George M. O'Brien Kidney and Urologic Diseases Center and Division of Nephrology, 1 Department of Medicine, and 2 Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennesee 37232
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ABSTRACT |
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We have previously shown that cyclooxygenase-2 (COX-2) is localized to the cortical thick ascending limb of the loop of Henle (cTALH)/macula densa of the rat kidney, and expression increases in response to low-salt diet and/or angiotensin-converting enzyme (ACE) inhibition. Because of the localization of neuronal nitric oxide synthase (nNOS) to macula densa and surrounding cTALH, the present study investigated the role of nitric oxide (NO) in the regulation of COX-2 expression. For in vivo studies, rats were fed a normal diet, low-salt diet or low-salt diet combined with the ACE inhibitor captopril. In each group, one-half of them were treated with the nNOS inhibitors 7-nitroinidazole (7-NI) or S-methyl-thiocitrulline. Both of these NOS inhibitors inhibited increases in COX-2 mRNA and immunoreactive protein in response to low salt and low salt+captopril. For in vitro studies, COX-2 expression was studied in primary cultures of rabbit cTALH cells immunodisssected with Tamm-Horsfall antibody. Basal COX-2 immunoreactivity expression was stimulated by S-nitroso-N-acetyl-penicillamine (SNAP), an NO donor, and intracellular cGMP concentration. The cultured cells expressed immunoreactive nNOS, and 7-NI inhibited basal COX-2 immunoreactivity expression, which could be partially overcome by cGMP. In summary, these studies indicate that NO is a mediator of increased renal cortical COX-2 expression seen in volume depletion and suggest important interactions between the NO and COX-2 systems in the regulation of arteriolar tone and the renin-angiotensin system by the macula densa.
cyclooxygenase; nitric oxide synthase; renin; macula densa
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INTRODUCTION |
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IN THE MAMMALIAN KIDNEY, the macula densa consists of a plaque of morphologically distinct tubular epithelial cells localized on the glomerular side of the distal end of the thick ascending limb of Henle's loop (TALH). By monitoring the salt concentration of the tubular fluid at the distal end of the loop of Henle, the macula densa monitors glomerular filtration rate (GFR) and proximal reabsorption. Since both GFR and tubule reabsorptive rates are dependent upon, and reflections of, effective circulating volume, the macula densa is situated to serve as both sensor and effector of total salt and volume homeostasis (20). It is well established that macula densa sensing of tubule NaCl concentration serves as a primary regulatory step in renin secretion and tubuloglomerular feedback (TGF) (34, 39).
There has been recent evidence that regulation of both TGF and renal renin production and release may be modulated by prostaglandins derived from the macula densa (24, 19, 40, 8), but the mechanisms of regulation appear complicated and are still poorly understood. Increasing juxtaglomerular cell cAMP leads to increased renin release, and prostaglandins that are coupled to Gs (PGI2, PGE2) have been shown to increase renin release (50, 25, 27). It has long been recognized that nonsteroidal anti-inflammatory drugs (NSAIDs) can predispose to a hyporeninemic, hypoaldosteronemic state (14). Recent evidence has indicated that cyclooxygenase-2 (COX-2) is localized to macula densa cells and associated cortical thick ascending limb cells, and macula densa COX-2 expression increases in high-renin states, such as salt restriction, volume depletion and renovascular hypertension (21, 22, 26, 48, 52). Furthermore, specific COX-2 inhibitors prevent the increase in renal renin levels seen with salt restriction, angiotensin-converting enzyme (ACE) inhibition and renovascular hypertension (19, 8, 48). However, the underlying mechanisms regulating this increased COX-2 expression have not been completely determined. Our previous studies have indicated that components of the renin-angiotensin system, including both angiotensin II and aldosterone, may serve as a negative feedback loop to decrease macula densa/cortical (c)TALH COX-2 expression (8). However, the signals mediating the stimulation of COX-2 expression have not been elucidated.
In addition to prostaglandin mediation of renin production and release, there is increasing evidence for a role for nitric oxide in the regulation of macula densa function. Neuronal nitric oxide synthase (nNOS; inducible NOS I) is localized to the macula densa and increases in response to salt restriction (51, 33, 45). Furthermore, NADPH diaphorase activity, measured by the nitroblue tetrazolium reaction, colocalizes with nNOS immunoreactivity, indicating active NO synthase activity in these cells (38). There is evidence that nNOS may be a mediator of renin release (15, 16, 23, 19, 4).
