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 effects of thyroid hormone on renin secretion, renin content, and renin mRNA levels in juxtaglomerular (JG) cells harvested from rat kidneys were determined by radioimmunoassays and reverse transcriptase-polymerase chain reaction. Despite a lack of immediate effect, incubation with triiodothyronine dose dependently increased renin secretion during the first 6 h and elevated renin content and renin mRNA levels during the subsequent period. Simultaneous incubation with triiodothyronine and the calcium ionophore A-23187 abolished the increase in renin secretion and attenuated the increase in renin content but did not affect the increase in renin mRNA levels. During simultaneous incubation with triiodothyronine and the adenylate cyclase inhibitor SQ-22536 or membrane-soluble guanosine 3',5'-cyclic monophosphate (cGMP), the increases in renin secretion, content, and mRNA were similar to those observed in the presence of triiodothyronine alone, except for a cGMP-induced attenuation of the increase in renin secretion. These findings suggest that thyroid hormone stimulates renin secretion by JG cells through the calcium-dependent mechanism, whereas the stimulation of renin gene expression by thyroid hormone does not involve intracellular calcium or cyclic nucleotides.
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PMID:Differential effects of thyroid hormone on renin secretion, content, and mRNA in juxtaglomerular cells. 948 51

It is well known that renal hypertrophy is induced by hyperthyroidism; however, the mechanism is not fully understood. We recently reported that cardiac hypertrophy in hyperthyroidism is mediated by enhanced cardiac expression of renin mRNA. The present study addresses the hypothesis that renal hypertrophy in hyperthyroidism is mediated by amplification of renal expression of renin mRNA. Twenty Sprague-Dawley rats were divided into control (n=5) and hyperthyroid groups by daily intraperitoneal injections of saline vehicle or thyroxine. The hyperthyroid group was subdivided further into hyperthyroid-vehicle (n=5), hyperthyroid-losartan (n=5), and hyperthyroid-nicardipine (n=5) groups by daily intraperitoneal injections of saline vehicle, losartan, or nicardipine. All rats were killed at 4 weeks, and the blood and kidneys were collected. The kidney-to-body weight ratio increased in the hyperthyroid groups (+34%). Radioimmunoassays and reverse transcriptase-polymerase chain reaction revealed increased renal renin (+91%) and angiotensin II (+65%) levels and enhanced renal renin mRNA expression (+113%) in the hyperthyroid groups. Losartan and nicardipine decreased systolic blood pressure to the same extent, but only losartan caused regression of thyroxine-induced renal hypertrophy. These results suggest that thyroid hormone activates the intrarenal renin-angiotensin system via enhancement of renal renin mRNA expression, which then leads to renal hypertrophy.
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PMID:Mechanism of hyperthyroidism-induced renal hypertrophy in rats. 979 36

