(Hypertension. 1997;29:297.)
© 1997 American Heart Association, Inc.
Arthur C. Corcoran Memorial Lecture |
Cyclooxygenase-2 Mediates Increased Renal Renin Content Induced by Low-Sodium Diet
From the Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Mich, and Cardiovascular Research Center (P.L.H., M.C.F.), Massachusetts General Hospital, Charlestown.
Correspondence to Oscar A. Carretero, MD, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsAnimalsRenal Renin ContentRNA Isolation and AnalysisDetermination of Systolic Blood...Statistical AnalysisProtocolsResultsDiscussionReferences |
|---|
We hypothesized that neuronal nitric oxide synthase and cyclooxygenase-2, which both exist in the renal cortex, predominantly in the macula densa, play a role in the control of renal renin tissue content. We studied the possible role of neuronal nitric oxide synthase in regulating renal renin content by using mice in which the neuronal nitric oxide synthase gene has been disrupted (nNOS -/-) compared with its two progenitor strains, the 129/SvEv and the C57BL/6, to determine if the absence of neuronal nitric oxide synthase would result in decreased renal renin content or blunt the increase observed during low sodium intake. Renal renin content from cortical slices was determined in adult mice from all three strains maintained on a normal sodium diet. Renal renin content was significantly reduced in the nNOS -/- mice compared with the 129/SvEv and the C57BL/6 mice (3.11±0.23 versus 5.66±0.50 and 7.55±1.17 µg angiotensin I/mg dry weight, respectively; P<.005), suggesting that neuronal nitric oxide synthase may stimulate renal renin content under basal conditions. Neither selective pharmacological inhibition of neuronal nitric oxide synthase using 7-nitroin-dazole or disruption of the neuronal nitric oxide synthase gene affected the increase in renal renin content observed during dietary sodium restriction. The influence of cyclooxygenase-2 on renal renin content through a macula densa-mediated pathway was studied using a selective cyclooxygenase-2 inhibitor, NS398, in 129/SvEv mice. A low-sodium diet increased renal renin content from 6.97±0.52 to 11.59±0.79 µg angiotensin I/mg dry weight (P<.005); but this increase was blocked by NS398. In addition, treatment with NS398 reduced renin mRNA in response to a low-sodium diet. Thus, increased renal renin content in response to dietary sodium restriction appears to require the induction of cyclooxygenase-2, while neuronal nitric oxide synthase appears to affect basal but not stimulated renal renin content.
Key Words: renin • cyclooxygenase • nitric oxide • mice
Abbreviations: Ang = angiotensin • COX = cyclooxygenase • eNOS = endothelial nitric oxide synthase • L-NAME = NG-nitro-L-arginine methyl ester • L-NMMA = NG-monomethyl-L-arginine • MEM = minimal essential medium • nNOS = neuronal nitric oxide synthase • NO = nitric oxide • NOS = nitric oxide synthase • PG = prostaglandin • PRC = plasma renin concentration
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsAnimalsRenal Renin ContentRNA Isolation and AnalysisDetermination of Systolic Blood...Statistical AnalysisProtocolsResultsDiscussionReferences |
|---|
The mechanism by which a decreased sodium chloride delivery to the macula densa is sensed, resulting in increased renin secretion by the juxtaglomerular cells, remains unknown. However, since humoral factors are known to affect renin, attention has focused on NO, which is localized in a prime position to affect renin secretion and which has been implicated in renin regulation by both in vivo and in vitro studies.1–4 The enzyme NOS acts on its substrate L-arginine to produce NO. It exists in three known isoforms that are discreetly localized throughout the nephron. Briggs et al5 demonstrated that the macula densa is rich in nNOS, whereas nNOS does not appear to be expressed in the glomerulus, mesangium, or juxtaglomerular cells. In contrast, eNOS is expressed in the glomerulus and blood vessels.6 Singh et al7 have also shown that the activity of nNOS in the macula densa is increased by a low-salt diet, whereas it does not affect eNOS. Therefore, NO produced in the macula densa could exert an effect directly on the adjoining juxtaglomerular cells or indirectly via other as yet unrecognized intermediates.
The role of NO in the regulation of renin is controversial. There have been studies showing that NO both stimulates and inhibits renin release. For example, studies using isolated juxtaglomerular cells in culture describe that NO inhibits renin release via its inhibitory second messenger, cGMP.8 Beierwaltes and Carretero9 have also reported that the NO donor, sodium nitroprusside, inhibits basal renin release from rat kidney cortical slices and that the nitric oxide synthesis inhibitor L-NMMA has the opposite effect. In contrast, other investigators have demonstrated stimulatory effects of NO on renin release. Scholz and Kurtz10 reported that in the isolated kidney preparation, NO stimulated renin secretion, a result that is similar to that described in conscious dogs.2 Studies by He et al11 using the isolated perfused juxtaglomerular apparatus also describe increased renin when L-arginine was added directly to the luminal side of the macula densa and a reduction when the NOS inhibitor L-NAME was applied. However, the same authors also reported that application of an NO donor to the bath decreased renin secretion. Taken altogether, these results imply that renin secretion may be influenced differently by NO originating from at least two sources, tubular or macula densa derived versus that derived from the endothelial cells of the afferent arteriole.
Although most investigators agree that the direct inhibitory effect of NO on renin release is mediated by cGMP,12 a contradictory pathway by which NO could stimulate renin remains unclear. However, other autacoids, such as PGs, are known to stimulate renin.13 Prostacyclin (PGI2) is predominantly derived from the arteriolar endothelial cells and directly stimulates renin release from the juxtaglomerular cells, presumably through its second messenger, cAMP.14 On the other hand, PGE2 stimulation of renin requires the presence of an intact macula densa,15 and PGs have been implicated in the feedback regulation of renin release. Similar to NOS, the COX enzyme that releases PGs from arachidonic acid exists in both a constitutive form,16 COX-1, and inducible form,17 COX-2. Both isoforms have been localized in the kidney. Like nNOS in the renal cortex, COX-2 has been localized predominantly in the macula densa, and Harris et al18 reported induction of COX-2 in the macula densa of rat kidney after dietary sodium restriction. This suggests a role for COX-2 in the regulation of salt, volume, and blood pressure homeostasis. Dietary sodium restriction increases both nNOS activity and induces COX-2 in the macula densa. Because of these similarities and because NO increases COX activity in other cell types,19 we hypothesized that an increase in nNOS, driven by dietary sodium restriction, is coupled to the induction of COX-2, resulting in the increase of renin through products of arachidonic acid metabolism.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsAnimalsRenal Renin ContentRNA Isolation and AnalysisDetermination of Systolic Blood...Statistical AnalysisProtocolsResultsDiscussionReferences |
|---|
Previous studies looking at nNOS and renin have been compromised by the lack of specificity in their pharmacological tools. However, the development of selective inhibitors of nNOS as well as the development of transgenic mice that have had the gene encoding for nNOS "disrupted" (nNOS -/- mice) provide more specific experimental tools.20 Thus, the use of these mice in this study and comparisons with both progenitor strains or with mice that have been treated with 7-NI, a selective inhibitor of nNOS,21 have allowed for an assessment of the role of macula densa-derived NO in the regulation of renin. Likewise, the formulation of specific COX-2 inhibitors has enabled us to examine the role of this enzyme in the macula densa mechanism for the regulation of renin.
