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 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.

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.

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).

Increased expression of cyclooxygenase 2 contributes to aberrant renin production in connexin 40-deficient kidneys

2007 ◽  
Vol 293 (5) ◽  
pp. R1781-R1786 ◽  
Author(s):  
Charlotte Wagner ◽  
Cor de Wit ◽  
Melanie Gerl ◽  
Armin Kurtz ◽  
Klaus Höcherl
Keyword(s):  
Plasma Renin ◽  
Cyclooxygenase 2 ◽  
Mrna Levels ◽  
Connexin 40 ◽  
Renin Mrna ◽  
The Media ◽  
Afferent Arterioles ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Inhibitor Treatment

We previously found that deletion of connexin 40 (Cx40) causes a misdirection of renin-expressing cells from the media layer of afferent arterioles to the perivascular tissue, extraglomerular mesangium, and periglomerular and peritubular interstitium. The mechanisms underlying this aberrant renin expression are unknown. Here, we questioned the relevance of cyclooxygenase-2 (COX-2) activity for aberrant renin expression in Cx40-deficient kidneys. We found that COX-2 mRNA levels were increased three-fold in the renal cortex of Cx40-deficient kidneys relative to wild-type (wt) kidneys. In wt kidneys, COX-2 immunoreactivity was minimally detected in the juxtaglomerular region, but renin expression was frequently associated with COX-2 immunoreactivity in Cx40-deficient kidneys. Treatment with COX-2 inhibitors for 1 wk lowered renin mRNA levels in wt kidneys by about 40%. In Cx40-deficient kidneys, basal renin mRNA levels were increased two-fold relative to wt kidneys, and these elevated mRNA levels were reduced to levels of untreated wt mice by COX-2 inhibitors. In parallel, renin immunoreactive areas were clearly reduced by COX-2 inhibitors such that renin expression vanished and decreased significantly in the periglomerular and peritubular extensions. Notably, COX-2 inhibitor treatment lowered plasma renin concentration (PRC) in wt kidneys by about 40% but did not affect the highly elevated PRC levels in Cx40-deficient mice. These findings suggest that aberrant renin-producing cells in Cx40-deficient kidneys express significant amounts of COX-2, which contribute to renin expression in these cells, in particular, those in the periglomerular and peritubular position. Apparently, these disseminated cells do not contribute to the enhanced renin secretion rates of Cx40-deficient kidneys.

scholarly journals Dense-core vesicle proteins IA-2 and IA-2β affect renin synthesis and secretion through the β-adrenergic pathway

2009 ◽  
Vol 296 (2) ◽  
pp. F382-F389 ◽  
Author(s):  
Soo Mi Kim ◽  
Franziska Theilig ◽  
Yan Qin ◽  
Tao Cai ◽  
Diane Mizel ◽  
...  
Keyword(s):  
Tyrosine Hydroxylase ◽  
Salt Intake ◽  
Plasma Renin ◽  
Dense Core ◽  
Dense Core Vesicle ◽  
Mrna Levels ◽  
Wild Type ◽  
Dense Core Vesicles ◽  
Renin Synthesis ◽  
Renin Mrna

IA-2 and IA-2β, major autoantigens in type 1 diabetes, are transmembrane proteins in dense-core vesicles, and their expression influences the secretion of hormones and neurotransmitters. The present experiments were performed to examine whether IA-2 and IA-2β modulate the release of renin from dense-core vesicles of juxtaglomerular granular cells in the kidney. Plasma renin concentration (PRC; ng angiotensin I·ml−1·h−1) was significantly reduced in mice with null mutations in IA-2, IA-2β, or both IA-2 and IA-2β compared with wild-type mice (876 ± 113, 962 ± 130, and 596 ± 82 vs. 1,367 ± 93; P < 0.01, P < 0.02, and P < 0.001). Renin mRNA levels were reduced to 26.4 ± 5.1, 39 ± 5.4, and 35.3 ± 5.5% of wild-type in IA-2−/−, IA-2β−/−, and IA-2/IA-2β−/− mice. Plasma aldosterone levels were not significantly different among genotypes. The regulation of PRC by furosemide and salt intake, and of aldosterone by salt intake, was maintained in all genotypes. IA-2 and IA-2β expression did not colocalize with renin but showed overlapping immunoreactivity with tyrosine hydroxylase. While propranolol reduced PRC in wild-type mice, it had no effect on PRC in IA-2/ IA-2β−/− mice. Renal tyrosine hydroxylase mRNA and immunoreactivity were reduced in IA-2/IA-2β−/− mice as was the urinary excretion of catecholamines. We conclude that IA-2 and IA-2β are required to maintain normal levels of renin expression and renin release, most likely by permitting normal rates of catecholamine release from sympathetic nerve terminals.

