Endothelin Peptides and Receptors in Human Kidney

Karet, Fiona E.

doi:10.1042/cs0910267

Cited by 18 publications

(11 citation statements)

References 15 publications

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“…Faint staining of ETA and ETB receptors has also been reported in human glomeruli, and proximal and distal tubules. In agreement with the rat studies, the distal nephron expresses more ET receptors that the proximal nephron 30,31 .…”

Section: Introductionsupporting

confidence: 89%

“…These members include ET-1, ET-2, ET-3 and ET-4 (analogue of human ET-2 in rat and mouse, also named as vasoactive intestinal contractor), and three isoforms of 31-amino-acid ETs (ET-1 1–31 , ET-2 1–31 and ET-3 1–31 ) 12 . Owing to the similarity of actions between ET-1 1–31 and ET-1 in vivo , it is possible that some of the effects of ET 1–31 result from their partial bioconversion into ETs 13 . Among these isoforms, ET-1 is the principal isoform and is the most potent and long-lasting constrictor of human vessels known to date 5 .…”

Section: Introductionmentioning

confidence: 99%

“…The transcription and translation of pre-pro-ET result in the formation of a 203-amino-acid peptide which is subsequently cleaved by a furin convertase to the 38-amino-acid peptide big ET 1–38 . Big ET is processed further into ET 1–31 by different isoforms of endothelin converting enzymes (ECEs), a group of proteases that belong to the metalloprotease family 16 , including ECE-1a, ECE-1b, ECE-1c and ECE-1d, derived from a single gene by the action of alternative promoters.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Sodium Transport in the Proximal Tubule by Endothelin

Zhang

José

Zeng

2011

Contributions to Nephrology

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Human essential hypertension and rodent genetic hypertension are associated with increased sodium transport in the renal proximal tubule and medullary thick ascending limb of Henle. The proximal tubule, which secretes endothelin, expresses the endothelin type B (ETB) receptor. Low (nM) concentrations of endothelin, via the ETB receptor, inhibit sodium and water transport and ATP-driven drug secretion in the proximal tubule. In contrast, very low (pM) and high nM concentrations of endothelin increase renal proximal sodium transport, the receptor involved remains to be determined. The natriuretic effect of ETB receptor stimulation is impaired in spontaneously hypertensive rats, due in part to a defective interaction with D3 dopamine and angiotensin II type 1 receptors. Impaired ETB receptor function in the renal proximal tubule may be important in the pathogenesis of genetic hypertension.

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Section: Introductionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regulation of Sodium Transport in the Proximal Tubule by Endothelin

Zhang

José

Zeng

2011

Contributions to Nephrology

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“…Endothelins comprise a family of at least three structurally related 21‐amino acid isopeptides [12]. Among the various ETs, ET‐1 represents the major isoform that mediates most of the biological effects within the kidney [13]. Although first identified in vascular endothelial cells, it is now clear that a broad spectrum of other cell types can produce ET‐1.…”

Section: Biology Of the Endothelin Systemmentioning

confidence: 99%

Endothelin receptor selectivity in chronic kidney disease: rationale and review of recent evidence

Neuhofer¹,

Pittrow

2009

Eur J Clin Investigation

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Endothelin (ET) is a potent vasoconstrictory peptide with proinflammatory and profibrotic properties that exerts its biological effects through two pharmacologically distinct receptor subtypes, namely ET(A) and ET(B). In addition to its substantial contribution to normal renal function, a large body of evidence suggests that derangement of the renal ET system is involved in the initiation and progression of chronic kidney disease (CKD) in diabetes, hypertension and glomerulonephritis. Thus, the use of ET receptor antagonists (ERAs) may offer potential novel treatment strategies in CKD. Recent literature on the role of the renal ET system in the healthy kidney was reviewed. In addition, an unbiased PubMed search was performed for studies published during the last 5 years that addressed the effects of ERAs in CKD. A particular objective was to extract information regarding whether selective or nonselective ERAs may have therapeutic potential in humans. ET-1 acts primarily as an autocrine or paracrine factor in the kidney. In normal physiology, ET-1 promotes diuresis and natriuresis by local production and action through ET(B) receptors in the renal medulla. In pathology, ET-1 mediates vasoconstriction, mesangial-cell proliferation, extracellular matrix production and inflammation, effects that are primarily conveyed by ET(A) receptors. Results obtained in animal models and in humans with the use of ERAs in CKD are encouraging; nevertheless, it is still under debate which receptor subtype should be targeted. According to most studies, selective inhibition of ET(A) receptors appears superior compared with nonselective ERAs because this approach does not interfere with the natriuretic, antihypertensive and ET clearance effects of ET(B) receptors. Although preliminary data in humans are promising, the potential role of ERAs in patients with CKD and the question of which receptor subtype should be targeted can only be clarified in randomized clinical trials.

