AJP - Renal Watch the video to see how APS reaches out to developing nations.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Renal Physiol 291: F891-F895, 2006. First published May 16, 2006; doi:10.1152/ajprenal.00512.2005
0363-6127/06 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
291/4/F891    most recent
00512.2005v2
00512.2005v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (14)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yang, T.
Right arrow Articles by Schnermann, J. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yang, T.
Right arrow Articles by Schnermann, J. B.

Nitric oxide stimulates COX-2 expression in cultured collecting duct cells through MAP kinases and superoxide but not cGMP

Tianxin Yang,1 Aihua Zhang,1 Anita Pasumarthy,2 Lihong Zhang,1 Zachary Warnock,1 and Jurgen B. Schnermann2

1Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah; and 2National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Submitted 21 December 2005 ; accepted in final form 12 May 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Collecting ducts are a major site of renal production and action of both prostaglandins and nitric oxide. Experiments were undertaken to examine whether nitric oxide regulates cyclooxygenase (COX)-2 expression and PGE2 release in cultured collecting duct cells. In mIMCD-K2 cells, sodium nitroprusside (SNP) in the 50- to 800-µM range induced a marked dose- and time-dependent increase in COX-2 protein levels, determined by immunoblotting, and the induction was detectable at 4 h. This was preceded by induction of COX-2 mRNA as determined by real-time-RT-PCR. The COX-2 induction was accompanied by a significant rise in PGE2 release as determined by enzyme immunoassay. S-nitroso-N-acetylpenicillamine (SNAP) had a similar stimulatory effect on COX-2 expression and PGE2 release. 8-bromo-cGMP (200 µM) had no effect on COX-2 expression. The SNP-stimulated COX-2 expression was not affected by the guanylyl cyclase inhibitor methylene blue or the protein kinase G inhibitor KT-5823 (2.0 µM). In contrast, the SNP-stimulated COX-2 expression was significantly reduced by either the Erk1/2 inhibitor PD-98059 or the P38 inhibitor SB-203580 and was abolished by combination of the two kinase inhibitors. The stimulation was also significantly blocked by the SOD mimetic tempol. Thus we conclude that NO stimulates COX-2 expression in collecting duct cells through mechanisms involving MAP kinase and superoxide, but not cGMP.

cyclooxygenase-2

IT IS WELL KNOWN that the renal medulla is enriched in nitric oxide (NO) synthetic capacity. Total nitric oxide synthase (NOS) enzymatic activity, determined by measurement of L-citrullin formation, is as much as 25 times greater in inner medulla than in cortex (22). Renal medullary interstitial NO concentration in anesthetized rats as determined by a microdialysis system coupled with an oxyhemoglobin-trapping technique is twice as much as in renal cortex (40). Immunoreactive eNOS, nNOS, and iNOS proteins are all predominantly present in renal inner medulla, and all three enzymes are induced by chronic salt loading (19). Using the renal medullary interstitial infusion technique, Mattson et al. (20, 21) selectively manipulated NO levels in the renal medulla and showed that acute infusion of N{omega}-nitro-L-arginine methyl ester (L-NAME) into rat renal medulla leads to a reduction of medullary blood flow (MBF) and urinary sodium excretion and that chronic medullary infusion of L-NAME over a period of 12 days significantly elevates arterial blood pressure. Thus renal medullary NO appears to participate in regulation of blood pressure, most likely through a local mechanism within the renal medulla. Similar to NO, prostaglandins (PGs) are also abundantly produced in renal medulla (3, 5). Constitutive expression of both COX-1 and COX-2 is detected at substantially higher levels in renal medulla than renal cortex (4, 9, 36, 37). Furthermore, Sprague-Dawley rats on a high-salt diet exhibit an over 10-fold increase in renal medullary COX-2 expression (37). Recent evidence suggests that renal medullary COX-2 plays an important role in stabilizing blood pressure during high-salt loading (38, 39), similar to renal medullary NOS. Given the general similarities between the effects of NO and PGs on renal sodium handling and blood pressure control, an interaction of the two systems is conceivable and might even be necessary for coordinating their antihypertensive actions in renal medulla. In support of this speculation, the induction of COX-2 expression in the rat renal medulla following chronic salt loading is inhibited by treatment with the nNOS inhibitor, 7-nitroindazole (7-NI), raising the possibility that renal medullary COX-2 expression might be under the control of NO (6). Therefore, we performed the present studies to determine whether NO exerts a direct stimulatory effect on COX-2 expression in a cell culture model of renal medullary origin and to investigate the intracellular signaling mechanisms underlying this interaction.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Materials. Cell culture media and serum were from Life Technologies, PD-98059 was purchased from New England Biological Lab (Beverly, MA), and SB-203580 from Upstate Biotechnology (Lake Placid, NY). SNP was from Sigma. Murine COX-2 polyclonal antibody, PGE2 enzyme immunoassay kit, and S-nitroso-N-acetylpenicillamine (SNAP) were from Cayman (Ann Arbor, MI).

