Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies were performed to determine the mechanism underlying deficient arginine vasopressin (AVP)-stimulated adenylyl cyclase activity in chronic renal failure (CRF). As compared to control, principal cells cultured from the inner medullary collecting tubule of rats previously made uremic by 5/6 nephrectomy fail to accumulate cAMP when stimulated with AVP. CRF cells do respond normally to forskolin or cholera toxin and the defect in AVP responsiveness is not prevented by treatment with pertussis toxin, by cyclooxygenase inhibition, or by inhibition or down-regulation of protein kinase C. In contrast to their lack of responsiveness to AVP, CRF cells respond normally to other agonists of adenylyl cyclase such as isoproterenol or prostaglandin E2. Plasma membranes prepared from the inner medullae of CRF rats exhibit a marked decrease in apparent AVP receptor number but no change in the apparent number of beta adrenergic receptors. Reverse transcriptase PCR of total RNA from the inner medullae of CRF animals reveals virtual absence of V2 receptor mRNA; mRNA for alpha s is present in normal abundance. These studies indicate that AVP resistance in CRF is due, at least in part, to selective down-regulation of the V2 receptor as a consequence of decreased V2 receptor mRNA.
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PMID:Vasopressin resistance in chronic renal failure. Evidence for the role of decreased V2 receptor mRNA. 761 8

Circulating endothelin (ET) levels are elevated in heart failure and positively correlated with severity of heart failure. Recent studies demonstrated arginine vasopressin (AVP) V2 mRNA expression was upregulated in the inner medullary collecting duct (IMCD) of cardiomyopathic hamsters (CM). The goal of the present studies was to determine if ET-1 is involved in upregulating the expression of AVP V2 mRNA in the IMCD of CM by using a mixed ETA/ETB receptor antagonist bosentan. Our results showed plasma ET-1 levels increased in CM hamsters and related with the severity of heart failure. The competitive reverse-transcriptase polymerase chain reaction (RT-PCR) method was used to quantify the expression of AVP V2 and aquaporin 2 (AQP2) mRNA in the IMCD. AVP V2 mRNA expression was elevated in placebo-treated CM hamsters and decreased significantly with 14 days of bosentan treatment. Similar results were seen with AQP2 mRNA. The effect of bosentan in normalizing the expression of AVP V2 and AQP2 mRNA in the IMCD of CM was confirmed by in situ hybridization studies. Bosentan treatments reduced the intensitites of the signals in the IMCD of CM hamsters to that seen in normal hamsters. This study demonstrated that AVP V2 and AQP2 mRNA are upregulated in CM hamsters and these upregulations are attenuated by bosentan treatment, suggesting that ET-1 plays a role in upregulating the expression of AVP V2 mRNA in CM hamsters.
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PMID:Attenuation of renal vasopressin V2 receptor upregulation by bosentan, an ETA/ETB receptor antagonist. 1450 20

To unravel the molecular regulation of renal transcellular Ca(2+) transport, a murine distal convoluted tubule (mpkDCT) cell line derived from distal convoluted tubules (DCT) microdissected from a SV-PK/Tag transgenic mouse was characterized. This cell line originated from DCT only, as mRNA encoding for the DCT marker thiazide-sensitive Na(+)/Cl(-) cotransporter was expressed, whereas mRNA encoding for the connecting tubule and collecting duct marker aquaporin-2 was not detected, as determined by reverse-transcriptase PCR. mpkDCT cells expressed mRNA encoding the Ca(2+) channels TRPV5 and TRPV6 and other key players necessary for transcellular Ca(2+) transport, i.e., calbindin-D(9k), calbindin-D(28k), plasma membrane Ca(2+)-ATPase isoform 1b, and Na(+)/Ca(2+) exchanger 1. Primary cultures of DCT cells exhibited net transcellular Ca(2+) transport of 0.4 +/- 0.1 nmol.h(-1).cm(-2), whereas net transcellular Ca(2+) transport across mpkDCT cells was significantly higher at 2.4 +/- 0.4 nmol.h(-1).cm(-2). Transcellular Ca(2+) transport across mpkDCT cells was completely inhibited by ruthenium red, an inhibitor of TRPV5 and TRPV6, but not by the voltage-operated Ca(2+) channel inhibitors felodipine and verapamil. With the use of patch-clamp analysis, the IC(50) of ruthenium red on Na(+) currents was between the values measured for TRPV5- and TRPV6-expressing HEK 293 cells, suggesting that TRPV5 and/or TRPV6 is possibly active in mpkDCT cells. Forskolin in combination with IBMX, 1,25-dihydroxyvitamin D(3), and 1-deamino-8-d-arginine vasopressin increased transcellular Ca(2+) transport, whereas PMA and parathyroid hormone had no significant effect. In conclusion, the murine mpkDCT cell line provides a unique cell model in which to study the molecular regulation of transcellular Ca(2+) transport in the kidney in vitro.
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PMID:Characterization of a murine renal distal convoluted tubule cell line for the study of transcellular calcium transport. 1462 1

