Fractional urinary excretion of endothelin-1 is reduced by acute ETB receptor blockade

Goddard, Jane; Johnston, Neil R.; Cumming, Allan D.; Webb, David J.

doi:10.1152/ajprenal.00101.2007

Cited by 17 publications

(14 citation statements)

References 27 publications

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“…Moreover, fractional excretion of ET-1, TGF-␤, and LCN2-NGAL was not significantly correlated with their serum levels or eGFR (data not shown). Collectively, these data suggest that the amount of ET-1, TGF-␤, and LCN2-NGAL filtered at the glomerulus contributed relatively little to the amount present in the urine, as previously reported in patients with chronic kidney disease (7,23).…”

Section: Identification Of Differentially Expressed Genes In Db/db Kisupporting

confidence: 80%

The renal transcriptome of db/db mice identifies putative urinary biomarker proteins in patients with type 2 diabetes: a pilot study

Simonson

Tiktin

Debanne

et al. 2012

American Journal of Physiology-Renal Physiology

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The renal transcriptome of db/db mice identifies putative urinary biomarker proteins in patients with type 2 diabetes: a pilot study. Am J Physiol Renal Physiol 302: F820-F829, 2012. First published December 28, 2011 doi:10.1152/ajprenal.00424.2011.-We sought to identify novel urinary biomarkers of kidney function in type 2 diabetes. We screened the renal transcriptome of db/db and db/m mice for differentially expressed mRNA transcripts that encode secreted proteins with human orthologs. Whether elevated urine levels of the orthologous proteins correlated with diminished glomerular filtration rate was tested in a cross-sectional study of n ϭ 56 patients with type 2 diabetes. We identified 36 putative biomarker genes in db/db kidneys: 31 upregulated and 5 downregulated. Urinary protein levels of six selected candidates (endothelin-1, lipocalin-2, transforming growth factor-␤, growth and differentiation factor-15, interleukin-6, and macrophage chemoattractant protein-1) were elevated in type 2 diabetic patients with subnormal glomerular filtration rate (i.e., Ͻ90 ml·min Ϫ1 ·1.73 m Ϫ2 ), independent of microalbuminuria, age, sex, race, and use of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists. In contrast, urinary levels of fibroblast growth factor were not increased. A composite variable of urine albumin and any of the six candidate markers was associated with subnormal estimated glomerular filtration rate more closely than albumin alone. In addition, urinary endothelin-1, growth and differentiation factor-15, and interleukin-6 were associated with a marker of proximal tubule damage, N-acetyl-␤-D-glucosaminidase activity. These results suggest that gene expression profiling in diabetic mouse kidney can complement existing proteomic-based approaches for renal biomarker discovery in humans.

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Section: Identification Of Differentially Expressed Genes In Db/db Kisupporting

confidence: 80%

The renal transcriptome of db/db mice identifies putative urinary biomarker proteins in patients with type 2 diabetes: a pilot study

Simonson

Tiktin

Debanne

et al. 2012

American Journal of Physiology-Renal Physiology

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“…First, as renal function declines, plasma ET-1 levels increase. 52,53 It remains unclear whether the rise in plasma ET-1 in chronic kidney disease (CKD) is because of biologically active or simply immunologically competent peptide, but infusion of exogenous ET-1 to bilaterally nephrectomized rats results in a increased plasma half-life of ET-1 and a prolonged rise in BP compared with shamoperated rats 54 consistent with the idea that elevated plasma ET-1 concentrations in CKD may contribute to hypertension. Second, there is an upregulation of renal ET-1 production in CKD, 55 as reflected by increased urinary ET-1 excretion.…”

Section: Hypertension Associated With Chronic Kidney Diseasementioning

confidence: 85%

“…Second, there is an upregulation of renal ET-1 production in CKD, 55 as reflected by increased urinary ET-1 excretion. 53,56 The effects of exogenous ET-1 on the renal vasculature are vasoconstriction, activating the renin-angiotensin-aldosterone system, and causing salt and water retention, both of which have the potential to raise BP. Animal data suggest that, in CKD, the renal vasculature may be more sensitive to the vasoconstrictor effects of ET-1 than in normal kidneys.…”