Cell culture. mIMCD-K2 is an established inner medullary collecting duct cell line provided by Dr. Bruce Stanton (11). The cells were routinely propagated in an Opti medium, supplemented with 10% fetal bovine serum, 100 U/ml penicillin, and 100 µg/ml streptomycin.

Western blotting for COX-2. mIMCD-K2 cells were lysed and subsequently sonicated in PBS containing 1% Triton X-100, 250 µM PMSF, 2 mM EDTA, and 5 mM DTT (pH 7.5). Protein concentration was determined by Coomassie reagent. Forty micrograms of protein from whole cell lysates were denatured in boiling water for 10 min, separated by SDS-PAGE, and transferred onto nitrocellulose membranes. The blots were blocked overnight with 5% nonfat dry milk in TBS, followed by incubation for 1 h with rabbit antimurine polyclonal antiserum to COX-2 (Cayman, Ann Arbor, MI) at a dilution of 1:1,000. After being washed with TBS, blots were incubated with a goat anti-rabbit horseradish peroxidase-conjugated secondary antibody and visualized with ECL kits (Amersham).

Real-time RT-PCR. For real-time PCR, oligonucleotides were chosen by Primer Express 1.0 (PE Applied Biosystems) with probes positioned at an exon-intron junction (26). Sequences of oligonucleotides were COX-2 sense: 5'-CCCTGAAGCCGTACACATCA-3', antisense: 5'-TGTCACTGTAGAGGGCTTTCAATT-3', and probe: 5'-(FAM)TGCAGCCATTTCCTTCTCTCCTGTAAGTTCT-(TAMARA) (Accession#: BC052900). Real-time PCR amplification was performed using the TaqMan Universal PCR Master Mix and the ABI Prism 7900 Sequence Detection System (Applied Biosystems). Cycling conditions were 50°C for 2 min and 95°C for 10 min, followed by 40 repeats of 95°C for 0.15 min and 60°C for 1 min. Relative amounts of mRNA, normalized by beta-actin, were calculated from threshold cycle numbers (CT; i.e., 2–{Delta}{Delta}CT), according to the manufacturer's suggestions.

PGE2 enzyme immunoassay. PGE2 in the culture media were measured with an enzyme immunoassay kit (Cayman). The assay was performed according to the manufacturer's instruction. Briefly, 25 or 50 µl of the medium, along with a serial dilution of PGE2 standard samples, were mixed with appropriate amounts of acetylcholinesterase-labeled tracer and PGE2 antiserum and incubated at room temperature for 18 h. After the wells were emptied and rinsed with wash buffer, 200 µl of Ellman's reagent containing substrate for acetylcholinesterase were added. The enzyme reaction was carried out at room temperature for 1 h on a slow shaker. Plates were read at 415 nm.

cGMP assay. mIMCD-K2 cells grown in six-well plates were pretreated with 100 µM 3isobutyl-1-methylxanthine for 30 min and then treated for 30 min with SNP or SNAP at appropriate concentrations. After treatment, medium was removed and the cells were washed with PBS. Immediately after being washed, 0.3 ml of 0.1 M HCl were added. After 20-min incubation, the cells were scraped and transferred into a centrifuge tube and spun for 10 min at 1,000 g to pellet the cell debris. The supernatant was neutralized with 20 µl of 0.5 M Tris, acetylated, and used for determination of cGMP by enzyme immunoassay (Cayman Chemicals).