The resistance to insulin (insulin resistance, IR) is a common feature and a possible link between such frequent disorders as non-insulin dependent diabetes mellitus (NIDDM), hypertension and obesity. Pharmacological amelioration of IR and understanding its pathophysiology are therefore essential for successful management of these disorders. In this review, we will discuss the mechanisms of action of thiazolidinediones (TDs), a new family of insulin-sensitizing agents. Experimental studies of various models of IR and an increasing number of clinical studies have shown that TDs normalize a wide range of metabolic abnormalities associated with IR. By improving insulin sensitivity in skeletal muscles, the adipose tissue and hepatocytes, TDs reduce fasting hyperglycaemia and insulinaemia. Furthermore, TDs markedly influence lipid metabolism--they decrease plasma triglyceride, free fatty acid and LDL-cholesterol levels, and increase plasma HDL-cholesterol concentrations. Although TDs do not stimulate insulin secretion, they improve the secretory response of beta cells to insulin secretagogues. TDs act at various levels of glucose and lipid metabolism--ameliorate some defects in the signalling cascade distal to the insulin receptor and improve glucose uptake in insulin-resistant tissues via increased expression of glucose transporters GLUT1 and GLUT4. TDs also activate glycolysis in hepatocytes, oppose intracellular actions of cyclic AMP, and increase intracellular magnesium levels. TDs bind to peroxisome proliferator activating receptors gamma (PPAR gamma), members of the steroid/thyroid hormone nuclear receptor superfamily of transcription factors involved in adipocyte differentiation and glucose and lipid homeostasis. Activation of PPAR gamma results in the expression of adipocyte-specific genes and differentiation of various cell types in mature adipocytes capable of active glucose uptake and energy storage in the form of lipids. Furthermore, TDs inhibit the pathophysiological effects exerted by tumour-necrosis factor (TNF alpha), a cytokine involved in the pathogenesis of IR. These effects are most likely also mediated by stimulation of PPAR gamma. In mature adipocytes, PPAR gamma stimulation inhibits stearoyl-CoA desaturase 1 (SCD1) enzyme activity resulting in a change of cell membrane fatty acid composition. Apart from their metabolic actions, TDs modulate cardiovascular function and morphology independently of the insulin-sensitizing effects. TDs decrease blood pressure in various models of hypertension as well as in hypertensive insulin-resistant patients, and inhibit proliferation, hypertrophy and migration of vascular smooth muscle cells (VSMC) induced by growth factors. These processes are considered to be crucial in the development of vascular remodelling, atherosclerosis and diabetic organ complications. TDs induce vasodilation by blockade of Ca2+ mobilisation from intracellular stores and by inhibition of extracellular calcium uptake via L-channels. Furthermore, TDs interfere with pressor systems (catecholamines, renin-angiotensin system) and enhance endothelium-dependent vasodilation. A key role of TDs effects in vascular remodelling is played by inhibition of the mitogen-activated protein (MAP) kinase pathway. This signalling pathway is important for VSMC growth and migration in response to stimulation with tyrosine-kinase dependent growth factors. In addition to the vasoprotective mechanisms mentioned above, troglitazone, the latest representative of this pharmacological group, possesses antioxidant actions comparable to vitamin E. In summary, TDs have the unique ability to attack mechanisms responsible for metabolic alterations as well as for vascular abnormalities characteristic for IR. Therefore, TDs represent a powerful research tool in attempts to find a common denominator underlying the pathophysiology of the metabolic syndrome X. A recently reported link between MAP kinase signalling pathway and PPAR gamma
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PMID:Thiazolidinediones--tools for the research of metabolic syndrome X. 980 67

We have reported previously that thyroid hormone activates the circulating and tissue renin-angiotensin systems without involving the sympathetic nervous system, which contributes to cardiac hypertrophy in hyperthyroidism. This study examined whether the circulating or tissue renin-angiotensin system plays the principal role in hyperthyroidism-induced cardiac hypertrophy. The circulating renin-angiotensin system in Sprague-Dawley rats was fixed by chronic angiotensin II infusion (40 ng/min, 28 days) via mini-osmotic pumps. Daily i.p. injection of thyroxine (0.1 mg/kg per day, 28 days) was used to mimic hyperthyroidism. Serum free tri-iodothyronine, plasma renin activity, plasma angiotensin II, cardiac renin and cardiac angiotensin II were measured with RIAs. The cardiac expression of renin mRNA was evaluated by semiquantitative reverse transcriptase-polymerase chain reaction. Plasma renin activity and plasma angiotensin II were kept constant in the angiotensin II and angiotensin II+thyroxine groups (0.12+/-0.03 and 0.15+/-0.03 microgram/h per liter, 126+/-5 and 130+/-5 ng/l respectively) (means+/-s.e.m.). Despite stabilization of the circulating renin-angiotensin system, thyroid hormone induced cardiac hypertrophy (5.0+/-0.5 vs 3.5+/-0.1 mg/g) in conjunction with the increases in cardiac expression of renin mRNA, cardiac renin and cardiac angiotensin II (74+/-2 vs 48+/-2%, 6.5+/-0.8 vs 3.8+/-0.4 ng/h per g, 231+/-30 vs 149+/-2 pg/g respectively). These results indicate that the local renin-angiotensin system plays the primary role in the development of hyperthyroidism-induced cardiac hypertrophy.
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PMID:Local renin-angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy. 985 75

