Prostaglandins that increase renin production in response to ACE inhibition are not derived from cyclooxygenase-1

2002 ◽  
Vol 283 (3) ◽  
pp. R638-R646 ◽  
Author(s):  
Hui-Fang Cheng ◽  
Sue-Wan Wang ◽  
Ming-Zhi Zhang ◽  
James A. McKanna ◽  
Richard Breyer ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Enzyme Inhibitor ◽  
Plasma Renin ◽  
Immunohistochemical Analysis ◽  
Renin Activity ◽  
Prostaglandin E ◽  
Receptor Subtype ◽  
Renin Mrna ◽  
Cox 2 ◽  
Cox 1

It is well known that nonselective, nonsteroidal anti-inflammatory drugs inhibit renal renin production. Our previous studies indicated that angiotensin-converting enzyme inhibitor (ACEI)-mediated renin increases were absent in rats treated with a cyclooxygenase (COX)-2-selective inhibitor and in COX-2 −/− mice. The current study examined further whether COX-1 is also involved in mediating ACEI-induced renin production. Because renin increases are mediated by cAMP, we also examined whether increased renin is mediated by the prostaglandin E2 receptor EP2 subtype, which is coupled to Gs and increases cAMP. Therefore, we investigated if genetic deletion of COX-1 or EP2 prevents increased ACEI-induced renin expression. Age- and gender-matched wild-type (+/+) and homozygous null mice (−/−) were administered captopril for 7 days, and plasma and renal renin levels and renal renin mRNA expression were measured. There were no significant differences in the basal level of renal renin activity from plasma or renal tissue in COX-1 +/+ and −/− mice. Captopril administration increased renin equally [plasma renin activity (PRA): +/+ 9.3 ± 2.2 vs. 50.1 ± 10.9; −/− 13.7 ± 1.5 vs. 43.9 ± 6.6 ng ANG I · ml−1 · h−1; renal renin concentration: +/+ 11.8 ± 1.7 vs. 35.3 ± 3.9; −/− 13.0 ± 3.0 vs. 27.8 ± 2.7 ng ANG I · mg protein−1 · h−1; n = 6; P < 0.05 with or without captopril]. ACEI also increased renin mRNA expression (+/+ 2.4 ± 0.2; −/− 2.1 ± 0.2 fold control; n = 6–10; P < 0.05). Captopril led to similar increases in EP2 −/− compared with +/+. The COX-2 inhibitor SC-58236 blocked ACEI-induced elevation in renal renin concentration in EP2 null mice (+/+ 24.7 ± 1.7 vs. 9.8 ± 0.4; −/− 21.1 ± 3.2 vs. 9.3 ± 0.4 ng ANG I · mg protein−1 · h−1; n = 5) as well as in COX-1 −/− mice (SC-58236-treated PRA: +/+ 7.3 ± 0.6; −/− 8.0 ± 0.9 ng ANG I · ml−1 · h−1; renal renin: +/+ 9.1 ± 0.9; −/− 9.6 ± 0.5 ng ANG I · mg protein−1 · h−1; n = 6–7; P < 0.05 compared with no treatment). Immunohistochemical analysis of renin expression confirmed the above results. This study provides definitive evidence that metabolites of COX-2 rather than COX-1 mediate ACEI-induced renin increases. The persistent response in EP2 nulls suggests involvement of prostaglandin E2 receptor subtype 4 and/or prostacyclin receptor (IP).

scholarly journals Role of prostanoids in regulation of the renin-angiotensin-aldosterone system by salt intake

2002 ◽  
Vol 283 (2) ◽  
pp. F294-F301 ◽  
Author(s):  
Klaus Höcherl ◽  
Martin C. Kammerl ◽  
Karl Schumacher ◽  
Dirk Endemann ◽  
Horst F. Grobecker ◽  
...  
Keyword(s):  
Plasma Renin Activity ◽  
Salt Intake ◽  
Plasma Renin ◽  
Plasma Aldosterone ◽  
Renin Activity ◽  
Plasma Aldosterone Concentration ◽  
Low Salt ◽  
Renin Mrna ◽  
Cox 2 ◽  
Cox 1

