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)

Androgen controls the expression of beta-glucuronidase and several other proteins in the kidney of the standard laboratory mouse, Mus musculus. Other species within the genus Mus exhibit a variety of response patterns for kidney beta-glucuronidase and other markers of androgen action. We have investigated the mechanism of androgen action in M. caroli, a Mus species that does not produce beta-glucuronidase in response to testosterone. The failure of testosterone to induce beta-glucuronidase in M. caroli females cannot be overcome by treatment with dihydrotestosterone, with pharmacological doses of testosterone propionate or dihydrotestosterone propionate, or with a variety of potent androgen analogues. All of these compounds induce kidney beta-glucuronidase in M. musculus females and kidney ornithine decarboxylase, submandibular gland renin, and submandibular gland epidermal growth factor in both M. caroli and M. musculus females. Furthermore, kidney androgen receptor proteins from M. caroli and M. musculus animals have the same sedimentation characteristics on sucrose density gradients. These data indicate that androgen resistance in M. caroli is not due to deficient 5 alpha-reductase or aberrant hormone metabolism producing suboptimal levels of functional androgen and is not caused by a defective androgen receptor. They suggest that the resistance of beta-glucuronidase in M. caroli kidney to induction by androgen occurs at the level of the beta-glucuronidase gene.
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PMID:Specificity of androgen resistance in Mus caroli kidney. 307 98

An estrogen receptor and an androgen receptor are present in the mammalian liver. In the liver of the rat, the estrogen receptor concentration increases markedly at puberty and this change correlates with enhanced estrogen stimulation of plasma renin substrate synthesis. High doses of estrogen are required for nuclear binding in liver when compared to doses for the uterus. The high dose requirement appears to be predominantly due to extensive metabolism in the hepatocyte of the estrogen to inactive derivatives. Furthermore, estradiol is much weaker than ethinyl estradiol for promoting nuclear binding in the liver. This is due to extremely rapid and extensive metabolism of estradiol. In human liver the concentration of estrogen receptor is low. An androgen receptor is present in high concentration in rabbit liver and is located predominantly in the nucleus after androgen administration. High concentrations of a putative androgen receptor are also present in human liver cytosol. Preliminary studies indicate that synthetic progestins can attach to the human liver androgen receptor. To date, a progesterone receptor has not been found in the mammalian liver. Thus, it appears that extensive steroid metabolism in liver preferentially diminishes sex steroid interaction with liver receptors and that androgen receptors may mediate progestin effects in liver. These observations provide a scientific basis for improved safety of oral contraceptives. Lowering the estrogen and progestin doses in oral contraceptives will decrease the major side-effects, which are liver mediated, and still maintain the desired effects at the hypothalamic-pituitary axis and uterus. Furthermore, it is likely that by selecting which estrogen, progestin or androgen is administered as well as by utilizing a parenteral route of administration that sex steroid effects on the liver could be minimized.
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PMID:Estrogen receptors and androgen receptors in the mammalian liver. 332 May 48

The development and maintenance of granular convoluted tubule cells in the mouse submandibular gland (SMG) and the production of renin-1, renin-2, and epidermal growth factor (EGF) by these cells are under complex hormonal control. Hypophysectomy causes profound involution and loss of renin activity in this gland. We have shown previously that T4 acts synergistically with 5 alpha-dihydrotestosterone (DHT) to restore SMG morphology and renin-2 activity in hypophysectomized female mice. Investigating the mechanism of T4 and DHT interaction in the hypophysectomized mouse proved impractical, and in the present study we have used genetically hypothyroid (hyt/hyt) mice that carry the structural gene for renin-1 but not for renin-2. Levels of SMG renin-1 and EGF in hyt/hyt mice were less than 4% of those in euthyroid (hyt/+) littermates. Administration of a pharmacological dose of T4 (2.5 micrograms/g BW X day, ip) to male hyt/hyt mice for 18 days restored SMG renin-1 and EGF to near-normal levels. The weights of SMG, seminal vesicle, and epididymis were also lower in hypothyroid mice and increased in response to T4. The effect on SMG renin-1 and EGF of either DHT (150 micrograms/g BW every other day, sc) or T4 (0.025-2.5 micrograms/g BW.day, ip) was blunted in female hyt/hyt mice. A combination of DHT and T4 (0.1 microgram/g BW.day) that restored total circulating T4 and T3 to physiological levels acted synergistically to increase SMG renin-1 and EGF. The administration of 2.5 micrograms T4/g BW.day plus DHT for 7 days increased the specific activity of SMG renin-1 and EGF to levels approaching those in euthyroid littermates given the same treatment. T4 (0.1 microgram/g BW.day) did not alter the quantity or sedimentation characteristics of high affinity androgen-binding protein in SMG from female hyt/hyt mice and induced SMG renin-1 in Tfm/Y mice. Thus, T4 does not appear to exert its effect via the androgen receptor. The administration of DHT and T4 to female hyt/hyt mice produced lower circulating levels of both T3 and T4 than the same dose of T4 given alone, suggesting that DHT does not act by enhancing the conversion of T4 to T3. This study demonstrates that the interaction of T4 and DHT is not a pharmacological phenomenon, but occurs at doses of T4 that restore serum T3 and T4 in female hyt/hyt mice to normal or near-normal levels.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The interaction of androgen and thyroid hormones in the submandibular gland of the genetically hypothyroid (hyt/hyt) mouse. 388 14