Statistical analysis. Values shown represent means ± SE. Statistical analysis was performed by ANOVA and Bonferroni tests with a P value <0.05 being considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Stimulation of COX-2 expression by NO donors. Figure 1A shows the dose-response relationship between SNP and COX-2 protein expression. As shown in Fig. 1A, SNP treatment induced a dose-dependent and robust increase in COX-2 protein expression that was detectable with 50 µM SNP and maximal with 400 µM SNP. SNP at 800 µM did not induce a further increase of COX-2 expression. To determine the time course of the COX-2 stimulation by SNP, mIMCD-K2 cells were treated with 100 µM SNP for various durations. As shown in Fig. 1B, the induction of COX-2 protein was observed 4 h after starting SNP treatment and gradually increased with time.


Figure 1
View larger version (16K):
[in this window]
[in a new window]
  		Fig. 1. Effect of the NO donor Na nitroprusside (SNP) on cyclooxygenase (COX)-2 protein expression. Confluent mIMCD-K2 cells were treated with SNP at various doses for 16 h (A, dose response) or at 100 µM for various durations (B, time course). COX-2 protein expression was determined by immunoblotting. Shown are representatives of 3 independent experiments.

 
To determine whether the COX-2 regulation by SNP can also be demonstrated at the mRNA level, we examined the effects of SNP on COX-2 mRNA expression in cultured mIMCD-K2 cells. The cells were treated with 100 µM SNP for various durations and COX-2 mRNA was determined by real-time RT-PCR and normalized by beta-actin. As shown in Fig. 2, SNP treatment induced a time-dependent and significant increase in COX-2 mRNA; the increase was detectable at 2 h and maximal at 16 h.


Figure 2
View larger version (7K):
[in this window]
[in a new window]
  		Fig. 2. Effect of SNP on COX-2 mRNA expression. Confluent mIMCD-K2 cells were treated with 100 µM SNP for the indicated period of time. COX-2 mRNA was determined by real-time RT-PCR and normalized by beta-actin. Values are means ± SE. *P < 0.05. #P < 0.01; n = 4 in each group.

 
Considering the concern about the specificity of SNP, we examined the effect of a second NO donor, SNAP. Confluent mIMCD-K2 cells were exposed to various concentrations of SNAP for 16 h and COX-2 protein was determined by immunoblotting. COX-2 protein expression was not obviously affected by 50 µM SNAP but was markedly induced by increasing doses at 200 and 400 µM (Fig. 3).


Figure 3
View larger version (11K):
[in this window]
[in a new window]
  		Fig. 3. Effect of the NO donor S-nitroso-N-acetylpenicillamine (SNAP) on COX-2 protein expression. Confluent mIMCD-K2 cells were treated with SNAP at various concentrations for 16 h. COX-2 protein expression was determined by immunoblotting. Shown are representatives of 3 independent experiments. Values are means ± SE. *P < 0.01 vs. vehicle; n = 3 each group.

 
To evaluate COX-2 enzyme activity, we determined the effects of NO donors on PGE2 production. Confluent mIMCD-K2 cells were treated with 100 µM SNP or 50 µM SNAP for 16 h and medium PGE2 concentration was determined by enzyme immunoassay. As shown in Fig. 4, both NO donors significantly increased PGE2 release with SNAP being more effective than SNP.


Figure 4
View larger version (6K):
[in this window]
[in a new window]
  		Fig. 4. Effect of the NO donors SNP and SNAP on PGE2 release. Confluent mIMCDK2 cells were exposed to 100 µM SNP or 50 µM SNAP for 16 h. Medium PGE2 concentration was determined by enzyme immunoassay. Values are means ± SE. *P < 0.05 vs. vehicle. #P < 0.01 vs. vehicle. SNP: n = 3; SNAP: n = 3; vehicle: n = 6.