We investigated the effect of cyclooxygenase (COX) activity on the regulation of the renin-angiotensin-aldosterone system by salt intake. Therefore, Sprague-Dawley rats were subjected to different salt diets [0.02, 0.6, and 8% NaCl (wt/wt)] and treated with the selective COX-2 inhibitor rofecoxib (10 mg · kg body wt−1 · day−1) or with ketorolac at a dose selective for COX-1 inhibition (2 mg · kg body wt−1 · day−1) for 3, 7, 14, and 21 days. Rofecoxib and ketorolac caused a similar reduction of renocortical PGE2 formation with a low-salt diet. Rofecoxib did not change plasma renin activity or renocortical renin mRNA abundance with any of the diets but clearly lowered plasma aldosterone concentration. In contrast, ketorolac delayed the increase in plasma renin activity and of renin mRNA in response to low salt intake but did not change plasma aldosterone concentration. Prolonged treatment with rofecoxib but not with ketorolac caused an upregulation of COX-2 expression while COX-1 mRNA abundance remained unchanged. These findings suggest that COX-1-derived, but not COX-2-derived, prostanoids are of relevance for the regulation of the renin system by salt intake.

scholarly journals Inhibition of nNOS expression in the macula densa by COX-2-derived prostaglandin E2

2004 ◽  
Vol 287 (1) ◽  
pp. F152-F159 ◽  
Author(s):  
Alex Paliege ◽  
Diane Mizel ◽  
Carmen Medina ◽  
Anita Pasumarthy ◽  
Yuning G. Huang ◽  
...  
Keyword(s):  
Plasma Renin Activity ◽  
Mrna Expression ◽  
Real Time ◽  
Plasma Renin ◽  
Macula Densa ◽  
Renin Secretion ◽  
Renin Activity ◽  
Rt Pcr ◽  
Cox 2 ◽  
Nnos Expression

It is well established that cyclooxygenase-2 (COX-2) and the neuronal form of nitric oxide synthase (nNOS) are coexpressed in macula densa cells and that the expression of both enzymes is stimulated in a number of high-renin states. To further explore the role of nNOS and COX-2 in renin secretion, we determined plasma renin activity in mice deficient in nNOS or COX-2. Plasma renin activity was significantly reduced in nNOS −/− mice on a mixed genetic background and in COX-2 −/− mice on either BALB/c or C57/BL6 congenic backgrounds. In additional studies, we accumulated evidence to show an inhibitory influence of PGE2 on nNOS expression. In a cultured macula densa cell line, PGE2 significantly reduced nNOS mRNA expression, as quantified by real-time RT-PCR. In COX-2 −/− mice, nNOS mRNA expression in the kidney, determined by real-time RT-PCR, was upregulated throughout the postnatal periods, ranging from postnatal day ( PND) 3 to PND 60. The induction of nNOS protein expression and NOS activity in COX-2 −/− mice was localized to macula densa cells using immunohistochemistry and NADPH-diaphorase staining methods, respectively. Therefore, these findings reveal that the absence of either COX-2 or nNOS is associated with suppressed renin secretion. Furthermore, the inhibitory effect of PGE2 on nNOS mRNA expression indicates a novel interaction between NO and prostaglandin-mediated pathways of renin regulation.