Basal activity of submaxillary gland (SMG) renin is high in female mice that carry the Rnrs allele and is induced to higher levels by treatment with dihydrotestosterone (DHT). To determine whether the difference in basal activity between high (Rnrs/Rnrs) and low (Rnrb/Rnrb) strains is due to enhanced sensitivity of Rnrs/Rnrs strains to endogenous androgen, we first studied the effect of several types of endocrine ablation on SMG renin in young female mice, and second, we removed normal androgen receptor protein by introducing the X-linked Tfm gene. Adrenalectomy with or without castration had no effect on basal SMG renin; hypophysectomy decreased basal renin activity 400-fold but did not abolish responsiveness to DHT. Loss of androgen receptor did not affect basal renin activity but did prevent enhancement by DHT. Basal and induced renin activities in L.AKR(Alll)/Cy, a congenic strain homozygous for Rnrs introduced from AKR/J into the background of C57L/J, an Rnrb/Rnrb type strain, are intermediate between levels observed in the original strains. We conclude that (1) the basal level of SMG renin is regulated directly or indirectly by some pituitary hormone(s) but not by androgen, (2) androgen induction of renin activity requires a normal androgen receptor, and (3) major gene(s) that regulate basal as well as induced SMG renin are in a circumscribed region of chromosome 1.
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PMID:Genetic and endocrine control of renin activity in the submaxillary gland of the mouse. 702 30

The renin-angiotensin system plays an important role in blood pressure homeostasis, but the contribution of the type 2 angiotensin II receptor (AT2R) is still unclear. The reports that the AT2R gene has been mapped to the X chromosome in human and rat and the previous report of a gene, Bp3, on the X chromosome responsible for an increase in blood pressure have suggested that the rat AT2R gene (Agtr2) could be this gene. To elucidate whether Agtr2 is Bp3, Agtr2 was cloned. A simple sequence repeat in the 3'-flanking region of this gene was identified and used as a genetic marker to map Agtr2 to the X chromosome at 18.1 cM distal to the androgen receptor locus. This map position is outside the confidence interval reported for Bp3, demonstrating that Agtr2 cannot be Bp3. However, these data will enhance the research into the AT2R biology as well as the study of the X chromosome.
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PMID:Cloning, characterization, and genetic mapping of the rat type 2 angiotensin II receptor gene. 749 Jan 61

We have previously immortalized a mouse submandibular gland (SMG) ductal epithelial cell line, SIMS, from pubertal male mice transgenic for the SV40 large T antigen under the control of the adenovirus 5 E1A promoter. Here we demonstrate the role of the extracellular environment in directing not only the morphogenetic behavior of the cells, but also their functional differentiation in terms of renin expression and secretion. First, we measured renin activity of polarized SIMS cells. Low levels of renin are secreted from both the apical and the basolateral domains; the mechanism appears to be direct as no renin was found to be transcytosed across the cell. Second, we studied homotypic and heterotypic mesenchymal cell interactions with SIMS cells. We found that epithelial-mesenchymal coculture in collagen I gels results in branching tubular morphogenesis of SIMS cells and that significant amounts of renin are secreted, probably into the lumen, as the precursor form, prorenin. Third, we investigated the effects of the basement membrane on SIMS cell morphology and function and found that this structure alone is sufficient to allow expression and secretion of both prorenin and active renin. Finally, we established that SIMS cells can express androgen-regulated genes in a transient transfection assay. In addition, in Matrigel cultures androgen receptor expression appears to be induced, suggesting that the SIMS cell line will be useful for further studies on the molecular basis of the observed high-level expression of SMG-specific genes in male mice.
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PMID:Tubular morphogenesis and mesenchymal interactions affect renin expression and secretion in SIMS mouse submandibular cells. 1009 24

