimmunoassay of generated angiotensin I by using the antibody-trapping technique in the presence of excess rat substrate (28). Renin activity is expressed in Goldblatt units (GU) and standardized by comparison with renin standards obtained from the Institute for Medical Research (MRC, Holly Hill, London, UK).
RT-PCR. RT-PCR was performed as previously described (41). cDNA was synthesized from total RNA by Moloney murine leukemia virus reverse transcriptase (Superscript; BRL, Gaithersburg, MD). PCR was performed on serial dilutions of cDNA in the presence of 1.5 µCi/50 µl [32P]dCTP. PCR products were separated on polyacrylamide gels and analyzed by phosphoimaging. The sequence of the oligonucleotide primers and their location in the published cDNA sequence are as follows: renin sense, 5'-TGGGTGCCCTCCACCAAGTG-3' (bp 335-398); renin antisense, 5'-CTCCCAGGGCTTGCATGATCA-3' (bp 919-939) (24); COX-1 sense, 5'- CTG CTG AGA AGG GAG TTC CAT-3' (bp 602-621); COX-1 antisense, 5'- GTC ACA CAC ACG GTT ATG CT (bp 981-1000) (10); COX-2 sense, 5'-ACA CTC TAT CAC TGG CAT CC-3' (bp 1229-1248); and COX-2 antisense, 5'-GAA GGG ACA CCC TTT CAC AT- 3' (bp 1794-1813) (23).
Statistical analysis. Data are expressed as means ± SD or SE as indicated. Statistical comparisons were made with Student's t-test or ANOVA with the Bonferroni test, with P < 0.05 being considered significant.
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RESULTS |
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Renin mRNA.
Renin mRNA was determined by Northern hybridization in 10 µg of total
RNA isolated from the renal cortex of 10 COX-2 /
and 10 COX-2 +/+
mice. Five mice in each strain received a normal diet, and five mice
were treated with a low-salt diet for 2 wk. Results are shown in Fig.
1. Renin mRNA, detected as a 1.8-kb band
and quantified by densitometric analysis, was found to be reduced in
COX-2
/
compared with COX-2 +/+ mice by 60%. Low-salt intake
caused a twofold increase in renin mRNA in COX-2 +/+ mice whereas it
was not associated with a significant change in renin mRNA in the COX-2
/
animals.
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Renin visualization.
Vascular trees were isolated from six wild-type and four COX-2-knockout
mice on a normal diet, and on four wild-type and four COX-2 /
mice
on a low-salt diet. Figure 3A
confirms the observations in earlier studies that renin-containing
cells at the vascular pole can be visualized without staining as dark
and grainy regions at the ends of the afferent arterioles
(3). The identity of these cells with renin has been
verified in these earlier studies (3, 33). Nevertheless,
renin immunocytochemistry was performed by using a renin-polyclonal
antibody in the kidney of a low-salt-treated, wild-type mouse (Fig.
3B). Renin positivity was detected in the same location as
the directly visualized renin signals, suggesting that the areas of
higher optical density in fact represent renin-containing cells. Renin
granularity was quantified by counting positive and negative arterioles
in 5-6 vessel trees from the same kidney (Fig. 4). In wild-type mice the ratio of
positive to negative arterioles averaged 1.93 ± 1.75 (means ± SD), indicating a percentage of 66% for positive and 34% for
negative vessels (total number of vessel trees assessed was 28). In
contrast, in the COX-2-knockout mice the ratio of positive to negative
arterioles decreased to 0.58 ± 0.2 (total number of vessel trees
was 20), i.e., to a percentage of 36% positive and 64% negative
arterioles. During salt restriction, the majority of arterioles in
wild-type mice was renin positive (ratio 2.8 ± 2; 20 vessel
trees). In contrast, presence of granules did not markedly change in
the COX-2
/
mice (ratio 0.81 ± 0.3; i.e., 45% positive and
55% negative arterioles). Analysis was restricted to an all-or-none
analysis because proximalization of renin expression was not
encountered in this series. By using the nomenclature proposed by Reddi
et al. (33), all arterioles examined fell into either
group IV (renin confined to the end of the vessel) or group V (renin
absent). A high fraction of renin-negative arterioles has been noted
earlier (3, 33). It is not clear whether this represents
true renin negativity, loss of renin during the vessel separation, or
expression below the level of detectability by visual inspection.