Roles of vasoconstrictor prostaglandins, COX-1 and -2, and AT1, AT2, and TP receptors in a rat model of early 2K,1C hypertension

2007 ◽  
Vol 293 (5) ◽  
pp. H2644-H2649 ◽  
Author(s):  
William J. Welch ◽  
Kinjal Patel ◽  
Paul Modlinger ◽  
Margarida Mendonca ◽  
Noritaka Kawada ◽  
...  
Keyword(s):  
Rat Model ◽  
Enzyme Inhibitor ◽  
Plasma Renin ◽  
Ang Ii ◽  
Tp Receptors ◽  
Cox 2 ◽  
Cox 1 ◽  
Plasma Malondialdehyde ◽  
Goldblatt Hypertension

Angiotensin (ANG) II activating type 1 receptors (AT1Rs) enhances superoxide anion (O2•−) and arachidonate (AA) formation. AA is metabolized by cyclooxygenases (COXs) to PGH2, which is metabolized by thromboxane (Tx)A2 synthase to TxA2 or oxidized to 8-isoprostane PGF2α (8-Iso) by O2•−. PGH2, TxA2, and 8-Iso activate thromboxane-prostanoid receptors (TPRs). We investigated whether blood pressure in a rat model of early (3 wk) two-kidney, one-clip (2K,1C) Goldblatt hypertension is maintained by AT1Rs or AT2Rs, driving COX-1 or -2-dependent products that activate TPRs. Compared with sham-operated rats, 2K,1C Goldblatt rats had increased mean arterial pressure (MAP; 120 ± 4 vs. 155 ± 3 mmHg; P < 0.001), plasma renin activity (PRA; 22 ± 7 vs. 48 ± 5 ng·ml−1·h−1; P < 0.01), plasma malondialdehyde (1.07 ± 0.05 vs. 1.58 ± 0.16 nmol/l; P < 0.01), and TxB2 excretion (26 ± 4 vs. 51 ± 7 ng/24 h; P < 0.01). Acute graded intravenous doses of benazeprilat (angiotensin-converting enzyme inhibitor) reduced MAP at 20 min (−36 ± 5 mmHg; P < 0.001) and excretion of TxA2 metabolites. Indomethacin (nonselective COX antagonist) or SC-560 (COX-1 antagonist) reduced MAP at 20 min (−25 ± 5 and −28 ± 7 mmHg; P < 0.001), whereas valdecoxib (COX-2 antagonist) was ineffective (−9 ± 5 mmHg; not significant). Losartan (AT1R antagonist) or SQ-29548 (TPR antagonist) reduced MAP at 150 min (−24 ± 6 and −22 ± 3 mmHg; P < 0.001), whereas PD-123319 (AT2R antagonist) was ineffective. Acute blockade of TPRs, COX-1, or COX-2 did not change PRA, but TxB2 generation by the clipped kidney was reduced by blockade of COX-1 and increased by blockade of COX-2. 2K,1C hypertension in rats activates renin, O2•−, and vasoconstrictor PGs. Hypertension is maintained by AT1Rs and by COX-1, but not COX-2, products that activate TPRs.

COX-2 activity determines the level of renin expression but is dispensable for acute upregulation of renin expression in rat kidneys

2007 ◽  
Vol 292 (6) ◽  
pp. F1782-F1790 ◽  
Author(s):  
Corina Matzdorf ◽  
A. Kurtz ◽  
Klaus Höcherl
Keyword(s):  
Salt Intake ◽  
Plasma Renin ◽  
Renin Activity ◽  
Prolonged Treatment ◽  
Left Renal Artery ◽  
Mrna Levels ◽  
Absolute Increase ◽  
Renin Mrna ◽  
Cox 2 ◽  
Rat Kidneys

The role of cyclooxygenase 2 (COX-2) in the control of renin is still a matter of debate, since studies with COX-2-deficient mice or with COX-2 inhibitors produced conflicting findings. Therefore, we studied the effect of the COX-2 inhibitor SC-58236 on the regulation of the renin system in adult rat kidneys. Renocortical tissue levels and urinary excretion of PGE2 were reduced to 65 and 40% of control values, respectively, after a single gavage of SC-58236 and did not further decrease on prolonged treatment. Plasma renin activity (PRA) and renin mRNA levels began to decrease after 3 days and reached a constant level of ∼60% of control values after 5 days of treatment. Isoproterenol or left renal artery clipping for 2 days increased PRA and renin mRNA to similar levels in both vehicle- and SC-58236-treated rats after 2 days. Pretreatment with SC-58236 for 5 days, however, reduced the absolute increase in PRA and renin mRNA levels. Notably, the relative increases were not different between vehicle- and SC-58236-treated rats. Similar findings were observed for the stimulation of the renin system by angiotensin II inhibition and low salt intake. These findings indicate that COX-2 inhibition attenuates renin secretion and renin gene expression stimulated by a variety of parameters in proportion to the lowering of basal renin activity, while it does not interfere with the different stimulatory mechanism per se. As a consequence, it appears as if COX-2 activity relevantly determines the set point of the activity of the renin system in rat kidneys.

