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)

Blockade of the renin-angiotensin system improves the impaired endothelium-dependent relaxations associated with hypertension and aging, partly through amelioration of endothelium-derived hyperpolarizing factor (EDHF)-mediated responses. Although the nature of EDHF is still controversial, recent studies have suggested the involvement of gap junctions in EDHF-mediated responses. Gap junctions consist of connexins (Cx), and we therefore tested whether the expression of Cx in vascular endothelial cells would be altered by hypertension and antihypertensive treatment. Spontaneously hypertensive rats (SHR) were treated with either the angiotensin II type 1 receptor antagonist candesartan or the combination of hydralazine and hydrochlorothiazide for 3 mo from 5 to 8 mo of age. Confocal laser scanning microscopy after immunofluorescent labeling with antibodies against Cx37, Cx40, and Cx43 revealed that the expression of Cx37 and Cx40 in endothelial cells of the mesenteric artery was significantly lower in SHR than in WKY. Treatment with candesartan, but not the combination of hydralazine and hydrochlorothiazide, significantly increased the expression of Cx37 and Cx40, although blood pressure decreased similarly. On the other hand, the expression of Cx43, though scarce and heterogeneous, was increased in SHR compared with WKY, and candesartan treatment lowered the expression of Cx43. These findings suggest that renin-angiotensin system blockade corrects the decreased expression of Cx37 and Cx40 in arterial endothelial cells of hypertensive rats, partly independently of blood pressure, whereas the expression of Cx43 changed in the opposite direction. It remains to be clarified whether these changes in Cx37 and Cx40 are related to endothelial function, particularly that attributable to EDHF.
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PMID:Angiotensin II receptor blockade corrects altered expression of gap junctions in vascular endothelial cells from hypertensive rats. 1501 32

Four connexin (Cx) molecules, namely Cx37, Cx40, Cx43 and Cx45, are expressed in the gap junctions that exist within and between the cellular layers of arteries. Endothelial cells are well coupled by large gap junctions expressing Cx37, Cx40 and, to a lesser extent, Cx43, whose expression may be more subject to regulation by physical factors. Smooth muscle cells are more heterogeneously coupled by gap junctions that are small and rare. The identity of the Cx expressed in the media may vary among different arteries. Myoendothelial gap junctions are small and more common in resistance arteries with fewer layers of smooth muscle cells. Given the small size of these gap junctions and the rapid turnover rate of Cxs, homocellular coupling in the media and heterocellular coupling between the cell layers may be subject to more dynamic control than coupling in the endothelium. Vascular gap junctions have been implicated in a number of vasomotor responses that may regulate vascular tone and blood pressure. These include the mechanism of action of the vasodilator, endothelium-derived hyperpolarizing factor (EDHF), the myogenic constriction to intramural pressure increase, the spontaneous or agonist-induced vasomotion of arteries and arterioles and the spreading vasodilation and constriction observed in microcirculatory networks. Few data are available on Cx expression in the media of resistance arteries during hypertension. Changes in the expression of Cx43 described in the media of the aorta of hypertensive rats vary with the hypertensive model studied and are likely to represent adaptations to structural changes in the vascular wall. In contrast, in the endothelium of the caudal and mesenteric arteries of spontaneously hypertensive rats, expression of Cxs is significantly decreased compared with arteries from normotensive rats and this decrease is reversed by inhibitors of the renin-angiotensin system. During hypertension, the activity of EDHF is decreased in the mesenteric artery, but this occurs much later than the initial increase in blood pressure and the decrease in endothelial Cxs, suggesting that changes in EDHF may not be causally related to hypertension or to the changes in endothelial Cxs. Upregulation of the myogenic response and the incidence of vasomotion has been reported in hypertension. Little is currently known of the effects of hypertension on spreading vasomotor responses. Deletion of specific Cxs in genetically modified mice is complicated by neonatal lethality or coordinate regulation and compensatory changes in the remaining Cxs. Nevertheless, mice in which Cx40 has been deleted are hypertensive and spreading vasodilatory responses are significantly impaired. Determination of a role for specific Cxs in the control of blood pressure must await the development of animals in which Cx expression can be modulated in a more complex temporal and tissue-specific manner.
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PMID:Vascular gap junctions and implications for hypertension. 1555 5