In the present study we have found age-related differences between the renal renin activity (RRA) and the immunoreactive renal renin (IRR) profiles during the neonatal development of the rat. RRA was markedly greater in newborn rats than in adult ones, while IRR was low at birth and progressively increased until adulthood. These observations suggest the existence of a control mechanism operating either at the level of the translation of the template or at a post-translational level which varies throughout the development. Since thyroid hormones have been demonstrated to affect several renin-angiotensin components, the neonatal RRA and IRR profiles in congenital hypothyroid rats were evaluated to determine whether renal renin activity or its synthesis could be endogenously regulated by thyroid hormones in the early stages of life. Although significant differences were observed in the RRA profiles of congenital hypothyroid and control rats, no changes were found in the relative amount of immunoreactive protein. These findings indicate that thyroid hormone deficiency does not directly affect renal renin expression during the critical period of the normal morpho-functional development of the newborn.
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PMID:Ontogeny of renal renin in congenital hypothyroid rats. 1044 11

-We previously reported that thyroid hormone stimulates renin synthesis in vivo and in vitro. Here, we analyzed the 5'-flanking sequence of the human renin gene for promoter activity responsive to thyroid hormone using Calu-6 cells, which secrete renin endogenously and express thyroid hormone receptor-ss. The luciferase reporter gene was cloned together with 5'-flanking portions of the human renin gene of various lengths into the pGL3-Basic vector. Luciferase activity assays were performed using the Dual Luciferase Reporter Assay System. 3,3',5-Triiodo-L-thyronine stimulated the promoter activity of pGL3-Basic-1111/+12 and pGL3-Basic-1298/+12 by 2.3+/-0.1- and 1.7+/-0.1-fold, respectively. Shorter constructs (pGL3-Basic-144/+12, pGL3-Basic-226/+12, pGL3-Basic-452/+12, and pGL3-Basic-953/+12) were not stimulated by thyroid hormone. These results suggest that there is a possible thyroid hormone response element (5'-AGG TCA GGT CAc aat GTT CCT-3') between nucleotides -1111 and -953. In 3 constructs with site-directed mutations in this sequence, basal promoter activities were significantly increased, whereas promoter activation by thyroid hormone was abolished. Electrophoretic mobility shift assays showed that the -1111/-953 DNA fragment of the intact human renin gene was bound to nuclear proteins of Calu-6 cells; however, none of the 3 mutant probes were bound to any nuclear proteins. These results suggest that thyroid hormone stimulates the promoter activity of the human renin gene through thyroid hormone response element-dependent mechanisms in Calu-6 cells.
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PMID:Thyroid Hormone Stimulates Renin Gene Expression Through the Thyroid Hormone Response Element. 1120 63

The objective of this study was to evaluate, using echocardiography, the involvement of the renin-angiotensin system (RAS) in left ventricular (LV) hypertrophy development in experimental hyperthyroidism. Thyrotoxicosis was produced by a daily intraperitoneal injection of L-thyroxine (T4), 0.1 mg/kg per day for 15 days in Wistar rats. Control (euthyroid) rats received intraperitoneal daily injection of the thyroxine solvent. Two series of experiments were performed. In the first series, euthyroid (n = 10) and hyperthyroid (n = 14) rats were surgically prepared with a femoral artery catheter. After a 3-day recovery period, blood pressure and heart rate were measured and blood samples were collected in conscious and unrestrained rats. In the second series of experiment, measurement of LV geometry was realized with two-dimensional time-movement echocardiography on the 15th day of treatment in control conditions and after long-term treatment with the angiotensin II type I receptor antagonist valsartan (10 mg/kg per day for 15 days) in both euthyroid and hyperthyroid rats. The dose and duration of T4 treatment was sufficient to induce a significant degree of hyperthyroidism with characteristic features including tachycardia, systolic hypertension, myocardial hypertrophy, hyperthermia, and weight loss. In addition, we measured an increase in free fractions of thyroid hormones, and a threefold increase in plasma renin activity. Echocardiographic examinations in rats revealed a strong correlation between LV weight and echocardiographic LV mass. Hyperthyroid rats exhibited an increased LV mass with a marked increase in the LV end-diastolic posterior wall and septal thickness. Chronic treatment with valsartan prevented this concentric LV hypertrophy (p < 0.01), with full prevention of the LV posterior wall hypertrophy (p < 0.001) and decreased LV septal hypertrophy (p < 0.05). In conclusion, the cardiovascular alterations of hyperthyroidism were reproduced with thyroid hormone injections in rats. Activation of the RAS in hyperthyroid rats was accompanied by increased LV mass. Using valsartan, we demonstrated that the RAS impinged on the LV remodelling in our experimental hyperthyroidism model. A chronic treatment with an angiotensin II type I receptor antagonist prevented the development of the concentric LV hypertrophy associated with thyrotoxicosis.
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PMID:Renin-angiotensin system contribution to cardiac hypertrophy in experimental hyperthyroidism: an echocardiographic study. 1120 99