scholarly journals NS-398 Upregulates Constitutive Cyclooxygenase-2 Expression in the M-1 Cortical Collecting Duct Cell Line

1999 ◽  
Vol 10 (11) ◽  
pp. 2261-2271
Author(s):  
SHAWN FERGUSON ◽  
RICHARD L. HÉBERT ◽  
ODETTE LANEUVILLE
Keyword(s):  
Protein Expression ◽  
Mrna Expression ◽  
Cell Line ◽  
Blot Analysis ◽  
Collecting Duct ◽  
Prostaglandin E ◽  
Intercalated Cells ◽  
Cortical Collecting Duct ◽  
Cox 2 ◽  
Cox 1

Abstract. The cortical collecting duct (CCD) is a major site of intrarenal prostaglandin E2 (PGE2) synthesis. This study examines the expression and regulation of the prostaglandin synthesizing enzymes cyclooxygenase-1 (COX-1) and -2 in the CCD. By indirect immunofluorescence using isoform-specific antibodies, COX-1 and -2 immunoreactivity was localized to all cell types of the murine M-1 CCD cell line. By immunohistochemistry, both COX-1 and COX-2 were localized to intercalated cells of the CCD on paraffin-embedded mouse kidney sections. When COX enzyme activity was measured in the M-1 cells, both indomethacin (COX-1 and -2 inhibitor) and the specific COX-2 inhibitor NS-398 effectively blocked PGE2 synthesis. These results demonstrate that COX-2 is the major contributor to the pool of PGE2 synthesized by the CCD. By Western blot analysis, COX-2 expression was significantly upregulated by incubation with either indomethacin or NS-398. These drugs did not affect COX-1 protein expression. Evaluation of COX-2 mRNA expression by Northern blot analysis after NS-398 treatment demonstrated that the COX-2 protein upregulation occurred independently of any change in COX-2 mRNA expression. These studies have for the first time localized COX-2 to the CCD and provided evidence that the intercalated cells of the CCD express both COX-1 and COX-2. The results also demonstrate that constitutively expressed COX-2 is the major COX isoform contributing to PGE2 synthesis by the M-1 CCD cell line. Inhibition of COX-2 activity in the M-1 cell line results in an upregulation of COX-2 protein expression.

Genetic deletion of COX-2 prevents increased renin expression in response to ACE inhibition

2001 ◽  
Vol 280 (3) ◽  
pp. F449-F456 ◽  
Author(s):  
Hui-Fang Cheng ◽  
Jun-Ling Wang ◽  
Ming-Zhi Zhang ◽  
Su-Wan Wang ◽  
James. A. McKanna ◽  
...  
Keyword(s):  
Enzyme Inhibitor ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Ace Inhibition ◽  
Renin Activity ◽  
Thick Ascending Limb ◽  
Afferent Arteriole ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Cox 2