Recent studies in our laboratory have demonstrated that bosentan, a mixed endothelin ET(A)/ET(B) receptor antagonist, prevented the upregulation of the arginine vasopressin (AVP) V(2) receptor in the inner medullary collecting duct (IMCD) of cardiomyopathic hamsters. These results suggested that endothelin-1 (ET-1) is involved in the upregulation of AVP V(2) receptors. Studies were performed to detect the effect of ET-1 on the expression of AVP V(2) receptors and the ET receptor mediating these effects within the IMCD of the rat. Rat IMCD tissue was isolated and incubated with the following: ET-1, or ET-1 in combination with ET(A) and ET(B) receptor antagonists BQ-123 and BQ-788, respectively, and sarafotoxin c (S6c), an ET(B) receptor-specific agonist. Tissue samples were then analyzed using quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blotting. ET-1 treatment resulted in increased V(2) mRNA from a control level of 186.8 +/- 15.0 amol/microg total RNA to 430.7 +/- 49.0 amol/microg total RNA (P <.003). ET-1/ET(A) treatment resulted in no significant decrease in V(2) mRNA expression 335.0 +/- 38.0 amol/microg total RNA. Whereas ET-1/ET(B), and ET-1/ET(B)/ET(A) treatment resulted in V(2) mRNA approaching control 256.0 +/- 15.0 amol/microg total RNA, and 215.6 +/- 42.3 amol/microg total RNA. However, ET-3 treatment produced no significant changes in V(2) receptor mRNA expression. Sarafotoxin treatment corroborated both the ET-1 and ET receptor antagonist data, demonstrating striking significant increases in V(2) receptor mRNA and protein expression. S6c treatment increased V(2) mRNA expression from a control level of 199 +/- 17.3 amol/microg total RNA to 284.3 +/- 42.1 amol/microg total RNA (P < 05). Western blotting revealed that changes in V(2) mRNA expression in the various treatment conditions were similar to changes in protein expression. Overall, these data indicate that in the IMCD ET-1 increases AVP V(2) receptor expression and these changes are mediated by the ET(B) receptor.
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PMID:Endothelin upregulates the expression of vasopressin V2 mRNA in the inner medullary collecting duct of the rat. 1533 81

The choroid plexus (CP) epithelium is one of the extrahypothalamic sources of arginine vasopressin (AVP). However, it is unclear whether the regulation of choroidal AVP synthesis in response to pathophysiological stimuli, such as hyperosmotic stress, is similar to that observed in the hypothalamus. In the present study, rats chronically implanted with cisterna magna cannulas, enabling the collection of cerebrospinal fluid (CSF) in freely moving animals, were subjected to salt loading. CSF osmolality increased from the baseline normonatremic levels ranging between 292 +/- 0.5 and 295 +/- 2 to 309 +/- 4 mosm/kg H(2)O at 2 days of hypernatremia. This elevated CSF osmolality was maintained at a relatively stable level until the end of a 10-day observation period. Changes in choroidal and hypothalamic AVP expression in response to hyperosmotic stress were assessed by semiquantitative reverse-transcriptase polymerase chain reaction. An increase in hypothalamic AVP expression was accompanied by augmented AVP synthesis in the CP. Compared to normonatremia, choroidal levels of AVP mRNA increased 5- and 10-fold at 2 and 5 days of salt loading, respectively. Salt loading also resulted in increased hypothalamic expression of the alpha-II, beta(1), and beta(2) subunits of voltage-gated Na(+) channels. Similarly, the choroidal mRNA levels for the alpha-II and beta(1) subunits increased approximately 2-fold after 5 days of salt loading; however, no changes in the beta(2) subunit expression were found in the CPs of hypernatremic rats. These experiments support the hypothesis that the regulation of choroidal AVP synthesis is similar to that observed in the hypothalamus. It is also suggested that the increased expression of voltage-gated Na(+) channels found in the hypothalamus and CP after salt loading may play a role in the adaptation of AVP-producing cells to chronic hypernatremia.
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PMID:Chronic hypernatremia increases the expression of vasopressin and voltage-gated Na channels in the rat choroid plexus. 1716 38