 
Role of cGMP. There is abundant evidence to show that guanylyl cyclase activation and cGMP production constitute the major signaling pathway mediating NO actions. Indeed, cGMP has been shown to mediate the COX-2 induction in response to NO donors in a primary culture of cortical thick ascending limb cells (6). Therefore, we examined whether cGMP mediates NO stimulation of COX-2 expression in cultured mIMCD-K2 cells. Contrary to our expectation, blockade of the cGMP pathway with either the soluble guanylyl cyclase inhibitor methylene blue (MB; Fig. 5A) or the protein kinase G (PKG) inhibitor KT-5823 (Fig. 5B) had no effect on SNP-induced COX-2 expression. Furthermore, treatment with the cGMP agonist 8-bromo-cGMP was without an effect on COX-2 expression (Fig. 5A). To rule out the possibility that this phenomenon might be the result of deficiency of the cGMP system in mIMCD-K2 cells, we measured cGMP content in these cells following treatments with the two NO donors. As shown in Fig. 5C, treatments for 30 min with SNP and SNAP both were able to elevate intracellular cGMP levels in mIMCD-K2 cells, suggesting an intact cGMP system in these cells.


Figure 5
View larger version (12K):
[in this window]
[in a new window]
  		Fig. 5. SNP increases COX-2 expression independently of cGMP. Confluent mIMCD-K2 cells were treated for 16 h with 200 µM 8-bromo-cGMP or 100 µM SNP in the presence or absence of 100 µM methylene blue (MB; A) or 0.2 µM KT-5823 (B). COX-2 protein expression was determined by immunoblotting. Production of cGMP in response to SNP and SNAP at the indicated doses was determined by enzyme immunoassay (C). Values are means ± SE. Shown are representatives from 2–3 experiments. C: *P < 0.05 vs. vehicle. #P < 0.01 vs. vehicle; n = 3 in each group.

 
Role of MAP kinases. NO has previously been shown in other cell types to activate ERK and p38 (10, 30). Therefore, we examined the role of MAP kinases in NO stimulation of COX-2 expression in cultured mIMCD-K2 cells. As shown in Fig. 6, the SNP-induced COX-2 expression was significantly reduced by either the ERK1/2 inhibitor PD-98059 or the p38 inhibitor SB-203580 and was completely blocked by the combined treatment with the two compounds.


Figure 6
View larger version (14K):
[in this window]
[in a new window]
  		Fig. 6. SNP increases COX-2 expression via ERK and p38. mIMCD-K2 cells (3 wells in each group) were treated for 16 h with 100 µM SNP in the presence or absence of 50 µM PD-98059 or 5 µM SB-203580. PD, PD-98059; SB, SB-203580. Shown are representatives of 2–3 experiments. B: ^P < 0.01 vs. control. Values are means ± SE. *P < 0.05 vs. SNP alone. #P < 0.01 vs. SNP alone.

 
Role of superoxide. There is evidence that peroxynitrite produced by the reaction of NO with superoxide can stimulate COX-2 expression (23) and activate MAP kinase (27). Therefore, we examined the possibility that NO stimulation of COX-2 expression may include the participation of superoxide. As shown in Fig. 7, tempol treatment effectively blocked the COX-2 induction by SNP.


Figure 7
View larger version (15K):
[in this window]
[in a new window]
  		Fig. 7. Effect of tempol on SNP-induced COX-2 expression. Confluent mIMCD-K2 cells (3 wells in each group) were treated for 16 h with 100 µM SNP in the presence or absence of 5.0 mM tempol. Shown are representatives of 2–3 experiments. B: Values are means ± SE. *P < 0.01 vs. control. #P < 0.05 vs. SNP alone.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The present study was undertaken to examine the role and mechanism of NO in regulation of COX-2 expression in cultured renal medullary epithelial cells. Our results indicate that the NO donor SNP has a stimulatory effect on COX-2 mRNA and protein expression, paralleled by stimulation of PGE2 release. Although cGMP is the major signaling pathway of NO, blockade of the cGMP pathway by the guanylyl cyclase inhibitor MB or the PKG inhibitor KT-5823 did not affect SNP-induced COX-2 expression, and activation of the cGMP pathway using 8-bromo-cGMP was also without an effect. In contrast, the COX-2 induction by SNP was effectively blocked by the MAP kinase inhibitors PD-98059 and SB-230580, as well as the superoxide scavenger tempol, suggesting involvement of ERK 1/2 and p38, as well as superoxide.