Cyclooxygenase-2 (COX-2) is expressed in macula densa (MD) and surrounding cortical thick ascending limb of the loop of Henle (cTALH) and is involved in regulation of renin production. We and others have previously found that selective COX-2 inhibitors can inhibit renal renin production (Cheng HF, Wang JL, Zhang MZ, Miyazaki Y, Ichikawa I, McKanna JA, and Harris RC. J Clin Invest 103: 953–961, 1999; Harding P, Sigmon DH, Alfie ME, Huang PL, Fishman MC, Beierwaltes WH, and Carretero OA. Hypertension 29: 297–302, 1997; Traynor TR, Smart A, Briggs JP, and Schnermann J. Am J Physiol Renal Physiol 277: F706–F710, 1999; Wang JL, Cheng HF, and Harris RC. Hypertension 34: 96–101, 1999). In the present studies, we utilized mice with genetic deletions of the COX-2 gene in order to investigate further the potential role of COX-2 in mediation of the renin-angiotensin system (RAS). Age-matched wild-type (+/+), heterozygotes (+/−), and homozygous null mice (−/−) were administered the angiotensin-converting enzyme inhibitor (ACEI), captopril, for 7 days. ACEI failed to significantly increase plasma renin activity, renal renin mRNA expression, and renal renin activity in (−/−) mice. ACEI increased the number of cells expressing immunoreactive renin in the (+/+) mice both by inducing more juxtaglomerular cells to express immunoreactive renin and by recruiting additional renin-expressing cells in the more proximal afferent arteriole. In contrast, there was minimal recruitment of renin-expressing cells in the more proximal afferent arteriole of the −/− mice. In summary, these results indicate that ACEI-mediated increases in renal renin production were defective in COX-2 knockout (K/O) mice and provide further indication that MD COX-2 is an important mediator of the renin-angiotensin system.

Acute upregulation of COX-2 by renal artery stenosis

2001 ◽  
Vol 280 (1) ◽  
pp. F119-F125 ◽  
Author(s):  
Bianca Mann ◽  
Andrea Hartner ◽  
Boye L. Jensen ◽  
Karl F. Hilgers ◽  
Klaus Höcherl ◽  
...  
Keyword(s):  
Plasma Renin Activity ◽  
Renal Artery ◽  
Renal Artery Stenosis ◽  
Plasma Renin ◽  
Artery Stenosis ◽  
Renin Activity ◽  
Mrna Levels ◽  
Renin Mrna ◽  
Intact Kidney ◽  
Cox 2

This study aimed to characterize the influence of acute renal artery stenosis on cyclooxygenase-2 (COX-2) and renin expression in the juxtaglomerular apparatus. For this purpose, male Sprague-Dawley rats received a left renal artery clip, and COX-2 mRNA, COX-2 immunoreactivity, plasma renin activity, and renin mRNA levels were determined. COX-2 mRNA and COX-2 immunoreactivity in the macula densa region in the clipped kidneys increased as early as 6 h after clipping and reached a maximal expression 1–2 days after clipping. Although values for plasma renin activity were elevated markedly at all time points examined, remaining renin mRNA levels were unchanged after 6 h and then increased to reach a maximum value 1–2 days after clipping. In the contralateral intact kidney, renin mRNA and COX-2 immunoreactivity decreased to ∼50% of their normal values. To investigate a possible causal relationship between the changes of COX-2 and of renin expression, clipped rats were treated with the COX-2 blocker celecoxib (40 mg · kg−1 · day−1). This treatment, however, did not change renin mRNA either in the clipped or in the contralateral intact kidney. Our findings indicate that renal artery stenosis causes ipsilaterally an acute upregulation and contralaterally a downregulation of juxtaglomerular COX-2 expression. The lacking effect of celecoxib on renin gene expression does not support the concept of a direct mediator function of COX-2-derived prostaglandins in the control of renin expression during renal hypoperfusion.