This study examines renal renin content in nNOS -/- mice and its progenitor strains, the 129/SvEv and C57BL/6 mice. Unlike humans or rats, certain strains of mice have significant extrarenal renin from sites such as the submandibular gland, which may affect plasma renin concentrations.22 Hence, plasma renin concentrations in mice do not accurately reflect renin release specifically from the kidney. Mouse plasma renin values are subject to wide variability and do not respond to stimuli known to stimulate renin, eg, a low-salt diet. Our own studies have found high circulating plasma renin concentrations that were not different between 129/SvEv control mice (0.35±0.09 µgAng I·mL-1·h-1) and nNOS -/- mice (0.47±0.19 µg Ang I·mL-1·h-1). Thus, we have focused our study on renal renin content. We examined the effect of selective nNOS inhibition or nNOS gene disruption on renal renin content in response to a chronic low-salt diet, a stimulus known to stimulate renin through the macula densa. Finally, we examined the effect of COX-2 inhibition on the stimulation of renal renin content exerted by dietary sodium restriction.
|
Animals |
|---|
|
TopAbstractIntroductionMethodsAnimalsRenal Renin ContentRNA Isolation and AnalysisDetermination of Systolic Blood...Statistical AnalysisProtocolsResultsDiscussionReferences |
|---|
Experiments were performed using 129/SvEv, C57BL/6, and nNOS -/- mice. 129/SvEv and C57BL/6 mice were obtained from Taconic Farms (Germantown, NY) and nNOS -/- mice breeding pairs were provided by Drs Paul Huang and Mark Fish-man, Massachusetts General Hospital. These breeding pairs were generated from initial nNOS +/- F1 hybrids of C57BL/6 and 129/ Sv strains from which nNOS -/- offspring were obtained. They were subsequently interbred and maintained as obligate nNOS -/-mice for an unspecified number of generations. From these parents, homozygous nNOS -/- mice were bred in our own animal facility. Unless otherwise specified, all mice were maintained on a normal diet and were allowed access to water ad libitum. All experiments were carried out within the guidelines of the Institutional Animal Care and Use Committee of Henry Ford Hospital.
|
Renal Renin Content |
|---|
|
TopAbstractIntroductionMethodsAnimalsRenal Renin ContentRNA Isolation and AnalysisDetermination of Systolic Blood...Statistical AnalysisProtocolsResultsDiscussionReferences |
|---|
Renal renin content was determined by measuring the Ang I-generating capacity of homogenized renal cortical slices. Briefly, mice were anesthetized with sodium pentobarbital and their kidneys removed and placed immediately into ice-cold MEM (composition: 125 mmol/L NaCl, 19 mmol/L NaHCO3, 4 mmol/L KCl, 2.6 mmol/L CaCl2, 1.2 mmol/L NaH2PO4, 0.8 mmol/L MgSO4, 2 g/mL glucose; oxygenated to pH 7.4). The kidneys were rinsed in cold MEM and decapsulated, and one slice of superficial cortex was cut from each lateral surface using a Stadie-Riggs microtome. The two slices were blotted and weighed, homogenized in 1 mL buffer, and centrifuged at 2000 rpm for 20 minutes, and the supernatant was removed. For the generation of Ang I, 1:50 dilutions of the supernatant were made with MEM buffer, then 5-µL aliquots were taken and diluted again with 95 µL buffer. A 200-µL aliquot of a peptidase inhibitor cocktail (3% PMSF in methanol and 3.8% EDTA, pH 6.5) and 200 µL sheep angiotensinogen (500 ng) were then added, and the total mixture was incubated at 37°C for 30 minutes. To terminate the reaction, samples were placed on ice and 500 µL of 0.015 mol/L HCl was added. Tubes were boiled for 10 minutes and centrifuged at 2000 rpm for 20 minutes and the supernatants removed. Generated Ang I was measured by radioimmunoassay using methods previously published,23 and the results are expressed as micrograms of Ang I per milligram of dry weight per hour. Dry weight was calculated to be 14% of wet weight based on data obtained from previous experiments. Experiments designed to test the validity of this assay have demonstrated that less than 10% of the substrate is consumed under these conditions and have shown linearity of product generated with time. Nephrectomized sheep angiotensinogen was used as a substrate since it is known that mouse renin can release Ang I from this heterologous substrate.24
|
RNA Isolation and Analysis |
|---|
|
TopAbstractIntroductionMethodsAnimalsRenal Renin ContentRNA Isolation and AnalysisDetermination of Systolic Blood...Statistical AnalysisProtocolsResultsDiscussionReferences |
|---|
Expression of renin mRNA was determined from two additional groups of mice that had been placed on either a low-salt diet alone or a low-salt diet plus the COX-2 inhibitor. At the end of the experimental period, the kidneys were removed and placed into ice-cold phosphate-buffered saline. Two cortical slices were taken from each surface of the kidney, and the four slices from each mouse were used for the preparation of total RNA. Briefly, slices were homogenized in 1 mL RNA Stat (Tel-Test B) and after ethanol precipitation, RNA pellets were resuspended in 25 µL water. Twenty micrograms total RNA was denatured with dimethyl sulfoxide and glyoxal, separated on a 1% agarose gel, and blotted onto a nylon membrane (Gibco BRL). Renin mRNA was detected using a 1400-bp cDNA probe (kindly provided by Dr K. Lynch, University of Virginia) and normalized to 18S as a loading control. Hybridization was performed at 60°C using renin cDNA as a probe and at 42°C using an 18S oligonucleotide probe. Washing conditions are as described: 2x SSC, two times for 15 minutes at room temperature; 0.1x SSC, two times for 15 minutes at room temperature; 0.1x SSC, two times for 15 minutes at 60°C. Nylon filters were exposed to Kodak X-Omat AR film for 1 to 5 days. Densitometry (model GS-670, Bio-Rad) was used to quantitate mRNA and was normalized to 18S as a loading control. Light exposures were used for densitometry whereas darker exposures were used to make Fig 4.