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Renin activity.
To assess juxtaglomerular renin activity, single glomeruli were
dissected from nonperfused kidneys immediately after the animals were
killed. To minimize possible contamination with plasma renin, the
dissected glomeruli were collected only when no attached vessels were
visible. Results are summarized in Fig.
5. On a normal-NaCl diet, mean glomerular
renin activity was 764 ± 158 mGU/glomerulus in wild-type mice
(n = 41, 6 mice), significantly higher than the average
of 188 ± 42 mGU/glomerulus in COX-2 /
animals
(n = 29, 4 mice; P = 0.047). In mice
fed a low-NaCl diet for 2 wk, glomerular renin activity increased to
2,214 ± 420 mGU/glomerulus (n = 27, 3 mice),
significantly higher than in wild-type mice on the normal-NaCl diet
(P < 0.0001). COX-2
/
mice on a low-NaCl diet had
a mean renin activity of 547 ± 97 mGU/min (n = 32, 5 mice), significantly lower than in low-salt-treated wild-type mice (P < 0.00001). Although the low-salt treatment
increased renin activity in the COX-2
/
mice, compared with the
knockout animals on a normal-NaCl intake, this difference did not quite reach statistical significance (P = 0.24). Background
renin activity in the washing medium was negligible in all cases and
was therefore not subtracted.
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Measurement of GFR.
Mean GFR in three female COX-2 /
mice at 11-12 wk of age was
220 ± 50 µl/min whereas it averaged 213 ± 48 µl/min in
three age-matched wild-type mice. Mean weight (KW) of left and right kidneys was 204 ± 3.5 and 268 ± 10 mg in COX-2
/
and COX-2 +/+ mice, respectively. Because of the lower KW in the
knockout mice, weight-corrected GFR was 1,076 ± 238 µl · min
1 · g KW
1 in
COX-2
/
, and 808 ± 201 µl · min
1 · g KW
1 in
wild-type mice (P = 0.42). Mean arterial blood pressure
of the anesthetized mice was 97 ± 10 mmHg in the COX-2
/
, and
81 ± 5 mmHg in the wild-type animals (P = 0.2).
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DISCUSSION |
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Prostaglandins have been shown to act as paracrine mediators in a pathway in which a reduction in luminal NaCl at the MD causes a stimulation of renin secretion (13, 14). Studies in the isolated perfused JGA preparation with isoform-specific inhibitors have identified COX-2 as the cyclooxygenase isoform involved in NaCl-dependent alterations of renin secretion (37). Because COX-2 has been found to be expressed rather selectively in MD cells and surrounding cells of the TAL, the tubular epithelium appears to be the likely source of prostanoids involved in control of renin secretion (15, 17, 18, 41). The experiments performed in this study have addressed the question, whether, in addition to controlling renin secretion, COX-2 may also be responsible for determining the level of renin expression in juxtaglomerular granular cells and its response to prolonged reductions in luminal NaCl concentration. This assumption seems justified, because, under numerous conditions, renin secretion and renin synthesis change in parallel. Furthermore, cAMP, the likely intracellular messenger in the renin-secretory response initiated by prostaglandins, also augments renin mRNA abundance (4, 26).
In the present study we used COX-2-knockout mice to investigate the
effect of chronic and selective deficiency of MD and TAL COX-2 on the
expression of renin by juxtaglomerular granular cells and on the
response of renin synthesis to low-salt stimulation (9,
29). Our results show that levels of renin mRNA and renin protein, as well as renin enzyme activities, are significantly reduced
in COX-2-deficient mice. Thus our data provide clear evidence in
support of the notion that the presence of COX-2 activity in epithelial
cells in the tubulovascular contact region is required for the
expression of renin under basal conditions. Kidneys of the 6-wk-old
female mice used in our studies had a normal macroscopical appearance.