Renin expression in COX-2-knockout mice on normal or low-salt diets

2000 ◽  
Vol 279 (5) ◽  
pp. F819-F825 ◽  
Author(s):  
Tianxin Yang ◽  
Yoshimi Endo ◽  
Yuning G. Huang ◽  
Ann Smart ◽  
Josie P. Briggs ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Contact Region ◽  
Contact Point ◽  
Renin Activity ◽  
Mrna Levels ◽  
Granular Cells ◽  
Wild Type ◽  
Low Salt ◽  
Renin Mrna ◽  
Cox 2

Experiments were performed in mice to investigate whether cyclooxygenase-2 (COX-2) in epithelial cells near the tubulovascular contact point (macula densa and TAL cells) may regulate renin gene expression in juxtaglomerular granular cells. Renin activity, afferent arteriolar granularity, and renin mRNA were determined in wild-type mice and in COX-2-knockout mice on control and low-NaCl diets. Renin activity in microdissected glomeruli assessed as angiotensin I formation in the presence of excess substrate and afferent arteriolar granularity determined by direct visualization and immunostaining were significantly reduced in COX-2 −/− compared with wild-type animals. Similarly, renal cortical mRNA levels were lower in COX-2 −/− than in wild-type mice. Maintaining mice on a low-salt diet for 14 days induced an increase in renin mRNA, afferent arteriolar granularity, and renin activity in wild-type mice. In contrast, renin mRNA and renin granularity did not significantly increase in low-salt-treated COX-2 −/− mice, whereas the increase in juxtaglomerular renin enzyme activity was markedly attenuated, but not fully blocked. In additional experiments we found that COX-2 mRNA was increased in angiotensin type 1A receptor-knockout mice compared with wild-type mice. We conclude that COX-2 in the tubulovascular contact region is a critical determinant of renin synthesis in granular cells under resting conditions and that it participates in the stimulation of renin expression caused by a low-NaCl intake.

VARIATIONS IN PLASMA RENIN ACTIVITY AND URINARY ALDOSTERONE EXCRETION IN NORMAL SUBJECTS AFTER SALT RESTRICTION AND ACUTE PITUITARY INHIBITION WITH 6-DEHYDRO-16-METHYLENE HYDROCORTISONE

1971 ◽  
Vol 67 (1) ◽  
pp. 159-173
Author(s):  
A. Peytremann ◽  
R. Veyrat ◽  
A. F. Muller
Keyword(s):  
Plasma Renin Activity ◽  
Salt Intake ◽  
Plasma Renin ◽  
Normal Subjects ◽  
Inhibitory Effect ◽  
Renin Activity ◽  
Sodium Balance ◽  
Experimental Conditions ◽  
Salt Restriction ◽  
Aldosterone Production

ABSTRACT Variations in plasma renin activity and urinary aldosterone excretion were studied in normal subjects submitted to salt restriction and simultaneous inhibition of ACTH production with a new synthetic steroid, 6-dehydro-16-methylene hydrocortisone (STC 407). At a dose of 10 mg t. i. d. this preparation exerts an inhibitory effect on the pituitary comparable to that of 2 mg of dexamethasone. In subjects maintained on a restricted salt intake, STC 407 does not delay the establishment of an equilibrium in sodium balance. The increases in endogenous aldosterone production and in plasma renin activity are also similar to those seen in the control subjects. A possible mineralocorticoid effect of STC 407 can be excluded. Under identical experimental conditions, the administration of dexamethasone yielded results comparable to those obtained with STC 407.