Because direct administration of NO elicits a complicated pattern of juxtaglomerular cell renin release, with both concentration- and time-dependent inhibitory and stimulatory effects reported, see (28) for an excellent recent review, and because stimulation of renin-producing cells may occur as much as 100 µm from the macula densa, a great distance for the short-half lived-NO to traverse (28), it is possible that macula densa nNOS-mediated stimulation of renin may occur through activation of an intermediary stimulatory mechanism. Therefore, the goal of the present studies was to determine whether nNOS may be a mediator of COX-2 expression in the macula densa and surrounding cTALH.
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MATERIALS AND METHODS |
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Materials. Rabbit polyclonal anti-murine COX-2 antibody was from Cayman (Ann Arbor, MI). Goat anti-human uromucoid antibody was from ICN (Costa Mesa, CA). Anti-nNOS was from Transduction Laboratories (Lexington, KY), Anti Goat IgG (H + L) was from Vector Laboratory (Burlingame, CA), and biotin-labeled mouse anti-rabbit IgG(H + L) antibodies were from Pierce (Rockford, IL). 7-Nitroinidazole (7-NI) was from Calbiochem (La Jolla, CA), nitro-L-arginine methyl ester (L-NAME) was from Sigma Chemical (St. Louis, MO), and S-methyl-L-thiocitrulline (SMTC) was from Alexis (San Diego, CA). [32P]CTP (3,000 Ci/mmol), enterochromaffin-like (ECL) and ECL Hyperfilm were from Amersham (Arlington, Height, IL). BCA protein assay reagent kit and Immunopure ABC peroxidase staining kit were from Pierce. Other reagents were purchased from Sigma Chemical.
Animals. Male Sprague-Dawley rats (Harlan, Indianapolis, IN), initially weighing 150-200 g, were either maintained on normal rat chow or were given a single intraperitoneal dose of furosemide (1 mg/kg) and then placed on rat chow deficient in sodium (0.02-0.03% Na+; ICN, Irvine, CA) for 1 wk. In addition, a subset of animals on the sodium-deficient diet was given the ACE inhibitor, captopril (400 mg/l) (32) in the drinking water for seven days. Subsets of each of these three groups (control, low salt and low salt + captopril) were administered 7-NI or SMTC intraperitoneally for 7 days at daily doses of 20 mg/kg and 15 mg/kg, respectively. A separate group of animals was fed a high (8%)-salt diet (ICN) for 7 days.
Primary culture of rabbit cTALH cells. cTALH cells were isolated from homogenates of rabbit renal cortex by immunodissection with anti-Tamm Horsfall antibody, as previously described (1, 11, 8). Briefly, the renal cortex was dissected, minced, and digested with 0.1% collagenase. After blocking with 10% BSA, the sieved homogenates were incubated with goat anti-human Tamm-Horsfall antiserum (50 mg/ml) for 30 min on ice, followed by washing in addition to plastic petri dishes coated with anti-goat IgG (8 mg/ml). Attached cells resistant to washing were dislodged and grown to confluence in DME/F-12 with 10% FCS. Quiescent cTALH cells were incubated with or without the indicated agents for 16 h prior to protein isolation.
RNA extraction and Northern blotting. Renal cortical RNA was extracted by the acid guanidium thiocyanate-phenol chloroform method (9). RNA samples were electrophoresed in denatured agarose gel, transferred to nitrocellulose membranes, and hybridized with a 1.3-kb 32P-labeled cDNA Kpn I/Xho I fragment of 3' untranslated region of rat COX-2 (21). The membranes were then stripped and rehybridized with glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
Immunoblotting. Renal cortices were homogenized in 30 mM Tris · HCl, pH 8.0, 100 µM phenylmethylsulfonyl fluoride (PMSF; 1:9, wt/vol). After a 10-min centrifugation at 10,000 g, the supernatant was centrifuged for 60 min at 110,000 g to prepare microsomes, as described previously (49). Microsomal proteins were resuspended in SDS-sample buffer, heated to 100°C for 5 min, separated on 8% SDS gels under reducing conditions and transferred to immobilon-P transfer membranes (Millipore, Bedford, MA). The blots were blocked overnight with 100 mM Tris · HCl, pH 7.4, containing 5% nonfat dry milk, 3% albumin, and 0.5% Tween-20, followed by incubation for 16 h with polyclonal rabbit anti-murine COX-2 antiserum (Cayman, Ann Arbor, MI) at 2.5 µg/ml dilution. The second reagent, biotinylated goat anti-rabbit antibody, was detected by using avidin and biotinylated horseradish peroxidase (Pierce) and exposed on film by using ECL (Amersham).
