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

The arachidonic acid metabolite 12-hydroxyeicosatetraenoic acid (12-HETE) inhibits renin secretion both in vivo and in vitro, but the enzymatic origin of the 12-HETE responsible for renin inhibition is unknown. These studies examined the effect of the 12-HETE stereoisomers (R)-12-HETE (a product of the cytochrome P-450 monooxygenase enzyme system) and (S)-12-HETE (a product of the lipoxygenase enzyme system) on basal and stimulated renin secretion from superficial cortical slices in the rat. First, rat cortex was shown to produce 12-HETE; chiral-phase high-performance liquid chromatography revealed that cortex produced 81% (S)-12-HETE and 19% (R)-12-HETE. (R)-12-HETE reduced basal renin release by 28 +/- 4% to 49 +/- 5% at concentrations of 10(-9) to 10(-7) M (P < 0.05 to 0.01). (S)-12-HETE did not significantly affect renin release. (R)-12-HETE also blunted isoproterenol-stimulated renin secretion (P < 0.05) at a concentration of 10(-6) M. 20-HETE, another cytochrome P-450 product, did not exert a significant effect on renin release. In summary, both (R)-12-HETE and (S)-12-HETE are synthesized by renal cortical tissue. Only (R)-12-HETE directly inhibits in vitro renin release. These findings suggest that the renal cytochrome P-450 enzyme system is capable of directly influencing local renin secretion.
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PMID:Inhibition of renin secretion from rat renal cortical slices by (R)-12-HETE. 141 38

In addition to cyclooxygenase and lipoxygenase, arachidonic acid (AA) is metabolized by the cytochrome P-450 monooxygenase system. The kidney is one of the major extrahepatic tissues that display cytochrome P-450 enzyme activities, in particular the cortex, specifically the proximal tubule demonstrate the highest concentration. AA is metabolized by the renal cytochrome P-450 epoxygenase and omega/omega 1 hydroxylases to epoxyeicosatrienoic acids and omega/omega-1 alcohols (20- and 19-mono-hydroxyeicosatetraenoic acids), respectively. These metabolites possess a broad spectrum of biological and renal effects which include: vasodilation, vasoconstriction, inhibition and stimulation of Na(+)-K(+)-ATPase, inhibition of ion transport mechanisms, natriuresis, inhibition of renin release and stimulation of cell growth. These metabolites are endogenous constituents of the kidney and are present in urine with increasing concentration under pathological conditions such as pregnancy-induced hypertension. The cytochrome P-450-dependent metabolism of AA is specifically localized to the proximal tubule and exhibits developmental changes, i.e., renal production of metabolites is very low in the fetus, newborn and up to 3 weeks of age, after which a remarkable increase in enzyme activities is observed. These characteristics call attention to the importance of this enzyme system in producing cellular mediators for regulating renal function in normal and diseased states.
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PMID:The renal cytochrome P-450 arachidonic acid system. 145 35

Increasing evidence indicates that the adrenal cortex of most mammalian species expresses distinct forms of cytochrome P-450(11 beta), a steroidogenic enzyme that catalyses the terminal steps in the biosynthesis of both glucocorticoids and mineralocorticoids. In the human, mouse, and rat, two genes have been isolated, designated CYP11B1 and CYP11B2. The product of CYP11B2 (aldosterone synthase) is required for the successive 11 beta-, 18-hydroxylations and 18-oxidation of deoxycorticosterone that lead to the production of aldosterone in the zona glomerulosa. In contrast, the product of CYP11B1 (11 beta-hydroxylase) mediates only the 11 beta-hydroxylation of deoxycorticosterone and 11-deoxycortisol. The recent identification of these two P-450(11 beta) isozymes mandates further analysis of their expression in different zones of the adrenal cortex, both under basal conditions and in response to conditions known to alter mineralocorticoid biosynthesis. To evaluate the expression of the two isozymes in different adrenocortical zones, we performed Northern blotting analyses with specific oligonucleotide probes that discriminated between the two forms of rat P-450(11 beta). The transcripts detected by the two probes were of similar size (2.7 kilobase), but differed in their zonal distribution: aldosterone synthase P-450 messenger RNA (mRNA) was detected only in zona glomerulosa, whereas 11 beta-hydroxylase P-450 was expressed in both zona fasciculata-reticularis and zona glomerulosa. Next, we analyzed the response of these two genes to various physiological and pharmacological interventions known to affect aldosterone biosynthesis. High potassium or low sodium diet given to rats for 1 week increased aldosterone synthase P-450 mRNA levels by approximately 5- and 6-fold, respectively. These increases, moreover, were significantly attenuated by treatment with captopril, an inhibitor of angiotensin-converting enzyme. In contrast, neither dietary manipulation significantly affected 11 beta-hydroxylase P-450 mRNA levels in any zone. Thus, stimulation of the terminal steps of aldosterone biosynthesis by variations in dietary intake of monovalent cations involves regulation of aldosterone synthase P-450 mRNA levels. Finally, captopril inhibited potassium induction of aldosterone synthase P-450 mRNA levels despite the presence of low plasma renin activity in the potassium-treated rats. This finding implicates intraadrenal angiotensin II formation in the effect of potassium on mineralocorticoid production.
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PMID:Dietary potassium supplementation and sodium restriction stimulate aldosterone synthase but not 11 beta-hydroxylase P-450 messenger ribonucleic acid accumulation in rat adrenals and require angiotensin II production. 159 35