It is well known that within the kidney the renal medulla has the greatest capacity of NO and PG synthesis. This is in agreement with the fact that COX-2 and all three isoforms of NOS are predominantly expressed in renal medulla. Furthermore, COX-2 and NOS are stimulated in parallel by a high-salt diet, and both pathways play a similar role in stabilizing blood pressure during high-salt intake (12, 18, 19, 21). In this regard, early studies by Mattson et al. (21) document that acute infusion of L-NAME into rat renal medulla leads to a reduction of MBF and urinary sodium excretion, whereas chronic infusion of the compound into the renal medulla over a period of 12 days significantly elevates arterial blood pressure (20). Similarly, recent studies show that chronic infusion of the COX-2 inhibitor NS-398 into the rat renal medulla induced salt-sensitive hypertension (38, 39). If operation of a renal medullary depressor natriuretic mechanism relies on the action of both NO and PGs, the question arises as to how the actions of these two autocrine/paracrine factors are coordinated. Induction of COX-2 expression in the rat renal medulla has been reported to be inhibited by chronic treatment with the nNOS inhibitor, 7-NI (6), suggesting a possible dependence of renal medullary COX-2 expression on NO. Because confounding factors such as changes in renal MBF and blood pressure associated with NOS inhibition in the renal medulla could have an impact on COX-2, it seemed necessary to use an in vitro cell culture model to determine the direct effect of NO on COX-2 expression and to investigate the underlying mechanisms. The present study provides clear-cut evidence that NO exerts a direct stimulatory effect on COX-2 expression in cultured renal medullary cells. This finding supports the idea that renal medullary COX-2 expression is under the control of NO, and this may be especially important when sodium balance changes.

Subsequent experiments were undertaken to elucidate the signaling pathway involved in NO regulation of COX-2 expression. cGMP generated by NO-mediated activation of cytoplasmic soluble guanylyl cyclase (sGC) mediates many of the known effects of NO (13, 14, 17). The primary target of cGMP is cGMP-dependent PKG through which cGMP induces phosphorylation of a number of transcription factors, leading to activation of gene transcription (8, 29, 31). However, contrary to our expectation, neither inhibition of guanylyl cyclase or PKG nor activation of cGMP signaling with 8-bromo-cGMP had a measurable effect on COX-2 expression. The cGMP system in mIMCD-K2 cells appeared intact as intracellular cGMP levels increased following treatment with NO donors. These findings strongly argue against an involvement of cGMP in NO-induced signaling in cultured mIMCD-K2 cells. In apparent contradiction to our observations are results from a previous study documenting cGMP mediation of NO stimulation of COX-2 expression in cultured cortical thick ascending limb cells (6). The difference in the requirement of cGMP for the NO signaling in cortical thick ascending limb cells and medullary collecting duct cells may indicate a cell type-specific phenomenon. Indeed, there are several fundamental differences between renal cortical and medullary cells. For example, in the former, a parallel induction of COX-2 and nNOS results from a low-salt diet (2, 9, 25, 32, 33), while in medullary cells the same result is achieved by a high-salt diet (19, 37).

NO has previously been shown in other cell types to activate ERK and p38 (10, 30). Therefore, we examined the role of MAP kinases in NO stimulation of COX-2 expression in cultured mIMCD-K2 cells. We found that the COX-2 stimulation by NO was significantly reduced by the use of either PD-98059 or SB-203580 and was completely abolished by combination of the two compounds. This finding is compatible with our previous studies documenting a significant role of MAP kinases in mediating COX-2 induction in response to hypertonicity (34) and low chloride (35). Taken together, this evidence strongly suggests that MAP kinase activation is a common terminal pathway of COX-2 induction, at least in renal cells.

NO and O2–· can react to produce peroxynitrite (ONOO–), which is a key oxidant and nitrating molecule (1, 15, 24). The amount of ONOO– depends on the competition for O2 between superoxide dismutase (SOD) and NO. Because the NO/O2–· reaction occurs at a rate of 2 x 1010 M–1/s–1 (16), it is thought that NO effectively competes with SOD for scavenging O2–·. Emerging evidence suggests that ONOO– functions as an active signaling molecule likely owing to its nitrating properties (28). Our studies show that NO stimulation of COX-2 expression was remarkably blocked by the superoxide scavenger tempol, indicating a requirement of O2–·. We speculate that ONOO–, the oxidant product of the NO/O2–· reaction might be responsible for induction of COX-2 expression in cultured mIMCD-K2 cells. Peroxynitrite has been shown to induce COX-2 expression in rheumatoid synovium (23) and human endothelial cells (7). In addition, ONOO–can activate and inhibit COX-1 and -2 activities, with low concentrations of ONOO– increasing COX activities, and high concentration of ONOO– decreasing them (7).