Kallikreins are a group of specific serine proteases and are an integral part of kallikrein-kinin system. The kallikrein-kinin system is hypotensive in nature and counteracts with the renin-angiotensin system in the maintenance of normal blood pressure. So far, four kallikrein-like enzymes, namely, mK9, mK13, mK22, and mK26, have been known to convert the inactive pro-renin into biologically active renin. Some of these enzymes are induced by the thyroid hormone. In the proposed study, we investigated the effects of thyroid hormone on the expression of genes for mk9, mk13, and mk22 enzymes. We used guinea pigs as models because these animals share many characteristics in common to humans. Male adult guinea pigs were intramuscularly injected with 2 mg/kg body weight of thyronine. Forty-eight hours following the last injection, the liver was processed for Northern blot analysis using labeled mK9, mK13, and mK22 specific RNA probes. Only mK9 was found to be transcriptionally regulated by the hormone.
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PMID:Induction of pro-renin converting enzyme mk9 by thyroid hormone in the guinea-pig liver. 1205 15

Most often, low-renin hypertension in the child or adolescent has a clearly definable hormonal cause; thus while each of its numerous forms is moderately rare, a specific hormonal basis is to be expected. An endocrine evaluation is indicated after exclusion of cardiologic pathology or renovascular or portal abnormality in a hypertensive child. The evaluation should include analysis of catecholamine and of thyroid hormone plasma levels, and plasma renin activity (PRA) level. Hormonal hypertension with high or normal renin conditions is rare. Elevated blood pressure with high or normal renin levels may be in fact within normal range in the context of growth at upper percentile limits, possibly in conjunction with simple obesity. Diagnosis may be made at any age in most forms of low-renin hypertension.
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PMID:Hypertension in congenital adrenal hyperplasia and apparent mineralocorticoid excess. 1238 49

A potent transcriptional enhancer was previously identified upstream of the mouse renin gene. Within the enhancer is a TGACCT direct-repeat motif, required for enhancer activity, that is the consensus sequence recognized by members of the thyroid hormone subfamily of steroid hormone receptors. We previously reported that RAR/RXR bind to this sequence and mediate the induction of renin promoter activity by retinoids. However, gel mobility shift assays clearly show that other as yet unidentified factors also bind to this motif. In order to identify some of these TGACCT binding factors, we screened a yeast one-hybrid cDNA library derived from mouse As4.1 cells. One of these encoded the orphan nuclear receptor Ear2. Recombinant Ear2 was purified from Escherichia coli and an antipeptide antisera was generated. EMSA showed that purified recombinant Ear2 specifically binds the TGACCT direct-repeat motif. Transfection assays showed that Ear2 potently decreases both baseline and retinoid-induced mouse renin promoter activity in a dose-dependent, enhancer-dependent, and sequence-specific manner. Mutations in Ear2, which abolish its binding to the TGACCT motif, also abolish transcriptional repression. Ear2 was identified as a nuclear protein in As4.1 cells, is one of the proteins binding to the TGACCT repeat motif, and its overexpression can repress transcription of the endogenous renin gene in As4.1 cells. These data suggest that Ear2 is a negative modulator of renin gene transcription in As4.1 cells, and that the renin enhancer may actually encode a complex positive and negative regulator of transcription.
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PMID:Identification of a nuclear orphan receptor (Ear2) as a negative regulator of renin gene transcription. 1269 40


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