Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The signaling molecules cGMP, cAMP, prostaglandin E(2) (PGE(2)), and prostaglandin F(2alpha) (PGF(2alpha)) play important roles in mediating the response of the kidney to changes in dietary sodium intake. We used a renal microdialysis technique in conscious rats to address the hypothesis that the renal ability to produce these mediators in response to dietary sodium intake is altered during maturation. Young (4-week-old) or adult (6-month-old) rats were studied after the consumption for 5 days of diets containing low (0. 04% NaCl), normal (0.28% NaCl), or high (4.0% NaCl) levels of sodium. Plasma renin activity was significantly increased by low-sodium diet and significantly decreased by high-sodium diet, with no significant difference between the responses of the 2 age groups. Renal interstitial fluid (RIF) levels of cGMP, cAMP, PGE(2), and PGF(2alpha) on normal-sodium diet were similar in the 2 age groups. Low-sodium diet caused a significant increase in RIF levels of all 4 mediators, with no significant differences between the responses of the 2 age groups. High-sodium diet also caused a significant increase in RIF levels of all 4 mediators. However, RIF production of cGMP, cAMP, and PGE(2) was significantly greater, and RIF PGF(2alpha) production was significantly lower, in young rats compared with adult rats. These data demonstrate that the kidneys of young and adult rats respond to dietary sodium restriction in a similar manner but that there are age-related changes in the renal response to sodium loading.
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PMID:Age-related changes in renal cyclic nucleotides and eicosanoids in response to sodium intake. 1067 11

Prostaglandin E(2) is a major renal cyclooxygenase metabolite of arachidonate and interacts with four G protein-coupled E-prostanoid receptors designated EP(1), EP(2), EP(3), and EP(4). Through these receptors, PGE(2) modulates renal hemodynamics and salt and water excretion. The intrarenal distribution and function of EP receptors have been partially characterized, and each receptor has a distinct role. EP(1) expression predominates in the collecting duct where it inhibits Na(+) absorption, contributing to natriuresis. The EP(2) receptor regulates vascular reactivity, and EP(2) receptor-knockout mice have salt-sensitive hypertension. The EP(3) receptor is also expressed in vessels as well as in the thick ascending limb and collecting duct, where it antagonizes vasopressin-stimulated salt and water transport. EP(4) mRNA is expressed in the glomerulus and collecting duct and may regulate glomerular tone and renal renin release. The capacity of PGE(2) to bidirectionally modulate vascular tone and epithelial transport via constrictor EP(1) and EP(3) receptors vs. dilator EP(2) and EP(4) receptors allows PGE(2) to serve as a buffer, preventing excessive responses to physiological perturbations.
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PMID:Prostaglandin E receptors and the kidney. 1089 84

Reducing luminal NaCl concentration in the macula densa region of the nephron stimulates renin secretion, and this response is blocked by a specific inhibitor of cyclooxygenase-2 (COX-2) (Traynor, T. R., Smart, A., Briggs, J. P., and Schnermann, J. (1999) Am. J. Physiol. Renal Physiol. 277, F706-710). To study whether low NaCl activates COX-2 activity or expression we clonally derived a macula densa cell line (MMDD1 cells) from SV-40 transgenic mice using fluorescence-activated cell sorting of renal tubular cells labeled with segment-specific fluorescent lectins. MMDD1 cells express COX-2, bNOS, NKCC2, and ROMK, but not Tamm-Horsfall protein, and showed rapid (86)Rb(+) uptake that was inhibited by a reduction in NaCl concentration and by bumetanide or furosemide. Isosmotic exposure of MMDD1 cells to low NaCl (60 mm) caused a prompt and time-dependent stimulation of prostaglandin E(2) (PGE(2)) release that was prevented by the COX-2 specific inhibitor NS-398 (10 microm). Reducing NaCl to 60 and 6 mm for 16 h increased COX-2 expression in a chloride-dependent fashion. Low NaCl phosphorylated p38 kinase within 30 min and ERK1/2 kinases within 15 min without changing total MAP kinase levels. Low NaCl-stimulated PGE(2) release and COX-2 expression was inhibited by SB 203580 and PD 98059 (10 microm), inhibitors of p38 and ERK kinase pathways. We conclude that low chloride stimulates PGE(2) release and COX-2 expression in MMDD1 cells through activation of MAP kinases.
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PMID:Low chloride stimulation of prostaglandin E2 release and cyclooxygenase-2 expression in a mouse macula densa cell line. 1098 5