Renin secretion is regulated by coordinated signaling between the various cells of the juxtaglomerular apparatus. The renin-secreting cells (RSC), which play a major role in the control of blood pressure, are coupled to each other and to endothelial cells by Connexin40 (Cx40)-containing channels. In this study, we show that Cx40 knockout (Cx40-/-) mice, but not their heterozygous littermates, are hypertensive due to the increase in the number of RSC, renin biosynthesis, and plasma renin. Treatment with the angiotensin II receptor AT1 antagonist candesartan or the angiotensin II-converting enzyme inhibitor ramipril reduced the blood pressure of the Cx40-/- mice to the same levels seen in wild-type (WT) mice. The elevated blood pressure of the knockout mice was not affected by clipping one renal artery (2K1C, renin-dependent model of hypertension) or after a high salt diet. Under these conditions, however, Cx40-/- mice showed an altered production and release of renin. The renin mRNA ratio between the clipped and the non-clipped kidney was lower in the knockout than in the WT 2K1C mice. This indicates that the response to a change in blood pressure was altered. The RSC of the Cx40-/- mice did not have a compensatory increase in the levels of either Cx43 or Cx37. Our data show that renin secretion is dependent on Cx40 and suggest the Cx40-/- mice may be a genetic model of renin-dependent hypertension.
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PMID:Connexin40 regulates renin production and blood pressure. 1788 39

Gap junctions are present in the juxtaglomerular apparatus enabling intercellular communication. Our study determined the location of different connexin subtypes within the juxtaglomerular apparatus of the rat, and the role of these subtypes in renal hemodynamics through the use of specific mimetic peptides. Immunohistochemical analysis showed connexins 37 and 40 expression in the endothelial and renin-secreting cells of the afferent arteriole, while connexin 40 was also found in extra- and intraglomerular mesangial cells. In contrast, connexin 43 was weakly expressed in endothelial cells of the afferent arteriole and within the glomerulus. Intra-renal infusion of the peptides (GAP) reported to block specific gap junctions ((Cx37,43)GAP27 or (Cx40)GAP27), elevated blood pressure, plasma renin activity, and angiotensin II levels, while decreasing renal plasma flow without a significant change in the glomerular filtration rate. Subsequent restoration of blood pressure reduced both renal plasma flow and glomerular filtration rate. In contrast, (Cx43)GAP26 reduced glomerular filtration rate without alterations in blood pressure, renal plasma flow, plasma renin activity, or angiotensin II levels. Hence, connexins 37 and 40 are expressed in the rat juxtaglomerular apparatus and these proteins control, in part, the renin-angiotensin system and renal autoregulation.
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PMID:Expression and role of connexins in the rat renal vasculature. 1804 20

Gap junctions are formed in the cardiovascular system by connexin40 (Cx40), Cx37, Cx43, and Cx45. These low resistance channels allow the transfer of ions and small molecules between cells. The longitudinal coupling of endothelial and smooth muscle cells via gap junctions allows the spread of changes in membrane potential along the vascular wall and hence provides conduction pathways within the vessel itself. Functionally, this tight coupling is reflected by the spread of locally initiated vasomotor responses along the arteriole which are termed conducted responses. Conducted dilations are initiated by the application of endothelium-dependent stimuli which result in local hyperpolarization. This signal spreads along the wall, most likely along the endothelial cell layer, to elicit a coordinated dilation of the arteriole over a considerable distance. Likewise, the opposite signal (depolarization) spreads along the vessel giving rise to a conducted constriction. The latter response is however most likely transmitted along the smooth muscle cell layer. Thus, conducted responses reflect the synchronized behavior of the cells of the vascular wall. It is assumed that conducted responses are critical for the matching of oxygen delivery and tissue needs because they contribute to an ascending dilation which lowers resistance along the length of the arterioles and upstream vessels in a well-tuned fashion. Herein, Cx40 is of special importance because it is critically required for intact signal transduction along the endothelial cell layer. In addition, Cx40 mediates pressure feedback inhibition on renin synthesis in the kidney. Both, vascular and renal function of Cx40, may be involved in the hypertension that is observed in Cx40-deficient animals. In this review, we will summarize physiologic function of connexins in arterioles and briefly address their role in the kidney with respect to renin secretion.
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PMID:Gap junctions synchronize vascular tone within the microcirculation. 1827 87