The medullipin system of BP control has its cellular component in the renomedullary interstitial cells (RICs) of the renal papilla. The RICs secrete medullipin I which is conveyed to the liver to be activated into Med II. This activation appears to involve the cytochrome P-450 dependent enzyme system of the liver. Med II is a vasodilator that suppresses sympathetic tone, causes diuresis-natriuresis and has a suppressive effect on the central nervous system (CNS). As such, Med II has biologic actions the exact opposite of major actions of the renin-angiotensin system. Angiotensin II is a vasoconstrictor that facilitates sympathetic tone, causes salt water retention by the kidney and has stimulatory effect on the CNS. These are double feedback BP control systems. One elevates the BP and is prohypertensive; the other lowers BP and is antihypertensive. Unclipped (UC) the one-kidney, one-clip hypertensive rat has assisted greatly in elucidating the medullipin system. The support for these contentions are documented in this presentation.
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PMID:The medullipin system of blood pressure control. 174 92

We studied the contents of aldosterone and cortisol (F) and the expression of mRNA of cytochrome P-450 for side-chain cleavage (P-450scc), 17 alpha-hydroxylase (P-450c17), 21-hydroxylase (P-450c21) and 11 beta-hydroxylase (P-450c11) in adrenocortical adenomas from three patients with primary aldosteronism. The aldosterone content was significantly higher in adrenocortical adenomas than in normal adrenal glands, while F content in adenomas was similar to the level in normal adrenal glands. The aldosterone-producing adenomas showed a markedly higher level of P-450c11 mRNA, a slightly but not significantly increased level of P-450c21 mRNA and a significantly decreased level of P-450c17 mRNA, compared with those in normal adrenal glands. The expression of P-450scc mRNA in adenomas was similar to the level in normal adrenal glands. These results suggested that the renin-independent overproduction of aldosterone in adrenocortical adenomas from the patients with primary aldosteronism results from increasing expression of the mRNA for P-450c11 and decreasing expression of the mRNA for P-450c17.
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PMID:Expression of cytochrome P-450 mRNAs in steroidogenesis of adrenocortical adenomas from patients with primary aldosteronism. 182 Sep 78

1. Medullipin I (Med I) is a hormone extracted from renal papillae and its renomedullary interstitial cells (RIC). Med I is stimulated by elevation of the renal artery perfusion pressure. 2. When isolated normal rat kidneys were perfused either with oxygenated blood or with 5% albumin bubbled with O2 at elevated perfusion pressures, Med I appeared to be secreted into the renal venous effluent (RVE). Addition of Tween 20, treatment of the assay rat with SKF 525A, inhibitor of cytochrome P-450 and removal of the liver from the systemic circulation prevented vasodepression of both the RVE and extracted Med I. The lipid in the RVE gave the same dose-response as extracted Med I. 3. Lowering the renal artery perfusion pressure below normal inhibited the secretion of Med I. As the perfusion pressure was elevated Med I secretion appeared to increase. 4. Previous observations and the present study support the view that the renin-angiotensin system and the Medullipin system are double feedback systems involved in blood pressure control.
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PMID:Secretion of medullipin I by isolated kidneys perfused under elevated pressure. 191 43