Cyclooxygenase-2 contributes to elevated renin in the early postnatal period in rats

2003 ◽  
Vol 284 (5) ◽  
pp. R1179-R1189 ◽  
Author(s):  
Jane Stubbe ◽  
Boye L. Jensen ◽  
Sebastian Bachmann ◽  
Peter Morsing ◽  
Ole Skøtt
Keyword(s):  
Kidney Development ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Secretory Activity ◽  
Postnatal Period ◽  
Thick Ascending Limb ◽  
Adult Rats ◽  
Renin Mrna ◽  
Cox 2 ◽  
Cox 1

We asked whether cyclooxygenase (COX) activity controls the renin-angiotensin system in the postnatal period. During kidney development, renin peaked at postnatal days 0–1 at the mRNA, tissue protein [renal renin concentration (RRC)], and plasma renin concentration (PRC) levels and was widely expressed along preglomerular vessels. PRC and renin mRNA expression was elevated until weaning in the 4th postnatal week compared with adult rats. Renocortical COX-2 was restricted to Tamm-Horsfall protein-positive cells in the thick ascending limb of Henle's loop, and cortical COX-2 mRNA and protein expression were elevated along with PRC in the 2nd and 3rd postnatal weeks. In contrast, cortical COX-1 expression was constant, but medullary COX-1 expression increased eightfold from the 1st to 4th postnatal week. A COX-2-selective blocker, parecoxib, and a nonselective blocker, indomethacin, given in a period with COX-2 induction from postnatal day 6 to day 12, markedly decreased PRC, but not renin mRNA or RRC. Inhibition of angiotensin AT1 receptors by candesartan from postnatal day 1 to day 5increased COX-2 mRNA (2.5-fold), protein, and distribution, renin mRNA (7-fold) and PRC (20- to 70-fold), but had no influence on COX-1 mRNA. Thus, due to very low levels of expression, COX-2 is unlikely to be responsible for the birth peak of renin, but COX-2 activity supports renin secretion later in the suckling period. ANG II negatively feeds back on renocortical COX-2 expression in the 1st postnatal days with high activity of the renin system. We suggest that suckling in the rat is correlated to an enhanced, COX-2-mediated, secretory activity of renin-producing juxtaglomerular cells.

scholarly journals ChTX induces oscillatory contraction in guinea pig trachea: role of cyclooxygenase-2 and PGE2

2003 ◽  
Vol 284 (6) ◽  
pp. L1045-L1054 ◽  
Author(s):  
Yukihiro Yagi ◽  
Masayoshi Kuwahara ◽  
Hirokazu Tsubone
Keyword(s):  
Guinea Pig ◽  
Prostaglandin E ◽  
Receptor Subtype ◽  
Phasic Contraction ◽  
Oscillatory Frequency ◽  
Cox Inhibitor ◽  
The Mean ◽  
Cox 2 ◽  
Cox 1

We examined the possible role of cyclooxygenase (COX) in charybdotoxin (ChTX)-induced oscillatory contraction in guinea pig trachea. Involvement of prostaglandin E2 (PGE2) in ChTX-induced oscillatory contraction was also investigated. ChTX (100 nM) induced oscillatory contraction in guinea pig trachea. The mean oscillatory frequency induced by ChTX was 10.7 ± 0.8 counts/h. Maximum and minimum tensions within ChTX-induced oscillatory contractions were 68.4 ± 1.8 and 14.3 ± 1.7% compared with K+ (72.7 mM) contractions. ChTX-induced oscillatory contraction was completely inhibited by indomethacin, a nonselective COX inhibitor. Valeryl salicylate, a selective COX-1 inhibitor, did not significantly inhibit this contraction, whereas N-(2-cyclohexyloxy-4-nitro-phenyl)-methanesulfonamide, a selective COX-2 inhibitor, abolished this contraction. Exogenously applied arachidonic acid enhanced ChTX-induced oscillatory contraction. SC-51322, a selective PGE receptor subtype EP1 antagonist, significantly inhibited ChTX-induced oscillatory contraction. Exogenously applied PGE2 induced only a slight phasic contraction in guinea pig trachea, but PGE2 induced strong oscillatory contraction after pretreatment with indomethacin and ChTX. Moreover, ChTX time-dependently stimulated PGE2 generation. These results suggest that ChTX specifically activates COX-2 and stimulates PGE2 production and that ChTX-induced oscillatory contraction in guinea pig trachea is mediated by activation of EP1 receptor.

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