Furthermore, GFR in a small group of 11-wk-old female COX-2-knockout
mice was not different from that in wild-type animals, indicating
maintained overall renal function. Nevertheless, we cannot exclude that
the small hypoplastic glomeruli in the superficial cortex have a
systematically lower renin content than the more mature midcortical and
juxtamedullary glomeruli (9, 29). Such heterogeneity was
not apparent, however, in the dissected vessel tree preparation that
provides an overview of the total afferent arteriole population.
Furthermore, in microdissection of glomeruli for renin activity, assay
care was taken to collect glomeruli from all regions of the kidney, and
preferential collection of hypoplastic glomeruli is actually quite
unlikely. COX-2 expression and enzyme activity, as well as renin
expression, are augmented rather than reduced in rat kidneys after
subtotal renal ablation (7, 39). To the extent that the
glomerular structural and functional alterations in the 5/6 ablation
model and in the mature glomeruli of the COX-2 /
mice are
comparable, it would appear that the decrease in renin expression
observed in the COX-2
/
mice is probably not secondary to
structural alterations. Thus our results indicate that COX-2 activity
in epithelial cells in the tubuloglomerular contact region is necessary
to direct the full expression of renin by granular cells. We cannot
exclude the possibility that COX-2 affects renin synthesis through some systemic action or that some consequence of medullary COX-2 deficiency impinges on the formation of renin. However, given the local character of most COX-dependent effects, it is more likely that MD COX-2 is an
integral part of a pathway by which the level of ambient luminal NaCl
concentration determines, at least in part, the level of renin gene
expression by juxtaglomerular granular cells.
The local mechanism linking COX-2 expression in MD cells and renin
expression in granular cells has not been elucidated. However, it would
appear likely that prostaglandins act as extracellular messengers in
the local control of renin synthesis. The stimulatory effect of
PGE2 and PGI2 on renin secretion from
juxtaglomerular cells in primary culture suggests that PGE2
and PGI2 receptors are present in these cells and that they
exert their effect through Gs-coupled stimulation of cAMP
formation (2, 21). In addition to augmenting renin
secretion, cAMP has also been shown to augment renin mRNA levels in
granular cells (4, 8). Nevertheless, it is unclear whether
renal prostanoid production is in fact decreased in the complete
absence of only one COX isoform. In one previous study, PG generation
was greatly reduced in peritoneal macrophages and gastric cells of
COX-1 /
mice, suggesting that the remaining cyclooxygenase, COX-2,
was not upregulated in these cells (27). On the other
hand, in lung fibroblasts, PGE2 production has been observed to actually increase in cells from COX-2
/
or COX-1
/
compared with wild-type mice, suggesting efficient compensation of PG
synthesis by the intact cyclooxygenase (25). Recent
preliminary results indicate that the overall production of
PGE2, PGI2, and thromboxane in kidneys of COX-2
/
mice is indistinguishable from that of wild-type mice
(30). This observation does not exclude the possibility of
prostaglandin deficiency in the restricted compartment of the
juxtaglomerular interstitium. Nevertheless, whereas our studies in
COX-2-knockout mice indicate a strong dependence of renin activity on
this specific isoform, the results could potentially be the product of
some systemic consequence of COX-2 deficiency.
In addition to a reduction in the level of basal renin expression,
COX-2-deficient mice displayed an attenuation of the stimulation of
renin synthesis in response to a low-NaCl intake. The approximately twofold stimulation of renin mRNA caused by low NaCl in wild-type mice
was essentially completely absent in the COX-2-knockout animals. Similarly, the increase in the number of renin-positive arterioles seen
in wild-type mice on low-NaCl intake was not seen in low-NaCl-treated COX-2-deficient mice. Furthermore, renin enzyme activity in dissected glomeruli of COX-2 /
mice on a low-salt diet was significantly reduced compared with control mice on the same diet. Some augmentation of renin enzymatic activity was observed in the COX
/
mice;
however, the increment was much reduced compared with wild-type mice.
