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)

Renin is a proteolytic enzyme that has been considered to have only one function which is to cleave angiotensinogen between the 10th and 11th amino acids to form angiotensin-1. This is then converted to angiotensin-II, a potent vasoconstrictor, antinatriuretic and antidiuretic by angiotensin-converting enzyme. We have investigated the action of renin to stimulate prostaglandin production by decidual cells and in so doing have generated data that challenge the prevailing dogma. Renin stimulates decidual prostaglandin production in a concentration-related fashion that is unaffected by saralasin treatment. This stimulatory action of renin is enhanced rather than reduced by arachidonic acid treatment but abolished by treatment with cycloheximide or actinomycin D. Renin caused a more rapid recovery of decidual prostaglandin biosynthesis from acetylsalicylic acid treatment than did control media. Moreover, renin treatment of both decidual and amnion cells induced increased levels of PGHS-2 within 2 h. Collectively, these results indicate that renin can act directly, separately from the generation of angiotensin-I and II. In this case renin can induce PGHS expression.
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PMID:Renin stimulates decidual prostaglandin production via a novel mechanism that is independent of angiotensin II formation. 882 12

Prostaglandins (PGs) are arachidonic acid (AA) derivatives via the PG endoperoxyde H synthase (PGHS) complex. Two PGHS isoforms have been recognized, constitutive (PGHS-1) and inducible (PGHS-2), respectively. Within the kidney, vascular endothelium mainly produces PGI2; the whole glomerulus synthesizes several prostanoids, the predominant AA metabolite in humans being PGI2; tubules and medullary interstitial cells produce mainly PGE2. Renal PGs modulates the action of other hormones and autacoids involved in the regulation of renal hemodynamics, glomerular filtration and the renal handling of sodium and water. Renal PGs are, at least in part, excreted into urine. Measurement of urinary PGs or their metabolites has been found to provide a reliable estimation of basal as well as stimulated PG synthesis. Patients with cirrhosis of the liver show an increased renal synthesis of vasodilating PGs, as indicated by the high urinary excretion of PGs and/or their metabolites. Administration of nonsteroidal anti-inflammatory drugs (NSAIDs) to these patients causes a profound reduction in renal blood flow and glomerular filtration rate, a reduction in sodium excretion, and an impairment of free water clearance. These data clearly indicate that the increased renal synthesis of vasodilating PGs has a relevant role in maintaining renal hemodynamics, sodium and water excretion in a clinical setting characterized by a reduction of effective plasma volume and a striking activation of the major vasoconstricting systems, namely the renin-angiotensin-aldosterone, the sympathetic nervous system, and vasopressin. Patients with hepato-renal syndrome have a reduced renal synthesis of vasodilating PGE2 in the setting of a striking activation of endogenous vasoconstrictors and a maintained or increased renal production of thromboxane A2. Therefore, an imbalance between vasoconstricting systems and the renal vasodilator PGE2 was proposed to explain the renal failure observed in this condition. The urinary excretion of 2-3-dinor 6-keto-PGF1 alpha, an index of systemic PGI2 synthesis, is increased in patients with cirrhosis and hyperdynamic circulation, thus raising the possibility that systemic synthesis of PGI2 may contribute to the arterial vasodilatation of these patients. Finally, administration of exogenous prostanoids to patients with cirrhosis is not effective either in ameliorating renal function or in preventing the deleterious effect of NSAIDs.
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PMID:Arachidonic acid derivatives and renal function in liver cirrhosis. 935 64

Luminal NaCl concentration at the macula densa (MD) has the two established effects of regulating glomerular arteriolar resistance and renin secretion. Tubuloglomerular feedback (TGF), the inverse relationship between MD NaCl concentration and glomerular filtration rate (GFR), stabilizes distal salt delivery and thereby NaCl excretion in response to random perturbations unrelated to changes in body salt balance. Control of vasomotor tone by TGF is exerted primarily by NaCl transport-dependent changes in local adenosine concentrations. During long-lasting perturbations of MD NaCl concentration, control of renin secretion becomes the dominant function of the MD. The potentially maladaptive effect of TGF under chronic conditions is prevented by TGF adaptations, permitting adjustments in GFR to occur. TGF adaptation is mechanistically coupled to the end point targeted by chronic deviations in MD NaCl, the rate of local and systemic angiotensin II generation. MD control of renin secretion is the result of the coordinated action of local mediators that include nitric oxide synthase (NOS) and cyclooxygenase (COX) products. Thus vascular smooth muscle cell activation during high MD transport and granular cell activation during low MD transport is achieved by different extracellular mediators. The coordinated regulation of NOS I and COX-2 expression in MD cells and of renin expression in granular cells suggests that control of juxtaglomerular regulation of gene transcription or mRNA metabolism may be another consequence of a chronic alteration in MD NaCl concentration.
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PMID:Juxtaglomerular cell complex in the regulation of renal salt excretion. 948 81

