Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously demonstrated that type 1A angiotensin II (Ang II) receptor (AT1A) is the predominant renal subtype and is upregulated by a low sodium diet. We have now tested the hypothesis that upregulation of AT1A mRNA induced by sodium deficiency is renal specific and is mediated by activation of type 1 Ang II receptor (AT1). Male Wistar rats were divided into four groups (n = 5 each) and treated for 2 weeks with normal sodium diet (0.5%), normal sodium plus 3 mg/kg per day losartan, low sodium diet (0.07%), or low sodium diet plus losartan. At the end of the 2 weeks, body weight and mean arterial pressure were not different among the four groups (P > .05). Plasma renin activity was elevated by losartan treatment, sodium restriction, or the combination of the two versus control (P < .05). Northern blot analysis showed that the ratio of renal AT1A to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA was increased by losartan treatment, sodium restriction, or the combination of the two versus control (P < .05). In contrast, the ratio of adrenal AT1A to GAPDH mRNA was increased only by sodium restriction versus three other groups (P < .05). Thus, sodium deficiency increases AT1A mRNA in both kidney and adrenal gland, while Ang II receptor blockade by losartan prevents low sodium-induced AT1A mRNA only in adrenal gland.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1995 Dec
PMID:Distinct mechanisms of upregulation of type 1A angiotensin II receptor gene expression in kidney and adrenal gland. 749 83

Recent studies have documented the presence of a complete renin-angiotensin system in the proximal tubule of the kidney: however, little is known about the regulation of renin in this proximal tubular system. Therefore, we performed the present studies to learn whether the behavior of the renin system in cultured proximal tubule is similar to that of the juxtaglomerular renin system. Basal renin secretion from rabbit proximal tubular cells in primary culture was low and not affected by isoproterenol (10(-5) mol/L), diltiazem (10(-5) mol/L), or a zero-calcium bath (O nmol/L). Only the calcium ionophore A23187 (10(-4) mol/L) significantly reduced renin secretion in these cells (from 2.44 +/- 0.37 to 1.14 +/- O.08 ng angiotensin I/mg protein per hour, P<.05). When the proximal tubular cells were lysed so the effects of the test agents on intracellular renin content could be assessed, isoproterenol caused a significant twofold (107 percent) increase (from 2.02 +/- 0.56 to 4.18 +/- 0.81 ng angiotensin I/mg protein per hour, P<.05), whereas diltiazem, A23187, and zero- and high-calcium baths did not produce a significant change. The effects of these agents on renin mRNA were examined in rabbit and rat proximal tubular cells in primary culture with the use of an S1 nuclease protection assay. Densitometry analysis of renin mRNA and either GAPDH mRNA (rat) or alpha-actin (rabbit) showed no significant alterations in renin mRNA abundance. In summary, these results confirm the presence of renin mRNA in cultured proximal tubular cells and suggest that a low-level, constitutive secretion of renin occurs in this system that is decreased by A23187. Moreover, the results also suggest that proximal tubular renin is regulated, albeit differently from the juxtaglomerular renin system. Finally, short-term increments in proximal tubular renin occur without a change in renin mRNA.
Hypertension 1996 Jun
PMID:Renin regulation in cultured proximal tubular cells. 864 45

The purpose of the present study was to test the hypothesis that hypertension induced by reduced renal mass (RRM) upregulates gene expression of the type 1 angiotensin II (Ang II) receptor (AT1) in the thoracic aorta and heart through an Ang II-dependent mechanism. Three groups of rats were given 1% NaCl water and subjected to RRM, RRM plus captopril (RRM+Cap, 30 mg/kg per day), or sham surgery. Tail-cuff systolic blood pressure was significantly elevated in RRM and RRM+Cap rats compared with sham-operated rats. The ratios of the medial wall area of the thoracic aorta and heart weight to body weight were significantly elevated in RRM and RRM+Cap rats compared with sham-operated rats. Northern blot analysis indicated that the ratio of AT1 to GAPDH mRNA in the aorta was significantly higher in RRM (1.85 +/- 0.52) compared with sham-operated (0.21 +/- 0.04) and RRM+Cap (0.55 +/- 0.20) rats. In contrast, the ratio of AT1 to GAPDH mRNA in the heart was significantly increased in both RRM (1.09 +/- 0.23) and RRM+Cap (1.00 +/- 0.09) compared with sham-operated (0.34 +/- 0.06) rats. Thus, RRM hypertension upregulates AT1 mRNA expression in both the hypertrophied aorta and heart. Captopril treatment without altering blood pressure in RRM rats prevents the increase in AT1 mRNA in the aorta but not the heart. These results suggest that different tissue-specific mechanisms of AT1 gene regulation exist; ie, in aorta, an Ang II-or kinin-dependent mechanism is operant, whereas in heart, RRM-induced upregulation of AT1 mRNA may be pressure dependent.
Hypertension 1997 May
PMID:Distinct mechanisms of modulation of angiotensin II type I receptor gene expression in heart and aorta. 914 73