Immunohistochemistry. Under deep anesthesia with Nembutal (70 mg/kg ip), rats were exsanguinated with 50 ml/100 g heparinized saline (0.9% NaCl, 2 U/ml heparin, 0.02% sodium nitrite) through a transcardial aortic cannula and fixed with glutaraldehyde-periodate acid saline (GPAS), as previously described (53). GPAS contains final concentrations of 2.5% glutaraldehyde, 0.011 M sodium metaperiodate, 0.04 M sodium phosphate, 1% acetic acid, and 0.1 M NaCl, and provides excellent preservation of tissue structure and COX-2 antigenicity. The fixed kidneys were dehydrated through a graded series of ethanols, embedded in paraffin, sectioned at 4 µm thickness and mounted on glass slides. COX-2 immunoreaction was localized with COX-2 antiserum diluted to 2.5 ng/ml. The first antibody was localized by using Vectastain ABC-Elite (Vector, Burlingame, CA) with diaminobenzidine as the chromogen, followed by a light counterstain with toluidine blue.
Quantitative image analysis based on the distinctive density and color of COX-2 immunoreactivity and the number, size, and position of stained cells in video images from kidney sections was determined by using BIOQUANT true-color windows system (R & M Biometrics, Nashville, TN) equipped with digital stage encoders that allow high-magnification images to be mapped to global coordinates throughout the whole kidney. Sections from at least four different rats were analyzed for each time point.Statistical analysis. All values are presented as means ± scanning electron microscopy (SE). ANOVA and Bonferroni t-tests were used for statistical analysis, and differences were considered significant when P < 0.05.
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RESULTS |
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In previous studies, we determined that administration of a
low-salt diet to adult rats induced expression of cTALH/macula densa
COX-2 mRNA and immunoreactive protein (21), which was further augmented by simultaneous ACE inhibition (8). To
determine whether neuronal NOS activity might be involved in mediating
this increased COX-2 expression, rats on either control or low-salt diets were administered the specific nNOS inhibitor, 7-NI
(31, 2). In rats fed a normal salt diet,
administration of 7-NI led to a numerical decrease in COX-2 mRNA
expression (0.62 ± 0.08 fold control; n = 5; NS).
The increased COX-2 mRNA expression noted with administration of a
low-salt diet alone or low salt + the ACE inhibitor, captopril
(5.12 ± 1.45 and 6.68 ± 2.25-fold control, respectively;
n = 5) were both significantly inhibited by
simultaneous administration of 7-NI (1.46 ± 0.37 and 1.52 ± 0.37-fold control respectively; n = 5;
P < 0.05 compared with the absence of 7-NI) (Fig.
1A).
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A similar inhibitory response was noted in the expression of immunoreactive renal cortical COX-2. Compared with rats on a normal salt diet, COX-2 immunoreactivity expression was 0.89 ± 0.12 fold control (n = 6; NS). Rats administered low salt or low salt + captopril had increased COX-2 immunoreactivity expression (1.91 ± 0.09 and 2.42 ± 0.18, respectively; n = 6; P < 0.01), which was significantly inhibited by 7-NI treatment (1.18 ± 0.12 and 1.30 ± 0.15-fold control; n = 6; P < 0.01) compared with non-7NI-treated rats (Fig. 1B).
To test further whether the in vivo effects of 7-NI were attributable
to nNOS inhibition, SMTC, another highly selective inhibitor of nNOS
(24) was employed. As demonstrated in Fig.
2, SMTC also decreased low salt- and low
salt + captopril-induced increases in COX-2 mRNA and COX-2
immunoreactivity expression.
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As reported previously (8), rats receiving both low-salt
diet and captopril expressed COX-2 in the macula densa of virtually every glomerulus (Fig. 3A, C,
E). Individual COX-2-positive
cells were also present in the preglomerular segment of the cortical thick ascending limb (cTAL) but were absent from the postglomerular epithelium (initial segment of the distal convoluted tubule). Administration of 7-NI to the low-salt/captopril animals decreased immunoreactive COX-2 expression, especially in the macula densa region
(Fig. 3B, D, F). Quantitation of
the amount of cortical COX-2 immunoreactivity confirmed that the
increases in COX-2 immunoreactivity with addition of captopril and low
salt were abolished by simultaneous treatment with 7-NI (COX-2
immunoreactivity/cortical area: control: 90 ± 30.1 µm2/mm2; low salt + captopril: 282 ± 28 µm2/mm2; n = 4;
P < 0.01 vs. control; low
salt + captopril + 7-NI: 49 ± 4
µm2/mm2; P < 0.001 vs. low
salt + captopril ; NS vs. control; n = 7 for all
groups) (Fig. 3G).