|
|
Determination of Systolic Blood Pressure |
|---|
|
TopAbstractIntroductionMethodsAnimalsRenal Renin ContentRNA Isolation and AnalysisDetermination of Systolic Blood...Statistical AnalysisProtocolsResultsDiscussionReferences |
|---|
Systolic blood pressure was determined using a newly designed and validated noninvasive computerized tail-cuff system (BP-2000, Visitech Systems). Mice were first trained for 7 days, then measurements were recorded daily on 5 consecutive days. Each session included two sets of 10 measurements for a total of 100. In order to include each set of measurements for an individual mouse, the computer had to successfully identify a blood pressure in at least 6 of the 10 trials within a set.
|
Statistical Analysis |
|---|
|
TopAbstractIntroductionMethodsAnimalsRenal Renin ContentRNA Isolation and AnalysisDetermination of Systolic Blood...Statistical AnalysisProtocolsResultsDiscussionReferences |
|---|
To examine differences between the three strains of mice, the data were transformed using natural logarithms because of unequal variances. Dunnett's test was then applied to the transformed data and values of P<.05 were considered significant. For all other analyses, log transformation was also applied and data were analyzed by Student's t test with a value of P<.05 considered significant.
|
Protocols |
|---|
|
TopAbstractIntroductionMethodsAnimalsRenal Renin ContentRNA Isolation and AnalysisDetermination of Systolic Blood...Statistical AnalysisProtocolsResultsDiscussionReferences |
|---|
Comparison of Renal Renin Content in nNOS -/-Mice With C57BL/6 and 129/SvEv Mice
Since the nNOS -/- mouse is derived from two different progenitor strains, the 129/SvEv and the C57BL/6 mice, both of these strains were initially used as controls. Male mice from all three strains weighing 25 to 30 g were maintained on a normal sodium diet and were allowed access to water ad libitum. Mice were anesthetized with sodium pentobarbital and their kidneys removed for determination of renal renin content. The number of mice studied for each strain was as follows: 129/SvEv, n=11; C57BL/6, n=10; and nNOS -/-, n=9. Because blood pressure and the renin-angiotensin system are so closely interdependent, systolic blood pressures were also measured from all three strains of mice by the tail-cuff method.
Effect of Dietary Sodium Restriction on Renal Renin Content in Mice Deficient in nNOS
To determine whether genetic disruption of the nNOS gene altered the increase in renin content by dietary sodium restriction, experiments were performed using nNOS -/- mice on a low-sodium diet. Male nNOS -/- mice were placed on a diet containing 0.02% sodium for 14 days (n=16), then the kidneys were removed and cortical slices harvested to determine renal renin content. These values were compared with those from nNOS -/-mice maintained on a normal sodium diet (n=9).
Effect of Chronic 7-NI on Renal Renin Content Stimulated by Dietary Sodium Restriction
We examined the effect of chronic treatment with the selective nNOS inhibitor 7-NI on renin content of 129/SvEv mice. Male 129/SvEv mice were placed on either a 0.02% low-sodium diet or a 0.4% normal sodium diet (Purina Mills) for 14 days. Mice from each group received either 7-NI (20 mg·kg-1·d-1 IP) or peanut oil vehicle during this period. On the last day, the mice were euthanatized and the kidneys removed to obtain cortical slices and determine renal renin content. The number of mice in each group is given in parentheses after each group description: low sodium plus vehicle (12), low sodium plus 7-NI (15), normal sodium plus vehicle (14), and normal sodium plus 7-NI (16).
Effect of COX-2 Inhibition on Renin Content Stimulated by Dietary Sodium Restriction and on Renin mRNA Expression
To determine whether COX-2 plays a role in the increase in renal renin content in response to dietary sodium restriction, control 129/SvEv mice were placed on a low-sodium diet for 14 days. During this period, each diet group received either vehicle or 1 mg·k-1·d-1 of a selective COX-2 inhibitor,25 NS 398 (Cayman Chemical Co), in the drinking water. On the final day, the kidneys were removed to determine renal renin content of cortical slices. The number of mice in each group was as follows: normal sodium plus vehicle, n=14; low sodium plus vehicle, n=12; and low sodium plus NS398, n=19. Two additional groups of mice were placed on either a low-sodium diet or a low-sodium diet plus NS398, as above. These mice were used for determination of systolic blood pressure and to measure expression of renin mRNA in the renal cortex.
Although we did not anticipate that inhibition of COX-2 would have any effect under conditions in which the enzyme was not induced, we subsequently ran an additional control in which two groups of mice were paired and placed on either a normal sodium diet (n=5) or normal sodium plus NS398 (n=10) for 2 weeks, as before. The kidneys were then harvested for determination of renal renin content, as above.
|
Results |
|---|
|
TopAbstractIntroductionMethodsAnimalsRenal Renin ContentRNA Isolation and AnalysisDetermination of Systolic Blood...Statistical AnalysisProtocolsResultsDiscussionReferences |
|---|
Comparison of Renal Renin Content in C57BL/6, 129/SvEv, and nNOS -/- Mice
As shown in Fig 1, renal renin content from the nNOS -/- mice (3.11±0.23 µg Ang I·mg-1·h-1) was 45% less than cortical content in 129/SvEv mice (5.66±0.50 µg Ang I·mg-1·h-1, P<.005) and 59% less than in C57BL/6 mice (7.55±1.17 µg Ang I·mg-1·h-1; P<.005). Renal renin content was not significantly different between the two control strains. Systolic blood pressures were similar in the 129/SvEv and nNOS -/- mice (116±2.3 and 110±2.7 mm Hg, respectively) but were reduced in the C57BL/6 mice (96±3.3 mm Hg). Because we were concerned about the impact of lower renal perfusion on renin content in the C57BL/6 mice, only 129/SvEv mice were used as a control strain in subsequent experiments.