Abstract 196: Role of Collecting Duct Renin in Blood Pressure Regulation

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Nirupama Ramkumar ◽  
Deborah Stuart ◽  
Sara Rees ◽  
Curt Sigmund ◽  
Donald E Kohan
Keyword(s):  
Blood Pressure ◽  
Collecting Duct ◽  
Dna Recombination ◽  
Plasma Renin ◽  
Blood Pressure Regulation ◽  
P System ◽  
Mrna Levels ◽  
Pressure Regulation ◽  
Renin Mrna ◽  
Exon 1

Recent studies propose that collecting duct (CD) renin is an important modulator of blood pressure regulation, especially in conditions such as angiotensin-II infused hypertension. We used gene targeting to generate a CD-specific renin knockout (KO) to assess if CD derived renin can regulate BP. Utilizing the Cre lox P system, exon 1 of the renin gene was ablated specifically in the CD. BP was recorded via telemetry and plasma and urine were collected in metabolic cages on normal, high and low Na diets. DNA recombination showed kidney specific recombination in KO mice. Compared to floxed mice, CD renin KO mice had 70 % lower medullary renin mRNA levels and 90% lower renin mRNA in micro-dissected cortical and inner medullary CD tubules. Urinary renin levels were significantly lower in the KO mice on normal and low Na diets (45% of floxed levels) but not with high Na intake. Plasma renin concentration was significantly higher in the KO mice on all three diets. While BP was similar between the two groups on all three diets, infusion of Ang-II delayed the increase in BP in the CD renin KO group for at least 4 days post-infusion. These findings suggest that CD renin likely plays a role in normal BP regulation (evidenced by an increase in PRC) and in response to AngII infusion.

Role of macula densa cyclooxygenase-2 in renovascular hypertension

2003 ◽  
Vol 284 (3) ◽  
pp. F498-F502 ◽  
Author(s):  
Andrea Hartner ◽  
Nada Cordasic ◽  
Margarete Goppelt-Struebe ◽  
Roland Veelken ◽  
Karl F. Hilgers
Keyword(s):  
Plasma Renin Activity ◽  
Renovascular Hypertension ◽  
Plasma Renin ◽  
Juxtaglomerular Apparatus ◽  
Macula Densa ◽  
Renin Activity ◽  
Disease States ◽  
Renin Synthesis ◽  
Cox 2

Upregulation of the inducible cyclooxygenase (COX-2) in the macula densa accompanies the activation of the juxtaglomerular apparatus in many high-renin conditions. The functional role of COX-2 in these disease states is poorly understood. We tested whether COX-2 is required to increase renin in renovascular hypertension. Rats with established two-kidney, one-clip (2K1C) hypertension were treated for 2 wk with two different inhibitors of COX-2, NS-398 and rofecoxib, respectively. Hypertension in 2K1C rats was not affected or slightly enhanced by COX-2 inhibition, as measured intra-arterially in conscious animals. The increase in plasma renin activity was also unchanged by both rofecoxib and NS-398. The number of glomeruli with a renin-positive juxtaglomerular apparatus was elevated in clipped kidneys and decreased in contralateral kidneys of 2K1C rats. This pattern was unaltered by COX-2 inhibition. To test the effects of COX-2 blockade on a primarily macula densa-mediated stimulus, we studied salt depletion for comparison. A low-salt diet induced a significant increase in plasma renin activity, which was partially inhibited by treatment with NS-398. We conclude that inhibition of COX-2 in established renovascular hypertension does not affect renin synthesis or release. Thus either COX-2 is not necessary for the macula densa mechanism or the macula densa is not important for maintaining high renin in renovascular hypertension.

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