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To examine whether NO directly modulated cTALH COX-2 expression,
primary cultures of rabbit cTALH were isolated by
immunodissection with an anti-Tamm- Horsfall antibody. As we have
previously reported, these cells expressed detectable basal levels of
COX-2 immunoreactivity, and COX-2 expression was induced in response to
treatment with phorbol esters (8). In the present studies,
we determined that these cells also expressed detectable immunoreactive
nNOS, as indicated by a 155-kDa band (Fig.
4A).
Treatment with the nNOS-specific inhibitor, 7-NI, significantly
inhibited basal COX-2 immunoreactivity expression in the cultured cTALH
7-NI: (0.48 ± 0.08-fold control; n = 5;
P < 0.01 ) (Fig. 4B). The nonselective NOS
inhibitor (L-NAME) produced a similar inhibition (0.55 ± 0.14; n = 5; P < 0.05). In
contrast, administration of the NO donor,
S-nitroso-N-acetyl penicillamine (SNAP),
significantly stimulated COX-2 immunoreactivity expression (1.70 ± 0.14-fold control; n = 6; P < 0.01)
(Fig. 4C). Intracellular cGMP concentration also stimulated
basal COX-2 expression (1.77 ± 0.07-fold control;
n = 6; P < 0.0.01) and overcame the inhibition of COX-2 immunoreactivity induced by 7-NI (1.18 ± 0.15-fold control; n = 5; P < 0.01)
(Fig. 4B and C).
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In addition to cortical expression, COX-2 is also expressed in
medullary interstitial cells in the papilla of rat kidney
(21). In contrast to cortical COX-2 expression, papillary
COX-2 expression increases in response to increases in dietary salt
(52, 26). As indicated in Fig.
5, a high-salt diet increased papillary
nNOS immunoreactivity (Fig. 5A) and COX-2 immunoreactivity
expression (Fig. 5B). The increased COX-2 expression in the
papilla in response to a high-salt diet was significantly inhibited by
administration of 7-NI (Fig. 5B).
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DISCUSSION |
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We have previously reported that components of the renin/angiotensin system, including angiotensin II and aldosterone, will decrease COX-2 expression in cTALH/macula densa cells (8). Because of the localization of nNOS to the same regions of the kidney as COX-2 (macula densa and inner medulla), the present studies were designed to examine whether neuronal NOS activity might be involved in mediating increased renal COX-2 expression. Increases in cTALH/macula densa COX-2 expression induced by a low-salt diet or low-salt diet + ACE inhibition were significantly inhibited by simultaneous administration of the selective nNOS inhibitors, 7-NI or SMTC. In addition, increased papillary COX-2 expression induced by a high-salt diet was significantly inhibited by simultaneous 7-NI administration.
In primary cultures of immunodissected rabbit cTALH cells, administration of either cGMP or an NO donor increased COX-2 expression, whereas administration of either nonselective (L-NAME) or nNOS-selective (7-NI) nitric oxide synthase inhibitors decreased basal COX-2 expression. Basal renal cortical COX-2 immunoreactivity and COX-2 mRNA were also decreased in response to nNOS inhibition. Therefore, it is plausible to suggest that NO may be a positive regulator of COX-2 expression under both basal and stimulated conditions.
The enzymatic formation of NO from arginine is catalyzed by a family of dioxygenases, the NO synthases. All the NO synthases require L-arginine, oxygen, and NADPH as cosubstrates and FADH/FAD, heme, and (6R)-tetrahydro-L-biopterin as cofactors (3). Macula densa has the highest levels of any cells in the kidney of glucose-6-phosphate dehydrogenase (G6PDH), which mediates formation of NADPH by reduction of NADP+ (3). In the kidney, eNOS is present in most endothelial cells, including the afferent arterioles of the kidney, while nNOS is localized to the macula densa (51, 33, 45) and inner medullary collecting duct cells (3, 37).