Section: Hypertension Associated With Chronic Kidney Diseasementioning

confidence: 99%

Role of Endothelin-1 in Clinical Hypertension

et al. 2008

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H ypertension is the most common risk factor worldwide for cardiovascular morbidity and mortality. 1,2 Currently it is estimated that a quarter of the world's adult population is hypertensive, and this number is projected to increase to Ϸ30% by 2025. 1 Although, there exist a number of drug therapies for hypertension, blood pressure (BP) control to target is still only achieved in Ϸ30% of patients. 3 Over the last 20 years, novel licensed therapies have primarily focused on the renin-angiotensin-aldosterone system. Endothelin (ET) receptor antagonism represents an innovative, but as yet only partially explored, alternative approach in the management of hypertension.A review in Hypertension 10 years ago outlined the potential role that ET-1 may play in the development of hypertension, 4 as proposed by Yanagisawa et al in their original Nature article in 1988. 5 This largely focused on preclinical data because, at that time, there was only 1 published study of ET receptor antagonism in patients with essential hypertension. 6 There were also few data that focused on the relative benefits of selective or mixed ET blockade. Finally, the lack of longer-term data on safety and tolerability for these drugs made their place in the antihypertensive armamentarium unclear. In this review we aim to answer many of these questions and outline some of the key findings in this field from the last decade. Biology of the ET SystemThe ET family consists of three 21-amino acid peptides (ET-1, ET-2, and ET-3) with powerful vasoconstrictor and pressor properties. 7 Of the 3 peptides, ET-1 is the major vascular isoform and of most importance in the cardiovascular system. 8 The gene product is the 212-amino acid prepro-ET-1. This is cleaved to big ET-1, after which an ETconverting enzyme (ECE) catalyzes the generation of the biologically active ET-1 and a C-terminal fragment.ET-1 acts by binding to 2 distinct receptors, the ET A and the ET B receptors (ET A R and ET B R). 9,10 ET receptors are expressed by a wide variety of cells and tissues. Within the vasculature, ET A R and ET B R, located on vascular smooth muscle cells, mediate the vasoconstrictor effects of ET B Rs are also found on vascular endothelial cells, where their activation results in vasodilation mediated mainly by NO. 12,13 In addition, ET B Rs have a major role in the clearance of circulating ET-1. The plasma half-life of ET-1 in health is Ϸ1 minute, 14 with removal through receptor-and nonreceptormediated mechanisms. ET-1 binds to ET B R, with subsequent ligand-receptor complex internalization and intracellular degradation accounting for the majority of clearance, particularly in the pulmonary circulation, 15 although the splanchnic and renal circulations also contribute. 16 Therefore, a reduction in ET B R number, or ET B R blockade, may reduce ET-1 clearance, increasing plasma concentrations without altering production. For this reason and, importantly, because most ET-1 is released albuminally, plasma concentrations of ET-1 do not accurately reflect ET-1 productio...

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“…Although plasma ET-1 levels are not a reliable measure of vascular ET-1 production, owing to its predominantly abluminal release (40), urinary ET-1 excretion is independent of plasma ET-1 concentrations (13,31) and is well-correlated with renal ET-1 production (4,38). A few small studies showed a rise in plasma (20) and urine (26) ET-1 in severe CKD, and our group previously demonstrated increases in plasma and urinary ET-1 concentrations in eight subjects with noninflammatory renal disease, across a range of glomerular filtration rates (GFR) (13). However, there are no data on how renal inflammation may alter these profiles and hence on the utility of urinary ET-1 as a potential biomarker of renal inflammation.…”

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confidence: 99%

Urinary endothelin-1 in chronic kidney disease and as a marker of disease activity in lupus nephritis

Dhaun¹,

Lilitkarntakul²,

MacIntyre³

et al. 2009

American Journal of Physiology-Renal Physiology

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Chronic inflammation contributes to the development and progression of chronic kidney disease (CKD). Identifying renal inflammation early is important. There are currently no specific markers of renal inflammation. Endothelin-1 (ET-1) is implicated in the pathogenesis of CKD. Thus, we investigated the impact of progressive renal dysfunction and renal inflammation on plasma and urinary ET-1 concentrations. In a prospective study, plasma and urinary ET-1 were measured in 132 subjects with CKD stages 1 to 5, and fractional excretion of ET-1 (FeET-1) was calculated. FeET-1, serum C-reactive protein (CRP), urinary ET-1:creatinine ratio, and urinary albumin:creatinine ratio were also measured in 29 healthy volunteers, 85 subjects with different degrees of inflammatory renal disease but normal renal function, and in 10 subjects with rheumatoid arthritis without renal involvement (RA). In subjects with nephritis associated with systemic lupus erythematosus (SLE), measurements were done before and after 6 mo of treatment. In subjects with CKD, plasma ET-1 increased linearly as renal function declined, whereas FeET-1 rose exponentially. In subjects with normal renal function, FeET-1 and urinary ET-1:creatinine ratio were higher in SLE subjects than in other groups (7.7 ± 2.7%, 10.0 ± 3.0 pg/μmol, both P < 0.001), and correlated with CRP, and significantly higher than in RA subjects (both P < 0.01) with similar CRP concentrations. In SLE patients, following treatment, FeET-1 fell to 3.6 ± 1.4% ( P < 0.01). Renal ET-1 production increases as renal function declines. In subjects with SLE, urinary ET-1 may be a useful measure of renal inflammatory disease activity while measured renal function is still normal.

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Fractional urinary excretion of endothelin-1 is reduced by acute ETB receptor blockade

Cited by 17 publications

References 27 publications

The renal transcriptome of db/db mice identifies putative urinary biomarker proteins in patients with type 2 diabetes: a pilot study

The renal transcriptome of db/db mice identifies putative urinary biomarker proteins in patients with type 2 diabetes: a pilot study

Role of Endothelin-1 in Clinical Hypertension

Urinary endothelin-1 in chronic kidney disease and as a marker of disease activity in lupus nephritis

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