In the adult mammalian kidney, high levels of cyclooxygenase (COX)-2 expression can be detected in the macula densa and associated cortical thick ascending limb cells and medullary interstitial cells. In the renal cortex, COX-2 expression increases in high renin states, and selective COX-2 inhibitors significantly decrease plasma renin levels. In the medullary region of the kidney, the expression of COX-2 increases in response to a high-salt diet and water deprivation. The most important prostanoids in the kidney are prostaglandin (PG)I(2), or prostacyclin, and PGE(2). PGE(2) diminishes sodium reabsorption; thereby, its inhibition results in sodium retention that can manifest clinically in a variety of ways, such as peripheral edema, increased blood pressure (mainly in treated hypertensive patients), weight gain, and occasionally deterioration of heart failure. PGI(2) increases potassium secretion. As such, its inhibition can result in hyperkalemia, particularly in patients with underlying renal insufficiency. PGI(2) is also a potent vasodilator and helps maintain renal perfusion in conditions of decreased actual or effective circulating volume; its inhibition in such patients can result in acute renal failure. A variety of studies has been conducted to examine the effects of celecoxib and rofecoxib on renal function. These incorporate various study designs directly, making it virtually impossible to compare data across studies. It is apparent from such studies, coupled with published case reports, that the impact of both celecoxib and rofecoxib on renal function (including development of edema and hypertension) is similar to that of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). Studies comparing the 2 COX-2 inhibitors conflict in their interpretation. Overall, the data suggest similar effects on renal function among all NSAIDs when used at comparable doses.
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PMID:Cyclooxygenase-2 inhibition and renal physiology. 1190 56

There is evidence that fetal growth restriction is associated with impaired nephrogenesis and reduced numbers of mature nephrons at birth. It has been proposed that such impairment of renal growth may contribute to increased blood pressure in later life. Although prostaglandins (PG) play a key role in kidney development, it is unknown whether a poor fetal substrate supply alters the synthesis or actions of PG within the fetal kidney. Using real-time reverse transcriptase PCR, we have measured the effect of chronic placental restriction (PR) on the renal expression of PG endoperoxide G/H synthase-2 (PGHS-2), PGE(2) receptors EP(2) and EP(4), and renin mRNA in the sheep fetus in late gestation. Restriction of placental growth reduced fetal body weight (PR: 3.2 +/- 0.2 kg, control: 4.8 +/- 0.2 kg) and total kidney weight (PR: 19.7 +/- 1.8 g, control: 25.1 +/- 1.3 g). Mean fetal arterial PO(2) was reduced by PR (PR: 15.03 +/- 0.67 mm Hg, control: 21.3 +/- 0.87 mm Hg). Renal PGHS-2 mRNA was increased in the PR group (PR: 2.26 +/- 0.38, control: 1.20 +/- 0.31) and was inversely related to mean fetal arterial PO(2) in the PR and control groups [PGHS-2: -0.17 (PO(2)) + 4.69, r(2) = 0.26]. PR also increased renal EP(2) (PR: 1.57 + 0.24, control: 0.82 + 0.13) but not EP(4) mRNA. Renin mRNA was directly related to renal EP(2) [renin = 0.37 (EP(2)) + 0.97, r(2) = 0.29] and EP(4), [renin = 0.75 (EP(4)) + 0.44, r(2) = 0.38] mRNA expression. Thus, the restriction of placental growth and associated chronic hypoxemia appear to increase the renal capacity to synthesize and respond to PG, which may play an important role in maintaining renin mRNA expression in the growth-restricted fetus.
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PMID:Placental restriction increases the expression of prostaglandin endoperoxide G/H synthase-2 and EP2 mRNA in the fetal sheep kidney during late gestation. 1243 65

Macula densa (MD) cells express COX-2 and COX-2-derived PGs appear to signal the release of renin from the renal juxtaglomerular apparatus, especially during volume depletion. However, the synthetic machinery and identity of the specific prostanoid released from intact MD cells remains uncertain. In the present studies, a novel biosensor tool was engineered to directly determine whether MD cells release PGE2 in response to low luminal NaCl concentration ([NaCl]L). HEK293 cells were transfected with the Ca2+-coupled E-prostanoid receptor EP1 (HEK/EP1) and loaded with fura-2. HEK/EP1 cells produced a significant elevation in intracellular [Ca2+] ([Ca2+]i) by 29.6 +/- 12.8 nM (n = 6) when positioned at the basolateral surface of isolated perfused MD cells and [NaCl]L was reduced from 150 mM to zero. HEK/EP1 [Ca2+]i responses were observed mainly in preparations from rabbits on a low-salt diet and were completely inhibited by either a selective COX-2 inhibitor or an EP1 antagonist, and also by 100 microM luminal furosemide. Also, 20-mM graduated reductions in [NaCl]L between 80 and 0 mM caused step-by-step increases in HEK/EP1 [Ca2+]i. Low-salt diet greatly increased the expression of both COX-2 and microsome-associated PGE synthase (mPGES) in the MD. These studies provide the first direct evidence that intact MD cells synthesize and release PGE2 during reduced luminal salt content and suggest that this response is important in the control of renin release and renal vascular resistance during salt deprivation.
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PMID:Luminal NaCl delivery regulates basolateral PGE2 release from macula densa cells. 1284 61