NO has been reported to inhibit acutely renin release from isolated juxtaglomerular cells (6, 41). However, there is evidence that tonic administration of NO will increase renin secretion (41). In isolated perfused kidney, NO has been shown to stimulate renin release (28), and studies in isolated juxtaglomerular apparatus (JGA) preparations indicate that selective inhibition of macula densa NOS inhibits the macula densa-mediated renin secretion in response to decreased luminal NaCl (16, 23). Macula densa nNOS expression increases in response to dietary salt restriction (7, 42, 43, 44), and, in rats, 7-NI blunted increased renin in response to salt restriction but not in response to decreased perfusion pressure (baroreceptor reflex) (5), and increased renin secretion secondary to furosemide-stimulated renin release, which is mediated by the macula densa (5, 40).
Although there is experimental evidence that macula densa-derived NO may counteract the vasoconstriction of TG feedback and also mediate renin release signaled by the macula densa, it has been argued that the short half life of NO and the long (for NO) potential distance between macula densa cells and the glomerular vascular pole make it less likely that macula densa-derived NO acts directly on renin producing cells, especially in conditions that lead to recruitment of renin-producing cells. Rather, direct effects of NO on juxtaglomerular cells would be expected to be mediated by NO derived from vascular eNOS (28). However, because the studies cited above clearly implicate macula densa nNOS in regulation of renin release and TGF, it is possible that nNOS may activate a second signaling system, and we suggest that COX-2-derived prostanoids may serve this role. Recent studies by Ichihara et al. have suggested that NO-mediated counteraction of TG feedback vasoconstriction is blocked by COX-2-specific inhibitors (24). There is also well documented evidence for a role for prostaglandins in macula densa-mediated regulation of renin production and release (13, 30, 25, 17). The observation that renal cortical COX-2 expression in the rat is localized to the macula densa and surrounding cTALH and imposition of a low-sodium diet or fluid restriction leads to significant increases in cTALH/macula densa COX-2 expression suggested a possible source for the prostaglandins involved in regulation of renin release (21, 52, 26, 46). Recent studies indicating that COX-2-selective inhibitors decrease renin levels in response to dietary sodium restriction, ACE inhibition, or renovascular hypertension (48, 22, 8) provide further evidence that macula densa COX-2 expression is a mediator of renin expression.
Therefore, we suggest that the present studies and our previous studies (8) indicate an interaction between the positive stimulus of nNOS and the negative stimulus of the renin-angiotensin system to regulate macula densa COX-2 expression in response to dietary salt restriction. Although salt restriction clearly increases macula densa nNOS expression, as mentioned above, there remains some controversy in the literature concerning the effect of the renin-angiotensin system to regulate nNOS expression. In control animals, the AT1 receptor antagonist, losartan, has been reported to either decrease (36) or not to change renal cortical nNOS expression (42). In contrast, in animals on a salt depleted diet, losartan increased macula densa nNOS expression (42, 44); in addition, losartan increased renal cortical nNOS expression in the remnant kidney (36).
The cellular mechanisms by which NO might increase renal COX-2 expression were not addressed in detail in the present studies, although it is of interest that cGMP increased COX-2 immunoreactivity in the cultured cTALH cells. There have been reports in a variety of cell types that NO will increase (12, 35, 47), decrease (12, 18) or not alter (10) COX-2 expression. Previous in vitro and in vivo studies have also suggested that NO may directly activate cyclooxygenase enzymatic activity (29) . It is therefore possible that in addition to regulating COX-2 protein expression, NO may also increase COX-2 enzymatic activity in the macula densa.
In summary, the present studies indicate that increases in macula densa/cTALH COX-2 expression are prevented by inhibition of nNOS. Furthermore, NO and/or cGMP will increase COX-2 expression in cultured cTALH cells. Therefore, in high-renin states, the necessary role for NO derived from macula densa nNOS in mediating renin production and release may be mediated in part by increasing COX-2 expression and activity.
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ACKNOWLEDGEMENTS |
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This work was supported by the Vanderbilt George O'Brien Kidney and Urologic Diseases Center (through National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-39261) and by funds from the Department of Veterans Affairs.
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. C. Harris, Div. of Nephrology, S 3223 MCN, Vanderbilt Univ. School of Medicine, Nashville, TN 37232 (E-mail: Ray.Harris{at}mcmail.vanderbilt.edu).
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. §1734 solely to indicate this fact.
Received 30 August 1999; accepted in final form 30 December 1999.
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