In summary, our results show that the NO donor SNP stimulates COX-2 expression in cultured renal collecting cells and that the signaling pathway involves MAP kinases and superoxide, but not cGMP. This study contributes to a better understanding of the interaction between NO and PGs in the renal medulla.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by National Institutes of Health Grants RO-1-HL-079453, RO-1-DK-066592, and KO-1-DK-064981 and by intramural funds from National Institute of Diabetes and Digestive and Kidney Diseases.


   FOOTNOTES
 

Address for reprint requests and other correspondence: T. Yang, Univ. of Utah and VA Medical Center, Bldg 2, Research Service (151 E), 500 Foothill Drive, Salt Lake City, UT 84148 (e-mail: tianxin.yang{at}hsc.utah.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. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Abe K, Pan LH, Watanabe M, Konno H, Kato T, and Itoyama Y. Upregulation of protein-tyrosine nitration in the anterior horn cells of amyotrophic lateral sclerosis. Neurol Res 19: 124–128, 1997.[Web of Science][Medline]
  2. Bosse HM, Bohm R, Resch S, and Bachmann S. Parallel regulation of constitutive NO synthase and renin at JGA of rat kidney under various stimuli. Am J Physiol Renal Fluid Electrolyte Physiol 269: F793–F805, 1995.[Abstract/Free Full Text]
  3. Breyer MD and Breyer RM. Prostaglandin E receptors and the kidney. Am J Physiol Renal Physiol 279: F12–F23, 2000.[Abstract/Free Full Text]
  4. Breyer MD and Harris RC. Cyclooxygenase 2 and the kidney. Curr Opin Nephrol Hypertens 10: 89–98, 2001.[Web of Science][Medline]
  5. Breyer MD, Jacobson HR, and Breyer RM. Functional and molecular aspects of renal prostaglandin receptors. J Am Soc Nephrol 7: 8–17, 1996.[Abstract]
  6. Cheng HF, Wang JL, Zhang MZ, McKanna JA, and Harris RC. Nitric oxide regulates renal cortical cyclooxygenase-2 expression. Am J Physiol Renal Physiol 279: F122–F129, 2000.[Abstract/Free Full Text]
  7. Eligini S, Habib A, Lebret M, Creminon C, Levy-Toledano S, and Maclouf J. Induction of cyclo-oxygenase-2 in human endothelial cells by SIN-1 in the absence of prostaglandin production. Br J Pharmacol 133: 1163–1171, 2001.[CrossRef][Web of Science][Medline]
  8. Feil R, Lohmann SM, de Jonge H, Walter U, and Hofmann F. Cyclic GMP-dependent protein kinases and the cardiovascular system: insights from genetically modified mice. Circ Res 93: 907–916, 2003.[Abstract/Free Full Text]
  9. Harris RC, McKanna JA, Akai Y, Jacobson HR, Dubois RN, and Breyer MD. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest 94: 2504–2510, 1994.[Web of Science][Medline]
  10. Jovanovic DV, Mineau F, Notoya K, Reboul P, Martel-Pelletier J, and Pelletier JP. Nitric oxide induced cell death in human osteoarthritic synoviocytes is mediated by tyrosine kinase activation and hydrogen peroxide and/or superoxide formation. J Rheumatol 29: 2165–2175, 2002.[Abstract/Free Full Text]
  11. Kizer NL, Lewis B, and Stanton BA. Electrogenic sodium absorption and chloride secretion by an inner medullary collecting duct cell line (mIMCD-K2). Am J Physiol Renal Fluid Electrolyte Physiol 268: F347–F355, 1995.[Abstract/Free Full Text]
  12. Kone BC. Localization and regulation of nitric oxide synthase isoforms in the kidney. Semin Nephrol 19: 230–241, 1999.[Web of Science][Medline]
  13. Kone BC. Molecular biology of natriuretic peptides and nitric oxide synthases. Cardiovasc Res 51: 429–441, 2001.[Abstract/Free Full Text]