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“…Additional physiological roles of this hormone are suggested by ET A and ET B receptor localization in nonvascular tissues, such as the nephron (11). Analysis of the ET receptor distribution in the nephron shows that ET B is expressed at 10-fold higher levels than ET A , suggesting a dominant role for ET B in renal tubule epithelial cells (45,46). Importantly, adult rats lacking functional ET B receptor activity display enhanced Na ϩ reabsorption in the distal nephron, implicating ET B in regulation of tubular function (22).…”

Section: Src Family Kinases Do Not Regulate Enac By Direct Phosphorylmentioning

confidence: 99%

Src Family Kinases Mediate Epithelial Na+ Channel Inhibition by Endothelin

Gilmore

Stutts²,

Milgram

2001

Journal of Biological Chemistry

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The epithelial Na ؉ channel (ENaC) is implicated in the pathogenesis of salt-sensitive hypertension. Recent evidence from animal models suggests that the vasoactive peptide, endothelin (ET-1), may be an important negative regulator of ENaC in vivo. We investigated the signaling pathway involved in endothelin-mediated ENaC inhibition. Experiments were performed in NIH 3T3 cells stably expressing genes for the three (␣, ␤, and ␥) ENaC subunits. In whole cell patch clamp experiments, we found that ET-1 treatment induced a dose-dependent decrease in amiloride-sensitive currents. Using receptor-specific antagonists, we determined that the effects of ET-1 were attributed to activation of the ET B receptor. Moreover, the inhibitory effect of ET-1 on ENaC could be completely blocked when cells were pretreated with the selective Src family kinase inhibitor, PP2. Further studies revealed that basal Src family kinase activity strongly regulates ENaC whole cell currents and single channel gating. These results suggest that Src family kinases lie in a signaling pathway activated by ET-1 and are components of a novel negative regulatory cascade resulting in ENaC inhibition. Endothelin (ET)1 1, a potent vasoactive peptide originally described as an endothelial cell-derived factor, is the founding member of a family of related 21-amino acid peptides (1, 2). Each endothelin (ET-1, ET-2, and ET-3) is encoded by a distinct gene and is processed from an inactive precursor via two proteolytic cleavages to generate a biologically active peptide (3,4). Endothelins are synthesized in many cell types, including endothelial, epithelial, fibroblast, and cardiac muscle cells, and function as autocrine or paracrine factors to regulate different cellular processes (1, 5-7). The two endothelin receptors, ET A and ET B , are broadly expressed with overlapping, but distinct, distributions (8 -11). ET A and ET B are heterotrimeric G protein-coupled receptors (GPCRs) that can couple with multiple G␣ subunits, depending on cell type (12)(13)(14). In addition, ET receptors stimulate the activity of nonreceptor tyrosine kinases in some cells (5,15,16). Although this activation is generally thought to mediate the mitogenic effects of endothelins, acute activation of NHE3 via ET-1 is blocked ϳ50% by tyrosine kinase inhibitors (17, 18). The ET-mediated activation of NHE3 occurs specifically via ET B receptors (19).Recent evidence indicates that renal ET B receptors may be important for sodium handling. The function of ET B has been examined in rats with naturally occurring mutation of the ET B gene. These studies indicate that ET B plays an essential role in development of enteric neurons because absence of functional ET B receptors causes perinatal lethality resulting from megacolon (20, 21). Gariepy et al. (22) rescued this phenotype by specifically expressing ET B only in adrenergic neurons using the dopamine ␤-hydroxylase promoter (22). On high salt diets, these rats developed salt-sensitive hypertension, which was restored to normal when animals ...

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Endothelin Peptides and Receptors in Human Kidney

Cited by 18 publications

References 15 publications

Regulation of Sodium Transport in the Proximal Tubule by Endothelin

Regulation of Sodium Transport in the Proximal Tubule by Endothelin

Endothelin receptor selectivity in chronic kidney disease: rationale and review of recent evidence

Src Family Kinases Mediate Epithelial Na+ Channel Inhibition by Endothelin

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