Changes in the levels of aldosterone synthase cytochrome P-450, a recently identified enzyme in rat adrenals, were studied in response to the renin-angiotensin system and K stimuli. As examined by an immunoblot technique, the zona glomerulosa mitochondria from rats fed on a low Na-normal K diet (8.6 mmol Na+ and 207 mmol K+/kg of diet) or a low Na-high K (0.2 M KCl in drinking water) diet for 4-10 days contained significantly higher amounts of aldosterone synthase cytochrome P-450 than those from rats fed on a normal diet (86 mmol Na+ and 207 mmol K+/kg of diet). Activities of the enzyme were also found to increase by about 10-fold on day 10. In concert with these changes, both plasma renin activity and plasma aldosterone concentration increased, indicating that the renin-angiotensin system was activated in these rats. Feeding with a normal Na-high K diet also induced significantly higher levels of both amount and activity of aldosterone synthase cytochrome P-450 together with an elevated serum K concentration on day 4, though they all decreased to near the control level on the following days. On the other hand, when enalapril malate, an angiotensin I-converting enzyme inhibitor, was administered to the low Na-normal K rats, the increases in the amount and activity of the enzyme as well as in plasma aldosterone concentration were suppressed altogether. However, the enalapril administration to the low Na-high K rats suppressed the increases only partially. These results indicate that the aldosterone synthase cytochrome P-450 is an ultimate target of the regulation of aldosterone biosynthesis by angiotensin II and K.
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PMID:Regulation of aldosterone synthase cytochrome P-450 in rat adrenals by angiotensin II and potassium. 201 65

In the presence of NADPH cytochrome P-450-dependent monooxygenases oxidize arachidonic acid giving rise to four epoxyeicosatrienoic acids (EETs) which are hydrolyzed enzymatically to dihydroxyeicosatrienoic acids (DHETs). EETs generate vasodilators. Allylic oxidation forms hydroxyeicosatetraenoic acids, of which 12(R)HETE is an inhibitor of Na(+)-K(+)-ATPase and renin release. Finally, omega and omega-1 hydroxylation of arachidonic acid generates 20- and 19-HETEs which are involved in the development of hypertension in SHR rats.
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PMID:Cytochrome P-450 metabolites of arachidonic acid: implications for blood pressure regulation. 212 86

The effects of products of the cytochrome P-450 epoxygenase pathway of arachidonate metabolism on renin have not been previously examined. Initial high-performance liquid chromatography and gas chromatography-mass spectrometry studies documented the synthesis of four epoxyeicosatrienoic acid (EET) regioisomers of epoxygenase in superficial cortical slices from male Sprague-Dawley rats. Each regioisomer was tested for effects on both isoproterenol (ISO)-stimulated and basal renin secretion from cortical slices. ISO increased renin release significantly (169%, P less than 0.01) in all incubations; 14,15-EET (10(-6) M) significantly reduced this increase in stimulated renin release to 47%. The 5,6-, 8,9-, and 11,12-EETs did not significantly affect renin release. Basal renin release was not affected by any of the four EETs. To examine the mechanism of this inhibitory action, the effects of 14,15-EET on tissue adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 5'-cyclic monophosphate (cGMP) concentrations were measured. Tissue cAMP concentrations were sharply increased (4.75-fold, P less than 0.001) by ISO; 14,15-EET did not blunt this increase significantly. ISO and 14,15-EET did not affect tissue cGMP concentrations. Incubation of [14C]EET with cortical slices resulted in only 10% conversion of the 14,15-EET to 14,15-dihydroxyeicosatrienoic acid (DHET) (diol) after 90 min; no other metabolites were observed. The 14,15 DHET did not alter either basal or stimulated renin release. These studies document the synthesis of EETs in rat kidney and demonstrate a direct effect of the 14,15-EET to inhibit stimulated renin release. This inhibitory action occurs without an effect on tissue cAMP or cGMP concentrations.
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PMID:Inhibition of renin release by 14,15-epoxyeicosatrienoic acid in renal cortical slices. 215 33

Aminoglutethimide blocks several cytochrome P-450 mediated steroid hydroxylation steps, including those required for conversion of cholesterol to pregnenolone and for the aromatization of androgens to estrogens. Through these actions it blocks adrenal steroidogenesis and the production of estrogens in extraglandular tissues. Aminoglutethimide is indicated for treatment of certain patients with Cushing's syndrome and breast cancer. Other potential uses (prostate carcinoma, low renin hypertension, etc.) remain investigational. For treatment of Cushing's syndrome, aminoglutethimide is usually given alone or in combination with metyrapone. In women with breast carcinoma, replacement hydrocortisone must be administered with aminoglutethimide to prevent reflex ACTH hypersecretion from overcoming adrenal inhibition. Administration of aminoglutethimide to patients with Cushing's syndrome results in improvement in clinical status in 56% of cases. Results are most favorable in patients with adrenal tumors and patients with ectopic ACTH production. Aminoglutethimide and replacement glucocorticoid produce objective disease regression in 32% of unselected postmenopausal patients with metastatic breast carcinoma and in 52% of women whose tumors are estrogen receptor positive. Responses are similar in duration and frequency to those produced by surgical adrenalectomy and hypophysectomy and the antiestrogen, tamoxifen.
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PMID:Aminoglutethimide: review of pharmacology and clinical use. 676 87


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