  14. Kone BC. Nitric oxide synthesis in the kidney: isoforms, biosynthesis, and functions in health. Semin Nephrol 24: 299–315, 2004.[CrossRef][Web of Science][Medline]
  15. Kooy NW, Lewis SJ, Royall JA, Ye YZ, Kelly DR, and Beckman JS. Extensive tyrosine nitration in human myocardial inflammation: evidence for the presence of peroxynitrite. Crit Care Med 25: 812–819, 1997.[CrossRef][Web of Science][Medline]
  16. Koppenol WH. The basic chemistry of nitrogen monoxide and peroxynitrite. Free Radic Biol Med 25: 385–391, 1998.[CrossRef][Web of Science][Medline]
  17. Kurtz A and Wagner C. Role of nitric oxide in the control of renin secretion. Am J Physiol Renal Physiol 275: F849–F862, 1998.[Abstract/Free Full Text]
  18. Mattson DL and Bellehumeur TG. Neural nitric oxide synthase in the renal medulla and blood pressure regulation. Hypertension 28: 297–303, 1996.[Abstract/Free Full Text]
  19. Mattson DL and Higgins DJ. Influence of dietary sodium intake on renal medullary nitric oxide synthase. Hypertension 27: 688–692, 1996.[Abstract/Free Full Text]
  20. Mattson DL, Lu S, Nakanishi K, Papanek PE, and Cowley AW Jr. Effect of chronic renal medullary nitric oxide inhibition on blood pressure. Am J Physiol Heart Circ Physiol 266: H1918–H1926, 1994.[Abstract/Free Full Text]
  21. Mattson DL, Roman RJ, and Cowley AW Jr. Role of nitric oxide in renal papillary blood flow and sodium excretion. Hypertension 19: 766–769, 1992.[Abstract/Free Full Text]
  22. Mattson DL and Wu F. Control of arterial blood pressure and renal sodium excretion by nitric oxide synthase in the renal medulla. Acta Physiol Scand 168: 149–154, 2000.[CrossRef][Web of Science][Medline]
  23. Migita K, Yamasaki S, Ida H, Kita M, Hida A, Shibatomi K, Kawakami A, Aoyagi T, and Eguchi K. The role of peroxynitrite in cyclooxygenase-2 expression of rheumatoid synovium. Clin Exp Rheumatol 20: 59–62, 2002.[Web of Science][Medline]
  24. Moriel P and Abdalla DS. Nitrotyrosine bound to beta-VLDL-apoproteins: a biomarker of peroxynitrite formation in experimental atherosclerosis. Biochem Biophys Res Commun 232: 332–335, 1997.[CrossRef][Web of Science][Medline]
  25. Mundel P, Bachmann S, Bader M, Fischer A, Kummer W, Mayer B, and Kriz W. Expression of nitric oxide synthase in kidney macula densa cells. Kidney Int 42: 1017–1019, 1992.[Web of Science][Medline]
  26. Paliege A, Mizel D, Medina C, Pasumarthy A, Huang YG, Bachmann S, Briggs JP, Schnermann JB, and Yang T. Inhibition of nNOS expression in the macula densa by COX-2-derived prostaglandin E2. Am J Physiol Renal Physiol 287: F152–F159, 2004.[Abstract/Free Full Text]
  27. Pesse B, Levrand S, Feihl F, Waeber B, Gavillet B, Pacher P, and Liaudet L. Peroxynitrite activates ERK via Raf-1 and MEK, independently from EGF receptor and p21Ras in H9C2 cardiomyocytes. J Mol Cell Cardiol 38: 765775, 2005.
  28. Petruzzelli S, Puntoni R, Mimotti P, Pulera N, Baliva F, Fornai E, and Giuntini C. Plasma 3-nitrotyrosine in cigarette smokers. Am J Respir Crit Care Med 156: 1902–1907, 1997.[Abstract/Free Full Text]
  29. Pilz RB and Casteel DE. Regulation of gene expression by cyclic GMP. Circ Res 93: 1034–1046, 2003.[Abstract/Free Full Text]
  30. Rakhit RD, Kabir AN, Mockridge JW, Saurin A, and Marber MS. Role of G proteins and modulation of p38 MAPK activation in the protection by nitric oxide against ischemia-reoxygenation injury. Biochem Biophys Res Commun 286: 995–1002, 2001.[CrossRef][Web of Science][Medline]
  31. Ruth P. Cyclic GMP-dependent protein kinases: understanding in vivo functions by gene targeting. Pharmacol Ther 82: 355–372, 1999.[CrossRef][Web of Science][Medline]