Pressor effects of the vasoconstrictor hormone arginine vasopressin (AVP), observed when systemic AVP concentrations are less than 100 pM, are important for the physiological maintenance of blood pressure, and they are also the basis for therapeutic use of vasopressin to restore blood pressure in hypotensive patients. However, the mechanisms by which circulating AVP induces arterial constriction are unclear. We examined the novel hypothesis that KCNQ potassium channels mediate the physiological vasoconstrictor actions of AVP. Reverse transcriptase polymerase chain reaction revealed expression of KCNQ1, KCNQ4, and KCNQ5 in rat mesenteric artery smooth muscle cells (MASMCs). Whole-cell perforated patch recordings of voltage-sensitive K+ (Kv) currents in freshly isolated MASMCs revealed 1,3-dihydro-1-phenyl-3,3-bis(4-pyridinylmethyl)-2H-indol-2-one (linopirdine)- and 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE-991)-sensitive KCNQ currents that were electrophysiologically and pharmacologically distinct from other Kv currents. Suppression of KCNQ currents by AVP (100 pM) was associated with significant membrane depolarization, and it was abolished by the protein kinase C (PKC) inhibitor calphostin C (250 nM). The KCNQ channel blocker linopirdine (10 microM) inhibited KCNQ currents in MASMCs, and it induced constriction of isolated rat mesenteric arteries. The vasoconstrictor responses were not additive when combined with 30 pM AVP, and they were prevented by the L-type Ca2+ channel blocker verapamil. Ethyl-N-[2-amino-6-(4-fluorophenylmethylamino)pyridin-3-yl] carbamic acid (flupirtine) significantly enhanced KCNQ currents, and it reversed constrictor responses to 30 pM AVP. In vivo, i.v. administration of linopirdine induced a dose-dependent increase in mesenteric artery resistance and blood pressure, whereas flupirtine had the opposite effects. We conclude that physiological concentrations of AVP induce mesenteric artery constriction via PKC-dependent suppression of KCNQ currents and L-type Ca2+ channel activation in MASMCs.
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PMID:Vascular KCNQ potassium channels as novel targets for the control of mesenteric artery constriction by vasopressin, based on studies in single cells, pressurized arteries, and in vivo measurements of mesenteric vascular resistance. 1827 10

Cirrhotic patients with portal hypertension and variceal hemorrhage are vulnerable to endotoxemia. However, the direct influence of endotoxemia on portal-systemic collateral vasculature remains unexplored. In this study, portal hypertension was induced in Sprague-Dawley rats by partial portal vein ligation. On the 7th day after portal vein ligation, at 0.5, 1.5, and 5 h post endotoxin (LPS; Escherichia coli serotype O111:B4, 3 mg/kg, i.p., E0.5, E1.5 and E5, respectively) or saline (control, C0.5, C1.5, and C5, respectively) injection, hemodynamic measurements and concentration-response relationships to arginine vasopressin (AVP; 10(-10)-10(-7) mol/L) in collateral vascular bed were obtained. In another six parallel groups, reverse-transcriptase-polymerase chain reaction of iNOS, eNOS, and endothelin 1 (ET-1) mRNA expressions for splenorenal shunt, the most prominent intra-abdominal collateral vessel, was performed. The results showed that E0.5 had lower perfusion pressure changes to AVP and higher splenorenal shunt eNOS expression than C0.5 group (P < 0.05). Compared with C1.5, tachycardia, higher perfusion pressure changes and enhanced splenorenal shunt iNOS and ET-1 expression were observed in E1.5 group (P < 0.05). In E5, systemic and portal hypotension with markedly enhanced collateral AVP responsiveness and splenorenal shunt iNOS and ET-1 expressions were noted (P < 0.05). In conclusion, vasoactive substances counterregulation participates, at least in part, the time-dependent changes of collateral AVP responsiveness in endotoxemic portal hypertensive rats.
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PMID:Evolution of portal-systemic collateral vasopressin response in endotoxemic portal hypertensive rats. 1929 90