Effects of endothelin-1 on renal function and renin secretion in vivo and in vitro

Abstract Objective Endothelin-1 plays an important role in the pathogenesis of severe pulmonary hypertension. The + 139 ‘A’, adenine insertion variant in 5′UTR of edn1 gene has been reported to be associated with increased expression of Endothelin-1 in vitro. The aim of present study was to explore the association of this variant with the circulating levels of Endothelin-1 in vivo using archived DNA and plasma samples from 38 paediatric congenital heart disease (cyanotic and acyanotic) patients with severe pulmonary hypertension. Results The plasma Endothelin-1 levels were highly varied ranging from 1.63 to75.16 pg/ml. The + 139 ‘A’ insertion variant in 5′UTR of edn1 was seen in 8 out of 38 cases with only one acyanotic sample demonstrating homozygosity of inserted ‘A’ allele at + 139 site (4A/4A genotype). The plasma Endothelin-1 levels in children with homozygous variant 3A/3A genotype were comparable in cyanotic and acyanotic groups. Lone 4A/4A acyanotic sample had ET-1 levels similar to the median value of ET-1 associated with 3A/3A genotype and was absent in cyanotic group presumably due to deleterious higher ET-1 levels. The discussed observations, limited by the small sample size, are suggestive of homozygous adenine insertion variant posing a risk in cyanotic babies with Severe Pulmonary Hypertension.

Download Full-text

In vivo and in vitro study of osteogenic potency of endothelin-1 on bone marrow-derived mesenchymal stem cells

Experimental Cell Research ◽

10.1016/j.yexcr.2017.04.018 ◽

2017 ◽

Vol 357 (1) ◽

pp. 25-32 ◽

Cited By ~ 6

Author(s):

Long-Wei Hu ◽

Xiao Wang ◽

Xin-Qun Jiang ◽

Li-Qun Xu ◽

Hong-Ya Pan

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

In Vitro Study ◽

Vitro Study ◽

Endothelin 1

Download Full-text

Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium

Journal of Experimental Medicine ◽

10.1084/jem.20182151 ◽

2019 ◽

Vol 216 (8) ◽

pp. 1874-1890 ◽

Cited By ~ 13

Author(s):

Nicolas Ricard ◽

Rizaldy P. Scott ◽

Carmen J. Booth ◽

Heino Velazquez ◽

Nicholas A. Cilfone ◽

...

Keyword(s):

Rapid Onset ◽

Cardiac Conduction ◽

Tgfβ Signaling ◽

Mesenchymal Transition ◽

Endothelin 1 ◽

Endocrine Organs ◽

Endothelial To Mesenchymal Transition

To define the role of ERK1/2 signaling in the quiescent endothelium, we induced endothelial Erk2 knockout in adult Erk1−/− mice. This resulted in a rapid onset of hypertension, a decrease in eNOS expression, and an increase in endothelin-1 plasma levels, with all mice dying within 5 wk. Immunostaining and endothelial fate mapping showed a robust increase in TGFβ signaling leading to widespread endothelial-to-mesenchymal transition (EndMT). Fibrosis affecting the cardiac conduction system was responsible for the universal lethality in these mice. Other findings included renal endotheliosis, loss of fenestrated endothelia in endocrine organs, and hemorrhages. An ensemble computational intelligence strategy, comprising deep learning and probabilistic programing of RNA-seq data, causally linked the loss of ERK1/2 in HUVECs in vitro to activation of TGFβ signaling, EndMT, suppression of eNOS, and induction of endothelin-1 expression. All in silico predictions were verified in vitro and in vivo. In summary, these data establish the key role played by ERK1/2 signaling in the maintenance of vascular normalcy.

Download Full-text

Hydrocortisone abolishes the angiotensin II-mediated potentiation of endothelin-I in bovine bronchi

Clinical Science ◽

10.1042/cs1000019 ◽

2000 ◽

Vol 100 (1) ◽

pp. 19-23

Author(s):

A. J. BROWN ◽

J. E. NALLY

Keyword(s):

Angiotensin Ii ◽

Species Differences ◽

Inhaled Corticosteroids ◽

Response Curves ◽

Endothelin 1 ◽

Asthmatic Patients ◽

Presence And Absence ◽

Evoked Contractions

Angiotensin II potentiates methacholine-evoked bronchoconstriction both in bovine airways in vitro and in asthmatic patients in vivo. Angiotensin II also potentiates endothelin-1-evoked contractions in vitro, but fails to alter such contractions in vivo. One possible confounding factor in patients is their use of inhaled corticosteroids. Accordingly the present study examined the effects of hydrocortisone (cortisol) on contractions evoked by methacholine and endothelin-1 in the presence and absence of angiotensin II. Contractions of rings of isolated bovine airways were measured isometrically in organ baths. Concentration–response curves were obtained for endothelin-1 or methacholine in the presence and absence of angiotensin II, hydrocortisone and a combination of angiotensin II and hydrocortisone. Hydrocortisone abolished the angiotensin II-mediated potentiation of endothelin-1-evoked, but not methacholine-evoked, contractions. Hydrocortisone alone evoked the enhancement of methacholine responses, similar to the effect produced by angiotensin II. While species differences may exist, our present results suggest that the use of corticosteroids can have a profound effect on the interaction between angiotensin II and endothelin-1. Accordingly, the presence of inhaled corticosteroids might explain the differences between the results obtained in vitro and in vivo.