In hyperprostaglandin E syndrome (HPGES) and classic Bartter syndrome (cBS), tubular salt and water losses stimulate renin secretion, which is dependent on enhanced cyclooxygenase-2 (COX-2) enzymatic activity. In contrast to other renal COX metabolites, only prostaglandin E(2) (PGE(2)) is selectively up-regulated in these patients. To determine the intrarenal source of PGE(2) synthesis, we analyzed the expression of microsomal PGE(2) synthase (mPGES; EC: 5.3.99.3), whose product PGE(2) has been shown to stimulate renin secretion in vitro. Expression of mPGES was analyzed by immunohistochemistry in eight patients with HPGES, in two patients with cBS, and in six control subjects. Expression of mPGES immunoreactive protein was observed in cells of the macula densa in five of eight HPGES patients and in one of two cBS patients. Expression of mPGES immunoreactive protein was not observed in cells associated with the macula densa in kidneys from control subjects without a history consistent with activation of the renin angiotensin system. Co-induction of COX-2 and mPGES in cells of the macula densa suggests that PGE(2) activates renin secretion in humans.
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PMID:Induction of microsomal prostaglandin E2 synthase in the macula densa in children with hypokalemic salt-losing tubulopathies. 1463 Sep 96

Renal prostaglandins (PG), renin, and cortisol are necessary for normal kidney development and function during fetal life. We examined the effects of cortisol infusion before completion of nephrogenesis (d 109-116 gestation; 2.0-3.0 mg hydrocortisone succinate/24 h) on the renal mRNA expression of PGHS-2, the PGE(2) receptors, EP(2) and EP(4), and renin in fetal sheep. Cortisol infusion raised plasma cortisol levels to 42.8 +/- 6.0 nmol/L compared with saline infusion levels of 1.5 +/- 0.5 nmol/L (p < 0.001), but had no effect on fetal body weight, proportional kidney mass, or blood gases. Cortisol decreased significantly the relative expression of renin mRNA (saline: 0.93 +/- 0.06 units; cortisol: 0.32 +/- 0.03 units, p < 0.05), however it had no effect upon the expression of PGHS-2, EP(2), or EP(4) mRNA in fetal sheep kidney. Although there is substantial evidence that PGE(2) acting through either the EP(2) or EP(4) receptor stimulates renin synthesis in the adult kidney, our results have demonstrated that before the completion of nephrogenesis, cortisol down-regulation of renin mRNA expression is independent of any change in the expression of PGHS-2, EP(2), or EP(4) mRNA expression. During nephrogenesis, the insensitivity of PGHS-2, EP(2), and EP(4) expression to down-regulation by cortisol may permit continued PG regulation of renal development and urine formation.
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PMID:Cortisol infusion decreases renin, but not PGHS-2, EP2, or EP4 mRNA expression in the kidney of the fetal sheep at days 109-116. 1471 86

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 PGE(2) on nNOS expression. In a cultured macula densa cell line, PGE(2) 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 PGE(2) on nNOS mRNA expression indicates a novel interaction between NO and prostaglandin-mediated pathways of renin regulation.
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PMID:Inhibition of nNOS expression in the macula densa by COX-2-derived prostaglandin E(2). 1501 Mar 56

PGE(2) is a potent stimulator of renin release. So far, the contribution of each of the four PGE(2) receptor subtypes (EP(1)-EP(4)) in the regulation of renin release has not been characterized. Therefore, we investigated the effects PGE(2) on renin secretion rates (RSR) from isolated, perfused kidneys of EP(1)-/-, EP(2)-/-, EP(3)-/-, EP(4)-/-, and wild-type mice. PGE(2) concentration dependently stimulated RSR from kidneys of all four knockout strains with a threshold concentration of 1 nM in EP(1)-/-, EP(2)-/-, EP(3)-/-, and wild-type mice, whereas the threshold concentration was shifted to 10 nM in EP(4)-/- mice. Moreover, the maximum stimulation of RSR by PGE(2) at 1 microM was significantly reduced in EP(4)-/- (12.8-fold of control) and EP(2)-/- (15.9-fold) compared with wild-type (20.7-fold), EP(1)-/- (23.8-fold), and EP(3)-/- (20.1-fold). In contrast, stimulation of RSR by either the loop diuretic bumetanide or the beta-adrenoceptor agonist isoproterenol was similar in all strains. PGE(2) exerted a dual effect on renal vascular tone, inducing vasodilatation at low concentrations (1 nmol/) and vasoconstriction at higher concentrations (100 nmol/) in kidneys of wild-type mice. In kidneys of EP(2)-/- as well as EP(4)-/- mice, vasodilatation at low PGE(2) concentrations was prevented, whereas vasoconstriction at higher concentrations was augmented. In contrast, the vasodilatory component was pronounced in kidneys of EP(1) and EP(3) knockout mice, whereas in both genotypes the vasoconstriction at higher PGE(2) concentrations was markedly blunted. Our data provide evidence that PGE(2) stimulates renin release via activation of EP(2) and EP(4) receptors, whereas EP(1) and EP(3) receptors appear to be without functional relevance in juxtaglomerular cells. In contrast, all four receptor subtypes are involved in the control of renal vascular tone, EP(1) and EP(3) receptors increasing, and EP(2) as well as EP(4) receptors, decreasing it.
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PMID:Stimulation of renin release by prostaglandin E2 is mediated by EP2 and EP4 receptors in mouse kidneys. 1511 45


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