Abnormal smooth muscle contraction may contribute to diseases such as asthma and hypertension. Alterations to myosin light chain kinase or phosphatase change the phosphorylation level of the 20-kDa myosin regulatory light chain (MRLC), increasing Ca2+ sensitivity and basal tone. One Rho family GTPase-dependent kinase, Rho-associated kinase (ROK or p160(ROCK)) can induce Ca2+-independent contraction of Triton-skinned smooth muscle by phosphorylating MRLC and/or myosin light chain phosphatase. We show that another Rho family GTPase-dependent kinase, p21-activated protein kinase (PAK), induces Triton-skinned smooth muscle contracts independently of calcium to 62 +/- 12% (n = 10) of the value observed in presence of calcium. Remarkably, PAK and ROK use different molecular mechanisms to achieve the Ca2+-independent contraction. Like ROK and myosin light chain kinase, PAK phosphorylates MRLC at serine 19 in vitro. However, PAK-induced contraction correlates with enhanced phosphorylation of caldesmon and desmin but not MRLC. The level of MRLC phosphorylation remains similar to that in relaxed muscle fibers (absence of GST-mPAK3 and calcium) even as the force induced by GST-mPAK3 increases from 26 to 70%. Thus, PAK uncouples force generation from MRLC phosphorylation. These data support a model of PAK-induced contraction in which myosin phosphorylation is at least complemented through regulation of thin filament proteins. Because ROK and PAK homologues are present in smooth muscle, they may work in parallel to regulate smooth muscle contraction.
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PMID:Different molecular mechanisms for Rho family GTPase-dependent, Ca2+-independent contraction of smooth muscle. 972 79

Insulin action starts with binding to a membrane receptor (insulin receptor-tyrosine kinase) and with activating an insulin receptor substrate 1 (IRS-1) and substrate 2 (IRS-2). Insulin receptors interact at least with three cascade reactions, phosphorylating G proteins and IRS-1, that activate PLC "ras" and PI-3-K. NIDDM can be defined as a disease caused by defective transduction of insulin signals and IR as a complex phenotype manifesting itself, emphasized by individual and environmental factors, in the cellular systems of signal transduction. IRS is a syndrome characterized by NIDDM, hypertension, visceral obesity, CHD: the X syndrome. Up to day the described mutations of the insulin-receptor gene are rare (e.g. the leprechaunism): genetic IR. Obesity is the principal cause of IR by receptorial and post-receptorial defects: metabolic IR. The obese skeletal muscle shows a reduction of insulin receptor and IRS-1 phosphorylation and of PI-3-K activation; the scarce expression of these proteins would determine the muscular IR. IR is a pattern of essential hypertension. Hypertension, dyslipidemia and abnormality of glucose metabolism are linked by IR. The so called high erythrocyte Na(+)-Li+ counter-transport is a new biochemical marker for IR and hypertension. These drugs can reduce IR: metformin, sulphonilureas, fibrats, dexfenfluramine, troglitazone, doxazosin, ACE-inhibitors.
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PMID:[Insulin resistance. Receptor and post-receptor abnormalities]. 984 54