|
Effect of Dietary Sodium Restriction on Renal Renin Content in Mice Deficient in nNOS
While nNOS -/- mice exhibited a 45% reduction in renal renin content compared with their control strains (Fig 1), they were able to respond to chronic dietary sodium restriction by increasing renal renin content twofold (Fig 2), from 3.11±0.23 to 6.54±0.40 µg Ang I·mg-1·h-1 (P<.005). This increase is of a similar magnitude as the increase in renal renin content observed in control 129/ SvEv mice fed a low-sodium diet.
|
Effect of Chronic 7-NI on Renal Renin Content Stimulated by Dietary Sodium Restriction
In 129/SvEv mice, renal renin content (Fig 2) was increased nearly twofold by 14 days' dietary sodium restriction to 11.59±0.79 µg Ang I·mg-1·h-1 compared with renal renin content on a normal sodium diet (6.97±0.53 µg Ang I·mg-1·h-1; P<.005). Chronic 7-NI had no significant influence on renal renin content from mice on either diet. Renal renin content was 6.24±0.51 µg Ang I·mg-1·h-1 for mice on a normal sodium diet receiving 7-NI and 9.53±0.97 µg Ang I·mg-1·h-1 for mice on a low-sodium diet receiving 7-NI.
Effect of COX-2 Inhibition on Renal Renin Content and Renin mRNA Stimulated by Dietary Sodium Restriction
In 129/SvEv mice maintained on a low-sodium diet for 14 days, renal renin content was 11.59±0.79 µg Ang I· mg-1·h-1, whereas concurrent treatment of mice on a low-salt diet with the COX-2 inhibitor NS398 reduced renal renin content (Fig 3) by 39%, to a value of 7.11±0.72 µg Ang I·mg-1·h-1 (P<.005), which was similar to that observed in mice on a normal sodium diet (6.97±0.52 µg Ang I·mg-1·h-1). In addition, inhibition of COX-2 reduced renin mRNA by 60% in mice on a low-sodium diet (Fig 4). Densitometric units (corrected to 18S) for renin mRNA were 1.9±0.07 on a low-sodium diet alone (n=3 mice) and 0.73±0.24 (n=5 mice) for the low-sodium diet plus NS398, P<.02. In contrast, in additional paired studies, renal renin content in mice on a normal sodium diet was the same as for mice on a normal sodium diet given NS398 (3.19±0.47 µg Ang I·mg-1·h-1 versus 3.44±0.28 µg Ang I·mg-1·h-1, respectively). The renin values here were reduced compared with our original normal sodium diet controls (above). Why renin content was lower in these mice is unclear, though many factors may influence basal renin. However, the NS398-treated mice were paired with their untreated controls. Since the treatment of paired animals with NS398 did not affect renal renin content, this suggests that inhibition of COX-2 has no measurable effect under basal conditions. We also observed that chronic COX-2 inhibition did not affect systolic blood pressure, which was 109±2 mm Hg in mice on a low-sodium diet and 113±2 mm Hg in mice on the low-sodium diet plus NS 398 (n=5 mice per group).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsAnimalsRenal Renin ContentRNA Isolation and AnalysisDetermination of Systolic Blood...Statistical AnalysisProtocolsResultsDiscussionReferences |
|---|
The major finding of this study is that the increase in renal renin content in response to a low-sodium diet, presumably through the macula densa, appears to depend on the induction of COX-2. In addition, although chronic inhibition of nNOS does not seem to alter the change in renal renin content elicited by dietary sodium restriction, we observed a reduced renin content in mice in which the nNOS synthase gene was disrupted. Thus, while nNOS may influence basal renin content in the mouse, it does not seem to be critical in the stimulation of renin content by chronic dietary sodium restriction.
Despite the development of transgenic animal models, there is a lack of current literature regarding normal mouse physiology and, in particular, of the regulation of the renin-angiotensin pathway in this species. Moreover, any such information is generally limited to plasma or circulating renin concentrations, which may be greatly affected by extrarenal renin. In particular, certain strains of mice have large amounts of submandibular renin,22 and we have found that PRC values in mice exhibit great variability. Additionally, our own studies demonstrate that although dietary sodium restriction increases renal renin content, it does not alter PRC in mice. Hence, it is unlikely that plasma values accurately reflect renin released from the kidneys. This study has measured renal renin content, which is a balance between synthesis and release, to more accurately reflect renin in the kidney.
Initial experiments compared renal renin content of cortical slices in the nNOS -/- mouse with those in its two progenitor strains, the 129/SvEv and the C57BL/6. Surprisingly, renal renin content was reduced in the nNOS -/ - mice compared with either control strain. The lack of difference between control strains was not unexpected even though the C57BL/6 mice has only one copy of the renin gene compared with the two copies in the 129/ SvEv.26 The Ren-2 gene present in the 129/SvEv strain is believed to be responsible for production of renin from extrarenal sites such as the submandibular gland and hence, its presence might not be expected to alter renin content of the kidneys. Since studies in our laboratory have demonstrated that blood pressure is similar in the nNOS -/- and 129/SvEv strains,27 it could be concluded that the reduced renin content in the nNOS -/- mice was not related to altered renal baroreceptor control secondary to altered renal perfusion. However, it may be a direct effect, related to the absence of nNOS in the macula densa or perhaps secondary to possible increased sympathetic drive in this strain of mouse (X.-P. Yang, unpublished observations, 1996).
To investigate the role of nNOS in macula densa-mediated changes in renin, we examined the effect of dietary sodium restriction on renal renin content in both nNOS -/- mice and control mice treated chronically with the selective nNOS inhibitor 7-NI. Similar to the rat, dietary sodium restriction for 14 days increased renal renin content in 129/SvEv mice by 66%.28 Both nNOS -/- mice and mice treated chronically with 7-NI were able to respond to sodium restriction by an increase in renal renin content. These results contrast with our original hypothesis and with previous studies by Reid and Chou29 and by Beierwaltes,30 who found that nNOS inhibition blocked renin stimulated by furosemide, a stimulus mediated through the macula densa. Whether these results reflect species differences is unclear. In the rat, renal renin content parallels the increase in plasma levels.28 In the mouse, we have found that PRC does not correlate with renal renin content because plasma values are affected by extrarenal renin, and we have not measured renin secretion rates. Thus, the difference between the present results and those in studies in the rabbit29 and in the rat30 is that they measured plasma renin in response to acute stimulation whereas we have studied chronic adaptation of renal renin content. In addition, although dietary sodium restriction is widely regarded as a stimulus for macula densa-mediated renin secretion, we are aware that ingestion of a low-sodium diet may influence other stimuli and sympathetic activity, all of which could affect renin and whose interaction with nNOS we cannot predict. However, we did find that either nNOS -/- mice or mice treated chronically with 7-NI still respond to dietary sodium restriction by increasing renin content. If this stimulus acts through the macula densa, as hypothesized, it implies a diminished role for NO in this particular pathway to increase renin content. However, the fact that basal renal renin content was reduced in the nNOS -/- mice suggests that it would be prudent to examine the involvement of nNOS in other mechanisms controlling renin.