  32. Schricker K, Hamann M, and Kurtz A. Nitric oxide and prostaglandins are involved in the macula densa control of the renin system. Am J Physiol Renal Fluid Electrolyte Physiol 269: F825–F830, 1995.[Abstract/Free Full Text]
  33. Singh I, Grams M, Wang WH, Yang T, Killen P, Smart A, Schnermann J, and Briggs JP. Coordinate regulation of renal expression of nitric oxide synthase, renin, and angiotensinogen mRNA by dietary salt. Am J Physiol Renal Fluid Electrolyte Physiol 270: F1027–F1037, 1996.[Abstract/Free Full Text]
  34. Yang T, Huang Y, Heasley LE, Berl T, Schnermann JB, and Briggs JP. MAPK mediation of hypertonicity-stimulated cyclooxygenase-2 expression in renal medullary collecting duct cells. J Biol Chem 275: 23281–23286, 2000.[Abstract/Free Full Text]
  35. Yang T, Park JM, Arend L, Huang Y, Topaloglu R, Pasumarthy A, Praetorius H, Spring K, Briggs JP, and Schnermann J. Low chloride stimulation of prostaglandin E2 release and cyclooxygenase-2 expression in a mouse macula densa cell line. J Biol Chem 275: 37922–37929, 2000.[Abstract/Free Full Text]
  36. Yang T, Schnermann JB, and Briggs JP. Regulation of cyclooxygenase2 expression in renal medulla by tonicity in vivo and in vitro. Am J Physiol Renal Physiol 277: F1–F9, 1999.[Abstract/Free Full Text]
  37. Yang T, Singh I, Pham H, Sun D, Smart A, Schnermann JB, and Briggs JP. Regulation of cyclooxygenase expression in the kidney by dietary salt intake. Am J Physiol Renal Physiol 274: F481–F489, 1998.[Abstract/Free Full Text]
  38. Ye W, Zhang H, Hillas E, Kohan DE, Miller RL, Nelson RD, Honeggar M, and Yang T. Expression and function of COX isoforms in the renal medulla: evidence for regulation of salt sensitivity and blood pressure. Am J Physiol Renal Physiol 00: F000–F111, 2005.
  39. Zewde T and Mattson DL. Inhibition of cyclooxygenase-2 in the rat renal medulla leads to sodium-sensitive hypertension. Hypertension 44: 424–428, 2004.[Abstract/Free Full Text]
  40. Zou AP and Cowley AW Jr. Nitric oxide in renal cortex and medulla. An in vivo microdialysis study. Hypertension 29: 194–198, 1997.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 FASEB J.Home page
M. M. Ndengele, S. Cuzzocrea, E. Esposito, E. Mazzon, R. Di Paola, G. M. Matuschak, and D. Salvemini
Cyclooxygenases 1 and 2 contribute to peroxynitrite-mediated inflammatory pain hypersensitivity
FASEB J, September 1, 2008; 22(9): 3154 - 3164.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
P. Abidi, H. Zhang, S. M Zaidi, W.-J. Shen, S. Leers-Sucheta, Y. Cortez, J. Han, and S. Azhar
Oxidative stress-induced inhibition of adrenal steroidogenesis requires participation of p38 mitogen-activated protein kinase signaling pathway
J. Endocrinol., July 1, 2008; 198(1): 193 - 207.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
C. Kuper, H. Bartels, M.-L. Fraek, F. X. Beck, and W. Neuhofer
Ectodomain shedding of pro-TGF-{alpha} is required for COX-2 induction and cell survival in renal medullary cells exposed to osmotic stress
Am J Physiol Cell Physiol, December 1, 2007; 293(6): C1971 - C1982.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
291/4/F891    most recent
00512.2005v2
00512.2005v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (14)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yang, T.
Right arrow Articles by Schnermann, J. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yang, T.
Right arrow Articles by Schnermann, J. B.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2006 by the American Physiological Society.