The apparent discrepancy between renin activity and
directly-visualized renin expression may indicate that a
larger fraction of total renin is present as active renin in the
COX-2-deficient animals. Alternatively, visualization of renin granules
may be a less sensitive method than measurements of renin activity.
Overall, our results agree with a previous study in rats in which the
application of the COX-2-specific inhibitor NS 398 completely prevented
the increase in renal renin content caused by a low-NaCl diet
(16). Aortic coarctation has been shown to be another
situation where renin gene expression is stimulated and where this
stimulation is attenuated by the administration of the specific
COX-2-inhibitor SC-58236 (38). In conjunction with these
previous results, our data support the concept that the expression
level of COX-2 in cells of the MD and TAL is a critical determinant not
only of renin release but also of renin gene expression. The present
results complement earlier evidence showing a rather striking
correlation between the expression of renal cortical COX-2 and renin.
For example, alterations in Na intake are accompanied by inverse
changes in the expression of both COX-2 and renin in the renal cortex
(17, 20, 41). Furthermore, renal artery constriction or
aortic coarctation is followed by marked increments in renal cortical COX-2 and renin expression (18, 38).
The localization of COX-2 in cells of the tubulovascular contact region is consistent with the concept that the signal directing the expression of COX-2, and subsequently of renin, is related to luminal NaCl concentration and NaCl transport. Thus the parallel expression of COX-2 and renin during varying salt intake and during renal artery constriction may be the result of alterations in luminal fluid composition in the MD region of the nephron. A low-salt intake and constriction of the renal artery are likely to be associated with reduced NaCl concentration and NaCl transport at the MD, and this may stimulate COX-2 expression. On the other hand, a high NaCl concentration during elevated NaCl intake may be the reason for inhibition of COX-2 expression. Further work is needed to permit generalization of the concept that a chronic change in NaCl transport by epithelial cells in the juxtaglomerular region causes an inverse change in COX-2 expression and that this in turn is followed by a change in renin gene expression.
Previous results, as well as our present data, provide evidence against the possibility that the stimulatory effect of a low-salt diet on the expression of COX-2 is mediated by angiotensin II. The fact that COX-2 expression is increased in AT1A-knockout mice implies that angiotensin II inhibits COX-2 expression and probably forms a local negative feedback loop to stabilize COX-2 expression levels. An increase in COX-2 expression in MD and TAL cells has previously been reported in AT1A/AT1B-double-knockout mice (5). Furthermore, inhibitors of angiotensin-converting enzyme and of angiotensin receptors have been shown to stimulate COX-2 expression (5, 40). The fact that the specific COX-2 blocker SC-58236 prevented activation of the renin-angiotensin system by converting enzyme blockade indicates that the inhibitory effect of angiotensin II on renin synthesis appears to be mediated at least in part by COX-2 (5). Downregulation of COX-2 expression and COX-2-dependent prostaglandin production by angiotensin II in MD and TAL cells appear to be cell specific. Recent observations indicate that angiotensin II increases COX-2 mRNA levels in cultured rat vascular smooth muscle cells (31). This finding is consistent with substantial previous support for the notion that angiotensin II stimulates the formation of prostaglandins (32). This response is thought to be an important mechanism for protecting the renal circulation against the constrictor effect of an angiotensin II excess. Stimulation of prostaglandin formation by angiotensin II may be mediated in part by vascular COX-1.
In summary, our results show that the expression of renin is markedly reduced in COX-2-deficient mice and that the stimulatory effect of a low-NaCl diet is attenuated. COX-2 expression in epithelial cells in the tubuloglomerular contact area appears to be a critical determinant in the expression of renin by juxtaglomerular granular cells. Our results are consistent with the notion that COX-2 activation is an intermediate step in the pathway that links luminal NaCl concentration with both renin release and renin gene expression.
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ACKNOWLEDGEMENTS |
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This work was supported by intramural funds of the National Institute of Diabetes and Digestive and Kidney Diseases.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. Schnermann, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 10, Rm. 4 D51, 10 Center Dr. MSC 1370, Bethesda, MD (Email: jurgens{at}intra.niddk.nih.gov).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 16 March 2000; accepted in final form 19 July 2000.
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