In the current literature, there is one report indicating that the nNOS -/- mouse may not be a true null mutation and that some residual nNOS activity remains in certain tissues, although it is greatly reduced.31 This study indicated that residual but greatly depressed NOS catalytic activity was detected in the brain. It did not examine whether any activity remains in the kidney. Thus, it is possible that some residual nNOS could contribute to the increase in renal renin content noted in nNOS -/- mice when placed on a low-sodium diet. Although we cannot rule out this possibility, the extent to which renin increased after dietary sodium restriction would seem incompatible with such a small residual amount of nNOS in the kidney, if it exists. Furthermore, the fact that we found that both disruption of the nNOS gene and pharmacological inhibition of nNOS with 7-NI had the same effect (ie, did not modify the response to dietary sodium restriction) further suggests that nNOS does not participate in this pathway to increase tissue renin content.
Treatment with the selective COX-2 inhibitor NS398 abolished the rise in renin content stimulated by 14 days' dietary sodium restriction, and we also found that it reduced renin mRNA. These results are the first to suggest that selective COX-2 inhibition reduces renin synthesis and provide clear evidence that COX-2 plays a significant role in the increase of renal renin content in response to dietary sodium restriction. Importantly, the renin response seems to require COX-2 induction by sodium restriction,18 as the inhibitor had no effect on renal renin content in kidneys of mice on a normal sodium diet. There is evidence in the rat from earlier studies that demonstrate the increase in plasma renin activity in response to a low-sodium diet is dependent on PG synthesis and can be prevented by treatment with indomethacin,32 which would inhibit both COX-1 and COX-2. Although the present study did not determine which prostanoid might be responsible for the increase in renal renin content in response to reduced sodium, one may speculate that PGE2 might be responsible since its effects have already been shown to require the presence of an intact macula densa15 and it stimulates renin. However, we did not measure PGE2 in the present study. Although COX-1 and COX-2 are 60% homologous in their amino acid sequence,33 no study has presented evidence as to the profile of prostanoids produced by the different isoenzymes. Likewise, the renal hemodynamic responses to COX-2 inhibition in the mouse have not been evaluated, though studies in the rat suggest that it does not change renal blood flow.34 Our study found that chronic treatment with NS398 does not alter systolic blood pressure of mice on a low-sodium diet. Thus, the changes in renal renin content observed in our study do not appear to be secondary to alterations in renal hemodynamics.
In conclusion, this study has demonstrated that COX-2 is a critical component of the pathway leading to increased renal renin content in response to dietary sodium restriction in the mouse, presumably mediated through the macula densa. We did not find any strong evidence that neuronal nitric oxide plays a role in mediating the increase in renal renin content under these conditions in the mouse. While the precise pathway by which COX-2 is associated with increased renin content is not yet clear, it does appear to be a critical and significant step in the renin response to dietary sodium restriction.
|
Acknowledgments |
|---|
This work was supported by a grant from the National Kidney Foundation of Michigan (Dr Harding), and Dr Huang is an Established Investigator of the American Heart Association. The authors wish to acknowledge Kevin Lynch, PhD (Department of Pharmacology, University of Virginia Health Sciences Center) for supplying rat renin cDNA.
|
References |
|---|
|
TopAbstractIntroductionMethodsAnimalsRenal Renin ContentRNA Isolation and AnalysisDetermination of Systolic Blood...Statistical AnalysisProtocolsResultsDiscussionReferences |
|---|
1. Sigmon DH, Carretero OA, Beierwaltes WH. Endothelium-derived relaxing factor regulates renin release in vivo. Am J Physiol. 1992; 263 : F256 –F261.[Medline] [Order article via Infotrieve]
2. Persson PB, Baumann JE, Ehmke H, Hackenthal E, Kircheim HR, Nafz B. Endothelium derived NO stimulates pressure-dependent renin release in conscious dogs. Am J Physiol. 1993; 264 : F943 –F947.[Medline] [Order article via Infotrieve]
3. Kramer BK, Ritthaler T, Ackermann M, Holmer S, Schricker K, Riegger GAJ, Kurtz A. Endothelium-mediated regulation of renin secretion. Kidney Int. 1994; 46 : 1577 –1579.[Medline] [Order article via Infotrieve]
4. Vidal MJ, Romero JC, Vanhoutte PM. Endothelium-derived relaxing factor inhibits renin release. Eur J Pharmacol. 1988; 149 : 401 –402.[Medline] [Order article via Infotrieve]
5. Briggs JP, Wang W, He X, Brosius FC, Schnermann J. Expression of cerebellar cNOS in kidney cortex: characterization by direct PCR sequencing. J Am Soc Nephrol. 1993; 3 : 11 . Abstract.
6. Ujiie K, Yuen J, Hogarth L, Dazinger R, Star RA. Localization and regulation of endothelial NO synthase mRNA expression in rat kidney. Am J Physiol. 1994; 267 : F296 –F302.[Medline] [Order article via Infotrieve]
7. Singh IJ, Grams M, Wang W-H, Yang T, Killen P, Smart A, Schermann J, Briggs JP. Coordinate regulation of renal expression of nitric oxide synthase, renin and angiotensinogen mRNA by dietary salt. Am J Physiol. 1996; 270 : F1027 –F1037.[Medline] [Order article via Infotrieve]
8. Greenberg SG, He X-R, Schnermann JB, Briggs JP. Effect of nitric oxide on renin secretion, I: studies in isolated juxtaglomerular granular cells. Am J Physiol. 1995; 268 : F948 –F952.[Medline] [Order article via Infotrieve]
9. Beierwaltes WB, Carretero OA. Nonprostanoid endothelium-derived factors inhibit renin release. Hypertension. 1992; 19 [suppl II]: 1168 –1173.