Hypertension has been shown to be associated with impaired endothelium-derived hyperpolarizing factor (EDHF)-mediated arterial relaxation and hyperpolarization. Treatments of hypertensive rats with inhibitors of the renin-angiotensin system have been shown to restore both EDHF-mediated responses and the expression of connexins involved in the intercellular transfer of the hyperpolarization in mesenteric arteries. The present study was designed to determine whether chronic treatment of rats with angiotensin II impairs EDHF-mediated responses and the expression of connexins in the mesenteric arterial wall. Male Wistar rats were treated with angiotensin II (0.4 mg/kg/day) for 21 days using osmotic minipumps. Arterial pressure was measured by tail-cuff plethysmography. Contractile responses and membrane potential were measured in isolated mesenteric arteries. The expression of the three connexins (Cxs), Cx37, Cx40, and Cx43, was quantified in segments of mesenteric arteries by immunohistochemistry and quantitative real-time reverse transcriptase-polymerase chain reaction. Angiotensin II administration increased the mean systolic blood pressure. EDHF-mediated relaxation and hyperpolarization to acetylcholine and red wine polyphenols were significantly impaired in mesenteric arteries from angiotensin II-treated rats in comparison with control animals, whereas nitric oxide-mediated relaxation was unaltered. The expression of connexins Cx37, Cx40, and Cx43 was significantly decreased in the mesenteric artery from angiotensin II-treated rats. These findings indicate that angiotensin II-induced hypertension is associated with a selective impairment of EDHF-mediated relaxation and hyperpolarization in the rat mesenteric artery. The inhibition of EDHF-mediated responses is due, at least in part, to a decreased expression of connexins Cx37, Cx40, and Cx43 in the arterial wall.
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PMID:Angiotensin II-induced hypertension is associated with a selective inhibition of endothelium-derived hyperpolarizing factor-mediated responses in the rat mesenteric artery. 1898 52

Absence of connexin 40 (Cx40) leads to ectopic juxtaglomerular renin expression and abrogates recruitment of renin-expressing cells in the adult kidney but does not disturb renin expression during kidney development. To find an explanation for these observations, we aimed to analyze the expression pattern of major vascular Cxs in normal juxtaglomerular epithelioid cells, in recruited renin-expressing cells, and in fetal renin-expressing cells. We found that during kidney development, the appearance of renin-producing cells paralleled the expression of Cx40 and, to a lesser extent, Cx45 but not other Cxs. In the adult kidney, juxtaglomerular epithelioid cells expressed Cx40 and lesser amounts of Cx37 and Cx43 but not Cx45, which localized to arteriolar smooth muscle cells. Recruitment of renin-producing cells in adult kidneys in response to long-term salt deprivation of mice correlated with the reappearance of only Cx40. Cx40-null renin-producing cells did not express Cx37, Cx43, or Cx45. These findings suggest that Cx40 expression is a characteristic of renin-producing cells in the kidney, and it seems to be essential in the recruitment of renin-producing cells in the adult but not the fetal kidney.
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PMID:Connexin expression in renin-producing cells. 1907 28