Cyclooxygenase (COX)-2 mRNA and immunoreactive protein localize to the macula densa and adjacent cortical thick ascending limb in renal cortex, and chronic NaCl restriction increases expression of this enzyme. These findings suggest an integral role for eicosanoids generated by macula densa-associated COX-2 in mediating renin release. As selective inhibitors of COX-2 become available, it will be important to assess their effects on the renin-angiotensin system and glomerular hemodynamics.
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PMID:Prostaglandins in macula densa function. 973 53

Previous results from our laboratory have shown that in the isolated perfused juxtaglomerular apparatus, nonselective inhibitors of cyclooxygenase (COX) activity prevent the stimulation of renin secretion by a reduction in luminal NaCl concentration at the macula densa. The present studies were performed to examine which COX isoform is involved in NaCl-dependent renin secretion. In the absence of COX inhibitors, a reduction in luminal NaCl (from Na 141/Cl 120 mM to Na 26/Cl 7 mM) caused an increase in renin secretion rate from 4.5 +/- 1.8 to 26.1 +/- 7.4 nGU/min (P < 0.01, n = 19). The presence of the COX-1 inhibitor valerylsalicylate (500 microM) in lumen and bath did not affect the stimulation of renin secretion by a reduction in luminal NaCl concentration (5 +/- 1.8 nGU/min at high NaCl, and 30.5 +/- 9.4 nGU/min at low NaCl; P < 0.01, n = 8). In contrast, the specific COX-2 inhibitor NS-398 (50 microM) in lumen and bath abolished the stimulating effect of low luminal NaCl (12.8 +/- 3.9 nGU/min at high NaCl, and 10.7 +/- 3.1 nGU/min at low NaCl; NS, n = 15). The finding that COX-2 is critically involved in macula densa control of renin secretion indicates that the COX-2-expressing epithelial cells in the tubuloglomerular contact area are a likely source of prostaglandins participating in the signaling pathway between the macula densa and renin-producing granular cells.
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PMID:Inhibition of macula densa-stimulated renin secretion by pharmacological blockade of cyclooxygenase-2. 1056 33

1. Selective inhibitors of cyclo-oxygenase-2 have been shown to be effective anti-inflammatory drugs with reduced gastrointestinal toxicity relative to conventional nonsteroidal anti-inflammatory drugs (NSAIDs). In the present study, we examined the possibility that selective COX-2 inhibition, by blocking prostacyclin synthesis, would increase blood pressure and cause leukocyte adherence and platelet aggregation. 2. Normal rats and rats with hypertension induced by chronic administration of Nomega-nitro-L-arginine methylester were given celecoxib (10 mg kg(-1)) daily for 3 weeks. Celecoxib significantly elevated of blood pressure in both the normal and hypertensive rats (mean increase of >33 mm Hg after 3 weeks). 3. In normal rats, celecoxib had no effect on serum 6-keto prostaglandin (PG)F(1alpha) levels. Hypertensive rats exhibited a significant increase (82%) in serum 6-keto PGF(1alpha) levels, and this was reduced to the levels of normal rats by treatment with celecoxib. 4. Rats treated with celecoxib exhibited significant increases in weight gain (20%), plasma arginine-vasopressin levels (148%) and plasma urea (69%) relative to vehicle-treated controls. Plasma creatinine levels were unaffected by treatment with celecoxib, while plasma renin levels were significantly decreased (30%) relative to controls. 5. Superfusion of mesenteric venules with celecoxib (3 microM) in vivo resulted in significant increases in leukocyte adherence to the endothelium in both normal and hypertensive rats. 6. These studies suggest that suppression of COX-2 significantly influences vascular and/or renal function, leading to elevated blood pressure and leukocyte adherence.
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PMID:Selective cyclo-oxygenase-2 inhibition with celecoxib elevates blood pressure and promotes leukocyte adherence. 1074 98

We have previously shown that in renal cortex, COX-2 expression is localized to macula densa and surrounding cortical thick ascending limb of Henle (cTALH). Dietary salt restriction increases local expression of COX-2, which mediates renin production and secretion. Given that decreased luminal chloride [Cl(-)] at the level of the macula densa increases renin production and secretion, we investigated the role of extracellular ion concentration on COX-2 expression. Quiescent rabbit cTALH cells were incubated in a physiological salt solution containing high or low levels of NaCl. Immunoreactive COX-2 expression increased significantly in the low NaCl solution. COX-2 expression also increased after administration of the Na(+)/K(+)/2Cl(-) cotransport inhibitor, bumetanide. Selective substitution of chloride led to increased COX-2 expression, whereas selective substitution of sodium had no effect. The p38 MAP kinase inhibitor PD169316 decreased low NaCl-induced COX-2 expression. Low-salt or low-chloride medium induced cultured cTALH to accumulate >/= 3-fold higher levels of pp38, the activated (phosphorylated) form of p38; low-salt medium also increased pJNK and pERK levels. Feeding rats a low-salt diet for 14 days induced a significant increase in renal cortical pp38 expression, predominantly in the macula densa and cTALH. These results suggest that reduced extracellular chloride leads to increased COX-2 expression, which may be mediated by activation of a p38-dependent signaling pathway.
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PMID:Role of p38 in the regulation of renal cortical cyclooxygenase-2 expression by extracellular chloride. 1097 15