10. Scholz H, Kurtz A. Involvement of endothelium-derived relaxing factor in the pressure control of renin secretion from isolated perfused kidney. J Clin Invest. 1993; 91 : 1088 –1094.[Medline] [Order article via Infotrieve]
11. He X-R, Greenberg SG, Briggs JP, Schnermann JB. Effect of nitric oxide on renin secretion, II: studies in the perfused juxtaglomerular apparatus. Am J Physiol. 1995; 268 : F953 –F959.[Medline] [Order article via Infotrieve]
12. Henrich WL, McAllister EA, Smith PB, Campbell WB. Guanosine 3', 5'-cyclic monophosphate as a mediator of inhibition of renin release. Am J Physiol. 1988; 255 : F474 –F478.[Medline] [Order article via Infotrieve]
13. Henrich WL. Role of prostaglandins in renin secretion. Kidney Int. 1981; 19 : 822 –830.[Medline] [Order article via Infotrieve]
14. Beierwaltes WH, Schryver S, Sanders E, Strand J, Romero JC. Renin release selectively stimulated by prostaglandin I2 in isolated rat glomeruli. Am J Physiol. 1982; 243 : F276 –F283.[Medline] [Order article via Infotrieve]
15. Ito S, Carretero OA, Abe K, Beierwaltes WB, Yoshinaga K. Effect of prostanoids on renin release from rabbit afferent arterioles with and without macula densa. Kidney Int. 1989; 35 : 1138 –1144.[Medline] [Order article via Infotrieve]
16. Smith WL, Bell TG. Immunohistochemical localization of the prostaglandin-forming cyclooxygenase in renal cortex. Am J Physiol. 1978; 235 : F451 –F457.[Medline] [Order article via Infotrieve]
17. Simmons DL, Xie W, Chipman JG, Evett GE. Multiple cyclooxygenases: cloning of a mitogen-inducible form. In: Bailey JM, ed. Prostaglandins, Leukotrienes, Lipoxins and PAF. New York, NY: Plenum Press; 1991: 67 –78.
18. Harris RC, McKanna JA, Akai Y, Jacobson HR, Dubois RN, Breyer MD. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest. 1994; 94 : 2504 –2510.[Medline] [Order article via Infotrieve]
19. Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P. Nitric oxide activates cyclooxygenase enzymes.
Proc Natl Acad Sci U S A. 1993;
90
: 7240
–7244.
20. Huang PL, Dawson TM, Bredt DS, Snyder SH, Fishman MC. Targeted disruption of the neuronal nitric oxide synthase gene. Cell. 1993; 75 : 1273 –1286.[Medline] [Order article via Infotrieve]
21. Moore PK, Babbedge RC, Wallace P, Gaffen ZA, Hart SL. 7-Nitroindazole, an inhibitor of nitric oxide synthase, exhibits anti-nociceptive activity in the mouse without increasing blood pressure. Br J Pharmacol. 1993; 108 : 296 –297.[Medline] [Order article via Infotrieve]
22. Bing J, Poulsen K, Hackenthal E, Rix E, Taugner R. Renin in the submaxillary gland. J Histochem Cytochem. 1980; 28 : 874 –880.[Medline] [Order article via Infotrieve]
23. Haber E, Koerber T, Page CB, Kilman B, Pernode A. Application of a radioimmunoassay for angiotensin I to the physiological measurement of plasma renin activity in normal human subjects.
J Clin Endocrinol Metab. 1969;
29
: 1349
–1355.
24. Oliver WJ, Gross F. Unique specificity of mouse angiotensinogen to homologous renin. Proc Soc Exp Biol Med. 1966; 122 : 923 –926.[Medline] [Order article via Infotrieve]
25. Masferrer JL, Zweifel BS, Manning PT, Hauser SD, Leahy KM, Smith WG, Isakson PC, Seibert K. Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic.
Proc Natl Acad Sci U S A. 1994;
91
: 3228
–3232.
26. Piccini N, Knopf JL, Gross KW. A DNA polymorphism, consistent with gene duplication, correlates with high renin levels in the mouse submaxillary gland. Cell. 1982; 30 : 205 –213.[Medline] [Order article via Infotrieve]
27. Alfie ME, Pomposiello SI, Cuello Picco J-M, Carretero OA. Salt-sensitive hypertension: role of bradykinin and nNOS-derived nitric oxide. Hypertension. 1996; 28 : 516 . Abstract.
28. Nakamura N, Soubrier F, Menard J, Panthier J-J, Rougeon F, Corvol P. Nonproportional changes in plasma renin concentration, renal renin content, and rat renin messenger RNA.
Hypertension. 1985;
7
: 855
–859.
29. Reid IA, Chou L. Effect of blockade of nitric oxide synthesis on the renin secretory response to frusemide in conscious rabbits. Clin Sci. 1995; 88 : 657 –663.[Medline] [Order article via Infotrieve]
30. Beierwaltes WB. Selective neuronal nitric oxide synthase inhibition blocks furosemide-stimulated renin secretion in vivo. Am J Physiol. 1995; 269 : F134 –F139.[Medline] [Order article via Infotrieve]
31. Brenman JE, Chao DS, Gee SH, McGee AW, Craven SE, Santillano DR, Wu Z, Huang F, Xia H, Peters MF, Froehner SC, Bredt DS. Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and 
1-syntrophin mediated by PDZ domains.
Cell. 1996;
84
: 757
–767.[Medline]
[Order article via Infotrieve]
32. Francisco LL, Osborn JL, DiBona GF. Prostaglandins in renin release during sodium deprivation. Am J Physiol. 1982; 243 : F537 –F542.[Medline] [Order article via Infotrieve]
33. Smith WL, DeWitt DL. Biochemistry of prostaglandin endoperoxide H synthase-1 and synthase-2 and their differential susceptibility to nonsteroidal anti-inflammatory drugs. Semin Nephrol. 1995; 15 : 179 –194.[Medline] [Order article via Infotrieve]
34. Gans KR, Galbraith W, Roman RJ, Haber SB, Kerr JS, Schmidt WK, Smith C, Hewes WE, Ackerman NR. Anti-inflammatory and safety profile of DuP 697, a novel orally effective prostaglandin synthesis inhibitor.
J Pharmacol Exp Ther. 1990;
254
: 180
–187.