Chronic elevations of circulating angiotensin II (Ang II) cause sustained hypertension and enhanced accumulation of intrarenal Ang II by an AT1 receptor-dependent process. The present study tested the hypothesis that chronic elevations in circulating Ang II regulate AT1 mRNA and protein expression in a tissue-specific manner. Sprague-Dawley rats were infused with Ang II (80 ng/min) or vehicle subcutaneously for 13 days via osmotic minipump. On day 12, systolic blood pressure averaged 186+/-12 mm Hg in Ang II-infused rats compared with rats given vehicle (121+/-2 mm Hg). Plasma renin activity was markedly suppressed in the Ang II-infused rats compared with vehicle-infused rats (0.1+/-0.01 versus 4.9+/-0.9 ng of Ang I. mL-1. h-1; P<0.05). Semiquantitative reverse transcription polymerase chain reaction using rat AT1A- and glyceraldehyde-3-phosphate-dehydrogenase (GAPDH)-specific primers was followed by Southern blot hybridization using specific radiolabeled cDNA or oligonucleotide probes. The results showed that the ratios of AT1A/GAPDH mRNA in the kidney (0.19+/-0.05 versus 0. 26+/-0.03) and liver (2.8+/-0.9 versus 3.0+/-0.5) were comparable in Ang II- and vehicle-infused rats. In contrast, AT1A/GAPDH mRNA levels were increased in the adrenal glands of Ang II-infused rats (0.49+/-0.04 versus 0.36+/-0.02; P<0.05). Western blot analysis showed that AT1 protein levels in the kidney and liver were also similar in the two groups. Therefore, these results indicate that renal and liver AT1 receptor gene expression is maintained in Ang II-induced hypertension. The failure to downregulate AT1 receptor mRNA and protein levels thus allows the sustained effects of chronic elevations in Ang II to elicit progressive increases in arterial pressure.
Hypertension 1999 Jan
PMID:Regulation of angiotensin II type 1 receptor mRNA and protein in angiotensin II-induced hypertension. 993 Nov 27

It has been proposed that the macula densa participates in the regulation of increased renin expression in renovascular hypertension (RVH) and that prostaglandins may be among the mediators of macula densa function. We have previously shown that in renal cortex, cyclooxygenase-2 (COX-2) expression is localized to the macula densa and surrounding cortical thick ascending limb and increases in high-renin states, such as salt restriction and angiotensin-converting enzyme inhibition. In the present studies, we examined the effect of the selective COX-2 inhibitor SC58236 on plasma renin activity (PRA) and renal renin expression in RVH in rats. The aorta was coarcted between right and left renal arteries, and animals received either SC58236 or vehicle for 1 week. At day 8, vehicle-treated coarcted rats were hypertensive (mean carotid arterial blood pressure: 138+/-3 versus 87+/-2 mm Hg in sham-operated controls; n=9 to 11; P<0.001) and exhibited a disparity of kidney size (ratio left/right kidney: 0.78+/-0.04 versus 1.02+/-0.02; n=9 to 10; P<0.001). PRA increased significantly (84.6+/-6.5 versus 9.0+/-1.4 ng angiotensin I [Ang I] per milliliter per hour; n=8 to 9; P<0.01). In the coarcted rats, neither renin mRNA expression nor renin activity of the right kidney was altered (renin/GAPDH mRNA: 1.12+/-0.05-fold levels in control rats; n=6; P=NS; renin activity: 23.4+/-1.8 versus 27.1+/-3.4 ng Ang I per hour per milligram protein; n=8 to 9; P=NS). However, the renin mRNA of the left kidney increased to 3.0+/-0.6-fold of control (n=6), and the renin activity increased to 189.0+/-28.6 ng Ang I per hour per milligram protein (n=8; P<0.01). Expression of COX-2 mRNA and immunoreactive protein increased in the affected left kidney but was not different from control in the unaffected right kidney. SC58236 treatment to coarcted rats did not affect kidney size (ratio left/right kidney: 0.79+/-0.06; n=9). However, PRA was significantly decreased compared with the vehicle-treated coarcted rats (19.8+/-2. 8 ng Ang I per milliliter per hour; n=9; P<0.01). The left kidney renin mRNA and renin content were also decreased (1.7+/-0.3-fold control; n=6; P<0.05; and 45.7+/-7.6 ng Ang I per hour per milligram protein; n=9; P<0.01, respectively), while renin mRNA and renin content of the right kidney were not altered. SC58236 lowered mean arterial blood pressure (122+/-5 mm Hg; n=14; P<0.05 compared with vehicle). A significant correlation was observed between PRA and mean blood pressure (r=0.75; P<0.01). In summary, these studies indicate that the selective COX-2 inhibitor SC58236 decreases renin production and release in RVH and suggest an important role for COX-2 regulation of the renin-angiotensin system.
Hypertension 1999 Jul
PMID:Cyclooxygenase-2 inhibition decreases renin content and lowers blood pressure in a model of renovascular hypertension. 1040 30