Download Full-text

Endothelin-1 and pancreatic islet vasculature: studies in vivo and on isolated, vascularly perfused pancreatic islets

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00640.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. E1616-E1623 ◽

Cited By ~ 22

Author(s):

En Yin Lai ◽

A. Erik G. Persson ◽

Birgitta Bodin ◽

Örjan Källskog ◽

Arne Andersson ◽

...

Keyword(s):

Blood Flow ◽

Pancreatic Islet ◽

Vascular Reactivity ◽

Blood Perfusion ◽

Receptor Subtype ◽

Endothelin 1 ◽

Islet Blood Flow ◽

Endothelin B

Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor, which also stimulates insulin release. The aim of the present study was to evaluate whether exogenously administered ET-1 affected pancreatic islet blood flow in vivo in rats and the islet arteriolar reactivity in vitro in mice. Furthermore, we aimed to determine the ET-receptor subtype that was involved in such responses. When applying a microsphere technique for measurements of islet blood perfusion in vivo, we found that ET-1 (5 nmol/kg) consistently and markedly decreased total pancreatic and especially islet blood flow, despite having only minor effects on blood pressure. Neither endothelin A (ETA) receptor (BQ-123) nor endothelin-B (ETB) receptor (BQ-788) antagonists, alone or in combination, could prevent this reduction in blood flow. To avoid confounding interactions in vivo, we also examined the arteriolar vascular reactivity in isolated, perfused mouse islets. In the latter preparation, we demonstrated a dose-dependent constriction in response to ET-1. Administration of BQ-123 prevented this, whereas BQ-788 induced a right shift in the response. In conclusion, the pancreatic islet vasculature is highly sensitive to exogenous ET-1, which mediates its effect mainly through ETA receptors.

Download Full-text

Renal effects induced by prolonged mPGES1 inhibition

AJP Renal Physiology ◽

10.1152/ajprenal.00492.2013 ◽

2014 ◽

Vol 306 (1) ◽

pp. F68-F74 ◽

Cited By ~ 10

Author(s):

Francisco Salazar ◽

Michael L. Vazquez ◽

Jaime L. Masferrer ◽

Gabriel Mbalaviele ◽

Maria T. Llinas ◽

...

Keyword(s):

Renal Function ◽

Plasma Renin ◽

In Vivo Studies ◽

Renal Effects ◽

Excretory Function ◽

Membrane Bound ◽

Inflammatory Drugs ◽

Chronically Instrumented Dogs

The importance of membrane-bound PGE synthase 1 (mPGES1) in the regulation of renal function has been examined in mPGES1-deficient mice or by evaluating changes in its expression. However, it is unknown whether prolonged mPGES1 inhibition induces significant changes of renal function when Na+ intake is normal or low. This study examined the renal effects elicited by a selective mPGES1 inhibitor (PF-458) during 7 days in conscious chronically instrumented dogs with normal Na+ intake (NSI) or low Na+ intake (LSI). Results obtained in both in vitro and in vivo studies have strongly suggested that PF-458 is a selective mPGES1 inhibitor. The administration of 2.4 mg·kg−1·day−1 PF-458 to dogs with LSI did not induce significant changes in renal blood flow (RBF) and glomerular filtration rate (GFR). A larger dose of PF-458 (9.6 mg·kg−1·day−1) reduced RBF ( P < 0.05) but not GFR in dogs with LSI and did not induce changes of renal hemodynamic in dogs with NSI. Both doses of PF-458 elicited a decrease ( P < 0.05) in PGE2 and an increase ( P < 0.05) in 6-keto-PGF1α. The administration of PF-458 did not induce significant changes in renal excretory function, plasma renin activity, and plasma aldosterone and thromboxane B2 concentrations in dogs with LSI or NSI. The results obtained suggest that mPGES1 is involved in the regulation of RBF when Na+ intake is low and that the renal effects elicited by mPGES1 inhibition are modulated by a compensatory increment in PGI2. These results may have some therapeutical implications since it has been shown that prolonged mPGES1 inhibition has lower renal effects than those elicited by nonsteroidal anti-inflammatory drugs or selective cyclooxygenase-2 inhibitors.

Download Full-text