This article has been cited by other articles:
 |
|
 |
|
  M. C. Ortiz-Capisano, T.-D. Liao, P. A. Ortiz, and W. H. Beierwaltes Calcium-dependent phosphodiesterase 1C inhibits renin release from isolated juxtaglomerular cells Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2009; 297(5): R1469 - R1476. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-B. Linhart and J. A. Majzoub Pomc Knockout Mice Have Secondary Hyperaldosteronism Despite an Absence of Adrenocorticotropin Endocrinology, February 1, 2008; 149(2): 681 - 686. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Ortiz-Capisano, P. A. Ortiz, J. L. Garvin, P. Harding, and W. H. Beierwaltes Expression and Function of the Calcium-Sensing Receptor in Juxtaglomerular Cells Hypertension, October 1, 2007; 50(4): 737 - 743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Ortiz-Capisano, P. A. Ortiz, P. Harding, J. L. Garvin, and W. H. Beierwaltes Adenylyl Cyclase Isoform V Mediates Renin Release From Juxtaglomerular Cells Hypertension, March 1, 2007; 49(3): 618 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Ortiz-Capisano, P. A. Ortiz, P. Harding, J. L. Garvin, and W. H. Beierwaltes Decreased Intracellular Calcium Stimulates Renin Release via Calcium-Inhibitable Adenylyl Cyclase Hypertension, January 1, 2007; 49(1): 162 - 169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. H. Beierwaltes cGMP stimulates renin secretion in vivo by inhibiting phosphodiesterase-3 Am J Physiol Renal Physiol, June 1, 2006; 290(6): F1376 - F1381. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Harris and M. D. Breyer Update on Cyclooxygenase-2 Inhibitors Clin. J. Am. Soc. Nephrol., March 1, 2006; 1(2): 236 - 245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Nusing, A. Treude, C. Weissenberger, B. Jensen, M. Bek, C. Wagner, S. Narumiya, and H. W. Seyberth Dominant Role of Prostaglandin E2 EP4 Receptor in Furosemide-Induced Salt-Losing Tubulopathy: A Model for Hyperprostaglandin E Syndrome/Antenatal Bartter Syndrome J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2354 - 2362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Jeck, K. P. Schlingmann, S. C. Reinalter, M. Komhoff, M. Peters, S. Waldegger, and H. W. Seyberth Salt handling in the distal nephron: lessons learned from inherited human disorders Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2005; 288(4): R782 - R795. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Paliege, D. Mizel, C. Medina, A. Pasumarthy, Y. G. Huang, S. Bachmann, J. P. Briggs, J. B. Schnermann, and T. Yang Inhibition of nNOS expression in the macula densa by COX-2-derived prostaglandin E2 Am J Physiol Renal Physiol, July 1, 2004; 287(1): F152 - F159. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. L. Braden, M. H. O'shea, J. G. Mulhern, and M. J. Germain Acute renal failure and hyperkalaemia associated with cyclooxygenase-2 inhibitors Nephrol. Dial. Transplant., May 1, 2004; 19(5): 1149 - 1153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Castrop, F. Schweda, D. Mizel, Y. Huang, J. Briggs, A. Kurtz, and J. Schnermann Permissive role of nitric oxide in macula densa control of renin secretion Am J Physiol Renal Physiol, May 1, 2004; 286(5): F848 - F857. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. LaPointe, M. Mendez, A. Leung, Z. Tao, and X.-P. Yang Inhibition of cyclooxygenase-2 improves cardiac function after myocardial infarction in the mouse Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1416 - H1424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-F. Cheng and R. C. Harris Cyclooxygenases, the Kidney, and Hypertension Hypertension, March 1, 2004; 43(3): 525 - 530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lum, E. G. Shesely, D'A. L. Potter, and W. H. Beierwaltes Cardiovascular and Renal Phenotype in Mice With One or Two Renin Genes Hypertension, January 1, 2004; 43(1): 79 - 86. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Schweda, C. Wagner, B. K. Kramer, J. Schnermann, and A. Kurtz Preserved macula densa-dependent renin secretion in A1 adenosine receptor knockout mice Am J Physiol Renal Physiol, April 1, 2003; 284(4): F770 - F777. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. L. Mertz, J. Liu, N. K. Valego, S. P. Stallings, J. P. Figueroa, and J. C. Rose Inhibition of cyclooxygenase-2: effects on renin secretion and expression in fetal lambs Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2003; 284(4): R1012 - R1018. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hartner, N. Cordasic, M. Goppelt-Struebe, R. Veelken, and K. F. Hilgers Role of macula densa cyclooxygenase-2 in renovascular hypertension Am J Physiol Renal Physiol, March 1, 2003; 284(3): F498 - F502. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Ollerstam and A.E. G Persson Macula densa neuronal nitric oxide synthase Cardiovasc Res, November 1, 2002; 56(2): 189 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-F. Cheng, S.-W. Wang, M.-Z. Zhang, J. A. McKanna, R. Breyer, and R. C. Harris Prostaglandins that increase renin production in response to ACE inhibition are not derived from cyclooxygenase-1 Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2002; 283(3): R638 - R646. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Kammerl, W. Richthammer, A. Kurtz, and B. K. Kramer Angiotensin II feedback is a regulator of renocortical renin, COX-2, and nNOS expression Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2002; 282(6): R1613 - R1617. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Theilig, V. Campean, A. Paliege, M. Breyer, J. P. Briggs, J. Schnermann, and S. Bachmann Epithelial COX-2 Expression Is Not Regulated By Nitric Oxide in Rodent Renal Cortex Hypertension, April 1, 2002; 39(4): 848 - 853. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Miyataka, K. A. Rich, M. Ingram, T. Yamamoto, and R. J. Bing Nitric Oxide, Anti-Inflammatory Drugs on Renal Prostaglandins and Cyclooxygenase-2 Hypertension, March 1, 2002; 39(3): 785 - 789. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Schnermann Cyclooxygenase-2 and macula densa control of renin secretion Nephrol. Dial. Transplant., September 1, 2001; 16(9): 1735 - 1738. [Full Text] [PDF]
|
|
|
|
|
|