We here review mechanisms that can regulate the activity of myosin II, in smooth muscle and non-muscle cells, by modulating the Ca2+ sensitivity of myosin regulatory light chain (RLC) phosphorylation. The major mechanism of Ca2+ sensitization of smooth muscle contraction and non-muscle cell motility is through inhibition of the smooth muscle myosin phosphatase (MLCP) that dephosphorylates the RLC in smooth muscle and non-muscle. The active, GTP-bound form of the small GTPase RhoA activates a serine/threonine kinase, Rho-kinase, that phosphorylates the regulatory subunit of MLCP and inhibits phosphatase activity. G-protein-coupled release of arachidonic acid may also contribute to inhibition of MLCP acting, at least in part, through the Rho/Rho-kinase pathway. Protein kinase C(s) activated by phorbol esters and diacylglycerol can also inhibit MLCP by phosphorylating and thereby activating CPI-17, an inhibitor of its catalytic subunit; this mechanism is independent of the Rho/Rho-kinase pathway and plays only a minor, transient role in the G-protein-coupled mechanism of Ca2+ sensitization. Ca2+ sensitization by the Rho/Rho-kinase pathway contributes to the tonic phase of agonist-induced contraction in smooth muscle, and abnormally increased activation of myosin II by this mechanism is thought to play a role in diseases such as high blood pressure and cancer cell metastasis.
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PMID:Signal transduction by G-proteins, rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. 1063 96

Phosphodiesterase (PDE) was shown to be downregulated in the failing hearts of transplant recipients, while it was upregulated in hypertrophied hearts induced by isoproterenol and calsequesterin overexpression. We examined the time course of gene expression and the activity of PDE3 and PDE4 in an animal model of salt-induced hypertension, left ventricular hypertrophy, and congestive heart failure (CHF). Dahl salt-sensitive (DS, n = 25) and salt-resistant rats (DR, n = 25) were fed with an 8% NaCl diet after the age of 6 weeks. At 11 weeks (hypertension and hypertrophy stage in DS), PDE4 activity in the heart was higher in DS than in DR. At 18 weeks (hypertension and CHF stage in DS), both PDE3 and PDE4 activity in both the heart and aorta was approximately twofold higher in DS than in DR. The ratios of PDE3 and PDE4 mRNA to GAPDH mRNA in the heart were both approximately twofold higher in DS than in DR at 11 and 18 weeks. The cardiac cyclic adenosine monophosphate content and plasma nitric oxide concentration were higher in DS than in DR at 11 weeks but both of them were lower in DS than in DR at 18 weeks of age. In this animal model, gene expressions of PDE3 and PDE4 were augmented from the hypertrophic stage. PDE3 and PDE4 activities were subsequently enhanced in the CHF stage and seemed to contribute to the development and exacerbation of CHF.
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PMID:Enhanced activities and gene expression of phosphodiesterase types 3 and 4 in pressure-induced congestive heart failure. 1238 34

Circulating natriuretic peptides such as atrial natriuretic peptide (ANP) counterbalance the effects of hypertension and inhibit cardiac hypertrophy by activating cGMP-dependent protein kinase (PKG). Natriuretic peptide binding to type I receptors (NPRA and NPRB) activates their intrinsic guanylyl cyclase activity, resulting in a rapid increase in cytosolic cGMP that subsequently activates PKG. Phosphorylation of the receptor by an unknown serine/threonine kinase is required before ligand binding can activate the cyclase. While searching for downstream PKG partners using a yeast two-hybrid screen of a human heart cDNA library, we unexpectedly found an upstream association with NPRA. PKG is a serine/threonine kinase capable of phosphorylating NPRA in vitro; however, regulation of NPRA by PKG has not been previously reported. Here we show that PKG is recruited to the plasma membrane following ANP treatment, an effect that can be blocked by pharmacological inhibition of PKG activation. Furthermore, PKG participates in a ligand-dependent gain-of-function loop that significantly increases the intrinsic cyclase activity of the receptor. PKG translocation is ANP-dependent but not nitric oxide-dependent. Our results suggest that anchoring of PKG to NPRA is a key event after ligand binding that determines distal effects. As such, the NPRA-PKG association may represent a novel mechanism for compartmentation of cGMP-mediated signaling and regulation of receptor sensitivity.
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PMID:Atrial natriuretic peptide induces natriuretic peptide receptor-cGMP-dependent protein kinase interaction. 1285 9


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