A sexual dimorphism in hypertension has been observed in both human and laboratory animal studies. The mechanisms by which male sex hormones regulate cardiovascular homeostasis are still not yet fully understood and represent the subject of this study. The possible involvement of androgen receptors in the development of hypertension and end-organ damage in transgenic rats harboring the mouse Ren-2 renin gene [TGR(mREN2)27] was studied. Male TGR(mREN2)27 rats were treated with the androgen receptor antagonist Flutamide starting at 4 wk of age. Also, an androgen receptor mutation (testicular feminization mutation [tfm]) was introduced in these rats by crossbreeding male TGR(mREN2)27 rats with tfm rats. The resulting offspring male rats that contain the tfm mutation are insensitive to androgens. Flutamide treatment or tfm mutation produced a significant attenuation of the development of hypertension. Besides a reduction in cardiac hypertrophy, urinary albumin excretion was blunted and no histologic characteristics of end-organ damage were observed in the kidney after Flutamide treatment. Testosterone levels increased 15-fold after Flutamide treatment and 2.7-fold by the tfm mutation. Also, plasma estrogens and luteinizing and follicle-stimulating hormones were significantly increased. Plasma renin concentrations and activity but not plasma angiotensinogen were reduced. Our results indicate that androgens contribute not only to the development of hypertension, but even more importantly to end-organ damage in TGR(mREN2)27 rats.
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PMID:Abolition of hypertension-induced end-organ damage by androgen receptor blockade in transgenic rats harboring the mouse ren-2 gene. 1239 37

We aimed at studying the role of androgens in the development of cardiovascular pathology in hypertensive female rats. Female TGR(mREN2)27 rats harboring the mouse Ren-2 renin gene were treated with Flutamide (specific antagonist of the androgen receptor, 30 mg/kg per day) starting at 4 weeks of age. Flutamide treatment significantly attenuated the development of hypertension in female rats (systolic blood pressure: treated, 134.5+/-5.4 versus control, 165.4+/-3.8 mm Hg). Heart hypertrophy was significantly reduced by the treatment (treated, 0.37+/-0.008 versus control, 0.45+/-0.01 g/100 g body wt). Urinary albumin excretion was blunted (treated, 0.4+/-0.1 versus control, 23.1+/-7.5 mg/24 hours), collagen III mRNA was significantly decreased, and no histological characteristics of end-organ damage were observed in the kidney after treatment. Flutamide treatment significantly reduced plasma renin concentrations and rat renin mRNA in kidney but not plasma angiotensinogen levels. Plasma levels of estrogens, testosterone, and luteinizing hormone were not altered. These results demonstrate that the androgen receptor antagonist Flutamide protects against hypertension and end-organ damage not only in male but also in female TGR(mREN2)27 rats.
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PMID:Abolition of end-organ damage by antiandrogen treatment in female hypertensive transgenic rats. 1262 4

We have previously shown that flutamide (specific antagonist of the androgen receptor) has antihypertensive effects. In the present study we examined the mechanisms of flutamide action in the vasculature. The vascular effects of flutamide were assayed in aortae isolated from male or female Sprague-Dawley rats and from rats or mice lacking a functional androgen receptor ( tfm, testicular feminization mutation). The effect of flutamide on coronary flow was tested in isolated hearts. In addition, male hypertensive rats with tfm mutation were treated with flutamide, and blood pressure was monitored. Flutamide induced a relaxation of rat aortae from all the strains used (maximum relaxation at 10 microM: 51.3+/-5.2% of phenylephrine contraction) and increased the coronary flow. The aortic relaxation to flutamide was abolished by endothelium removal, or by inhibition of nitric oxide synthase, guanylyl cyclase, and tyrosine kinase but not by calmodulin inhibition. Flutamide treatment attenuated the development of hypertension in mouse renin transgenic rats with the tfm mutation. Flutamide produces direct vasodilation by inducing release of NO from the endothelium and causes subsequent activation of soluble guanylyl cyclase in an active androgen receptor independent manner. This response may contribute to the observed antihypertensive actions of flutamide.
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PMID:Androgen receptor independent cardiovascular action of the antiandrogen flutamide. 1280 2

Adipose tissue inflammation and insulin resistance are central to the pathogenesis of the metabolic syndrome. Spironolactone, an antagonist of mineralocorticoid receptor, glucocorticoid receptor and androgen receptor, and agonist of progesterone receptor, has anti-inflammatory activity. Blockade of the renin-angiotensin-aldosterone system has been shown to improve glucose metabolism. We have investigated whether spironolactone has direct effects on glucose uptake and interleukin-6 secretion in human adipocytes. Spironolactone, but not its active metabolite canrenoic acid, significantly increased basal and insulin-stimulated glucose uptake in cultured IN VITRO-differentiated adipocytes of women, without affecting insulin sensitivity. The effect was not due to changes in abundance of glucose transporters 1 or 4 or in degree of cell differentiation. Spironolactone, but not canrenoic acid, significantly reduced basal interleukin-6 secretion by cultured stromal-vascular cells. These effects of spironolactone were not mediated by ligand-dependent antagonism of the mineralocorticoid, glucocorticoid, or androgen receptors. Spironolactone may have a novel role in increasing glucose uptake into adipose cells and attenuating adipose tissue inflammation, with implications for management of metabolic syndrome.
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PMID:Effects of spironolactone on glucose transport and interleukin-6 secretion in adipose cells of women. 1807 71


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