The kidney is the second most frequent target of serious adverse effects of non-steroidal antiinflammatory drugs (NSAIDs). The renal side effects of NSAIDs related to inhibition of cyclooxygenase (COX) comprise reduction in renal blood flow (RBF) and glomerular filtration rate (GFR), sodium/water retention, water intoxication and hyperkalemia. The discovery of two COX-isoenzymes, a constitutive COX-1, serving homeostatic prostanoid synthesis, and an inducible COX-2, responsible for proinflammatory prosta noid production, led to the development of new NSAIDs: Preferential and specific COX-2 inhibitors, promising minimal NSAID-typical toxicity with equivalent efficacy. However, we learned that there is no clear distinction in "physiologic" constitutive COX-1 and "inflammatory" inducible COX-2. This is particular true for the kidney of humans and other mammalians, where COX-2 was found constitutively in meaningful amounts. Animal experiments and clinical trials with preferential and specific COX-2 inhibitors revealed that COX-2 is the critical enzyme for sodium excretion, renin release and likely antagonism of antidiuretic hormone. Additionally, a significant role of COX-2 for nephro genesis is suggested. For renal hemodynamics the given evidence point to COX-1 as the predominant enzyme, but further investigations are required. In summary, the gain of renal safety by use of preferential or specific COX-2 inhibitors is small or negligible with respect to sodium retention, hyperkalemia and probably water intoxication. These drugs may be advantageous regarding renal perfusion, but presently the same precautions as for conventional NSAIDs must be used.
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PMID:COX-2 and the kidneys. 1110 61

The role of vascular endothelial growth factor (VEGF), a potent endothelium-specific angiogenic factor, in the regulation of angiotensin-converting enzyme (ACE) in cultured human umbilical vein endothelial cells (HUVECs) was studied. VEGF (0.07-1.2 x 10(-6) mmol/l) caused a dose-dependent increase in ACE measured in intact endothelial cells and increased the expression of ACE mRNA. The stimulatory effect of VEGF was inhibited by pretreatment of endothelial cells with the tyrosine kinase inhibitor herbimycin (4.35 x 10(-5) mmol/l). The stimulatory effect of VEGF was potentiated by the selective cGMP phosphodiesterase inhibitor zaprinast (0.1 mmol/l). The nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 5.4 mmol/l) suppressed the stimulatory effect of VEGF. The nonselective cyclooxygenase (COX) inhibitor indomethacin (5 microM) and the selective COX-2 inhibitor NS-398 (5 microM) potentiated the stimulatory effect of VEGF, whereas the selective COX-1 inhibitor resveratrol (5 microM) was without effect. ACE induction by VEGF was inhibited by the selective protein kinase C (PKC) inhibitor GF109203X (2.5 x 10(-3) mmol/l) and by downregulating PKC with phorbol 12-myristate 13-acetate. In summary, VEGF induced ACE in cultured HUVECs. Intracellular events such as tyrosine kinase activation, PKC activation, and increase of cGMP were probably involved in ACE induction by VEGF. Nitric oxide may partially contribute to ACE induction by VEGF. The powerful capacity of VEGF to increase ACE in endothelial cells shown here suggests a synergistic relation between VEGF and the renin-angiotensin system in vascular biology and pathophysiology.
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PMID:Upregulation of angiotensin-converting enzyme by vascular endothelial growth factor. 1115 90

Non-steroidal anti-inflammatory drugs (NSAID) are used since years as tocolytic due to their capacity to inhibit cyclo-oxygenase (COX) expressed in uterus and fetal membranes, fundamental for labour initiation and maintenance. The use of nimesulide, a COX-2 selective NSAID, has been recently proposed due to its capacity to selectively inhibit the enzyme expressed in the myometrium and endometrium. A case of neonatal irreversible end stage renal failure after maternal assumption of nimesulide as tocolytic for 6 week is reported. Cesarean section at the 32nd week due to oligohydramnios gave birth to a baby girl of 2090 g, in good general conditions, without signs of respiratory distress and of visible abnormalities. From birth she displayed oligo-anuria which required dialytic substitutive therapy from the second day of life. At US scan both kidneys had normal diameters for gestational age slightly increased echogenicity and a reduced cortico-medullary differentiation. On the 20th day of life she had a surgical renal biopsy for the persistence of oligo-anuria, showing fetal glomeruli, without lymphocytic interstitial infiltrate, and normal tubuli without evidence of necrosis. She is now 16 months old and under automated peritoneal dialysis on a home dialysis program. The occurrence of chronic renal failure in strict relationship with maternal nimesulide assumption in this case is strongly suggestive for a pharmacological damage, either direct or mediated by renin angiotensin inhibition, and possibly modulated by genetic factors, likely to account for the different outcome of similarly treated patients. A cautious use of this drug as long term tocolytic should be recommended while waiting for ad hoc experimental and clinical evidences of safeness.
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PMID:[Neonatal chronic kidney failure associated with cyclo-oxygenase-2 inhibitors administered during pregnancy]. 1145 21


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