Within the juxtaglomerular apparatus, renin-producing cells and endothelial cells of the afferent arterioles express connexin (Cx)37 and Cx40, which form abundant gap junctions among these cells. Deletion of Cx40 leads to strong hyperreninemia and ectopic localization of renin-producing cells; however, the relevance of Cx37 for the renin system in the kidney has not been investigated. We therefore studied renin expression and renin secretion in kidneys from Cx37-deficient mice, both on normal salt diet and during chronic challenge of the renin system by pretreatment of mice with a low-salt diet in combination with an angiotensin I-converting enzyme inhibitor. This treatment procedure strongly enhances renin gene expression and renin secretion. We found that renal renin mRNA abundance and plasma renin concentration did not differ between wild-type and Cx37-/- mice under normal conditions. The stimulation of renin gene expression and renin secretion by salt depletion was even more pronounced in Cx37-/- as compared to wild-type mice. The regulation of renin secretion from isolated perfused kidneys by perfusion pressure and by angiotensin II was normal in Cx37-/- mice. In addition, the localization of renin-expressing cells was also regular in Cx37-/- kidneys. Finally, the expression pattern of other vascular Cxs such as Cx40, Cx43, and Cx45 was not altered in Cx37-/- kidneys. Our findings suggest that Cx37 is not essential for normal development and function of renin-producing cells. As a consequence, it appears unlikely that Cx40 exerts its important function in renin-producing cells via Cx37/Cx40 heteromeric gap junctions.
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PMID:Connexin 37 is dispensable for the control of the renin system and for positioning of renin-producing cells in the kidney. 1967 18

Connexins (Cxs) are widely-expressed proteins that form gap junctions in most organs, including the kidney. In the renal vasculature, Cx37, Cx40, Cx43, and Cx45 are expressed, with predominant expression of Cx40 in the endothelial cells and Cx45 in the vascular smooth muscle cells. In the tubules, there is morphological evidence for the presence of gap junction plaques only in the proximal tubules. In the distal nephron, Cx30, Cx30.3, and Cx37 are expressed, but it is not known whether they form gap junctions connecting neighboring cells or whether they primarily act as hemichannels. As in other systems, the major function of Cxs in the kidney appears to be intercellular communication, although they may also form hemichannels that allow cellular secretion of large signaling molecules. Renal Cxs facilitate vascular conduction, juxtaglomerular apparatus calcium signaling, and tubular purinergic signaling. Accordingly, current evidence points to roles for these Cxs in several important regulatory mechanisms in the kidney, including the renin angiotensin system, tubuloglomerular feedback, and salt and water reabsorption. At the systemic level, renal Cxs may help regulate blood pressure and may be involved in hypertension and diabetes.
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PMID:Connexins and the kidney. 2016 5

Gap junction channels facilitate chemical and electrical communication between adjacent cells. Gap junction protein, connexin (Cx), is expressed in the endothelial cells of vessels, glomerulus, and renin-secreting cells of the kidney. The purpose of this study was to investigate the role of Cx in renin release using Cx-overexpressing As 4.1 cells. The adenovirus-induced Cx overexpression was conducted by using recombinant adenovirus containing the cDNA encoding Cx37, Cx40, Cx43 (Ad-Cx), and beta-galactosidase (Ad-beta-gal). In 40-overexpressing cells, basal renin release increased in a time-dependent manner but it was significantly lower than that in Ad-beta-gal-treated cells. In Cx37- and Cx43-overexpressing cells, basal renin release was increased in a time-dependent manner, which was not different from control cells. 18-beta glycyrrhetinic acid (GA), a gap junction blocker, stimulated renin release dose-dependently and increased intracellular Ca(2+) in both Cx43-overexpressing cells and control cells. However, no significant differences were observed. An increase in renin release by 3,4,5-trimethoxybenzoic acid 8-(diethylamino)-octyl ester, a putative antagonist of Ca(2+) release from intracellular sequestration sites, was also similar between two groups. These results suggest that Cx43 may unlikely alter the regulation of renin release and intracellular Ca(2+) by gap junction blocker in As 4.1 cells.
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PMID:Regulation of renin release by connexin 43 in As 4.1 cell line. 2018 75


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