A. D. Dobrian, S. D. Schriver, and R. L. Prewitt Role of Angiotensin II and Free Radicals in Blood Pressure Regulation in a Rat Model of Renal Hypertension Hypertension, September 1, 2001; 38(3): 361 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. G. Leon, J. Marchetti, and C. P. Vio Renal Cyclooxygenase-2: Evidence for Recruitment of Thick Ascending Limb of Henle Cells in Microdissected Nephron Segments Hypertension, September 1, 2001; 38(3): 630 - 634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. VALLON, T. TRAYNOR, L. BARAJAS, Y. G. HUANG, J. P. BRIGGS, and J. SCHNERMANN Feedback Control of Glomerular Vascular Tone in Neuronal Nitric Oxide Synthase Knockout Mice J. Am. Soc. Nephrol., August 1, 2001; 12(8): 1599 - 1606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Harris and M. D. Breyer Physiological regulation of cyclooxygenase-2 in the kidney Am J Physiol Renal Physiol, July 1, 2001; 281(1): F1 - F11. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. VIO, S.-J. AN, C. CESPEDES, J. C. MCGIFF, and N. R. FERRERI Induction of Cyclooxygenase-2 in Thick Ascending Limb Cells by Adrenalectomy J. Am. Soc. Nephrol., April 1, 2001; 12(4): 649 - 658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Weichert, A. Paliege, A. P. Provoost, and S. Bachmann Upregulation of juxtaglomerular NOS1 and COX-2 precedes glomerulosclerosis in fawn-hooded hypertensive rats Am J Physiol Renal Physiol, April 1, 2001; 280(4): F706 - F714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-F. Cheng, J.-L. Wang, M.-Z. Zhang, S.-W. Wang, James. A. McKanna, and R. C. Harris Genetic deletion of COX-2 prevents increased renin expression in response to ACE inhibition Am J Physiol Renal Physiol, March 1, 2001; 280(3): F449 - F456. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Mann, A. Hartner, B. L. Jensen, K. F. Hilgers, K. Hocherl, B. K. Kramer, and A. Kurtz Acute upregulation of COX-2 by renal artery stenosis Am J Physiol Renal Physiol, January 1, 2001; 280(1): F119 - F125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Imig Eicosanoid regulation of the renal vasculature Am J Physiol Renal Physiol, December 1, 2000; 279(6): F965 - F981. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. HARRIS Cyclooxygenase-2 in the Kidney J. Am. Soc. Nephrol., December 1, 2000; 11(12): 2387 - 2394. [Full Text]
|
|
|
|
|
|
T. Yang, Y. Endo, Y. G. Huang, A. Smart, J. P. Briggs, and J. Schnermann Renin expression in COX-2-knockout mice on normal or low-salt diets Am J Physiol Renal Physiol, November 1, 2000; 279(5): F819 - F825. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Harris Macula densa signalling--a potential role of cyclooxygenase-2 (COX-2)? Nephrol. Dial. Transplant., October 1, 2000; 15(10): 1504 - 1506. [Full Text] [PDF]
|
|
|
|
 |
|
 M.-Z. Zhang, R. C. Harris, and J. A. McKanna Regulation of cyclooxygenase-2 (COX-2) in rat renal cortex by adrenal glucocorticoids and mineralocorticoids PNAS, December 21, 1999; 96(26): 15280 - 15285. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. SCHNERMANN Micropuncture Analysis of Tubuloglomerular Feedback Regulation in Transgenic Mice J. Am. Soc. Nephrol., December 1, 1999; 10(12): 2614 - 2619. [Abstract] [Full Text]
|
|
|
|
|
|
T. R. Traynor, A. Smart, J. P. Briggs, and J. Schnermann Inhibition of macula densa-stimulated renin secretion by pharmacological blockade of cyclooxygenase-2 Am J Physiol Renal Physiol, November 1, 1999; 277(5): F706 - F710. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. FERGUSON, R. L. HÉBERT, and O. LANEUVILLE NS-398 Upregulates Constitutive Cyclooxygenase-2 Expression in the M-1 Cortical Collecting Duct Cell Line J. Am. Soc. Nephrol., November 1, 1999; 10(11): 2261 - 2271. [Abstract] [Full Text]
|
|
|
|
|
|
J. M. Gross, J. E. Dwyer, and F. G. Knox Natriuretic Response to Increased Pressure Is Preserved With COX-2 Inhibitors Hypertension, November 1, 1999; 34(5): 1163 - 1167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. C. Wu, P. J. Harris, and E. J. Johns Nitric oxide and renal nerve-mediated proximal tubular reabsorption in normotensive and hypertensive rats Am J Physiol Renal Physiol, October 1, 1999; 277(4): F560 - F566. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. L. Sanchez, L. M. Salgado, N. R. Ferreri, and B. Escalante Effect of Cyclooxygenase-2 Inhibition on Renal Function After Renal Ablation Hypertension, October 1, 1999; 34(4): 848 - 853. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Wolf, H. Castrop, A. Hartner, M. Goppelt-Strube, K. F. Hilgers, and A. Kurtz Inhibition of the Renin-Angiotensin System Upregulates Cyclooxygenase-2 Expression in the Macula Densa Hypertension, September 1, 1999; 34(3): 503 - 507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-L. Wang, H.-F. Cheng, and R. C. Harris Cyclooxygenase-2 Inhibition Decreases Renin Content and Lowers Blood Pressure in a Model of Renovascular Hypertension Hypertension, July 1, 1999; 34(1): 96 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N.-E. Rhaleb, H. Peng, M. E. Alfie, E. G. Shesely, and O. A. Carretero Effect of ACE Inhibitor on DOCA-Salt– and Aortic Coarctation–Induced Hypertension in Mice : Do Kinin B2 Receptors Play a Role? Hypertension, January 1, 1999; 33(1): 329 - 334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kurtz and C. Wagner Role of nitric oxide in the control of renin secretion Am J Physiol Renal Physiol, December 1, 1998; 275(6): F849 - F862. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-L. Wang, H.-F. Cheng, M.-Z. Zhang, James. A. McKanna, and R. C. Harris Selective increase of cyclooxygenase-2 expression in a model of renal ablation Am J Physiol Renal Physiol, October 1, 1998; 275(4): F613 - F622. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Schnermann Juxtaglomerular cell complex in the regulation of renal salt excretion Am J Physiol Regulatory Integrative Comp Physiol, February 1, 1998; 274(2): R263 - R279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hartner, M. Goppelt-Struebe, and K. F. Hilgers Coordinate Expression of Cyclooxygenase-2 and Renin in the Rat Kidney in Renovascular Hypertension Hypertension, January 1, 1998; 31(1): 201 - 205. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-Z. Zhang, J.-L. Wang, H.-F. Cheng, R. C. Harris, and J. A. McKanna Cyclooxygenase-2 in rat nephron development Am J Physiol Renal Physiol, December 1, 1997; 273(6): F994 - F1002. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hocherl, M. Kammerl, F. Kees, B. K. Kramer, H. F. Grobecker, and A. Kurtz Role of renal nerves in stimulation of renin, COX-2, and nNOS in rat renal cortex during salt deficiency Am J Physiol Renal Physiol, March 1, 2002; 282(3): F478 - F484. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||