Biochemical and Biophysical Research Communications
Regular ArticleClearance of Circulating Endothelin-1 by ETB Receptors in Rats
Abstract
Exogenous endothelin (ET) is rapidly cleared from the circulation. We investigated which ET receptor subtypes (ETA and ETB) participate in ET-1 clearance. Following an intravenous (i.v.) bolus dose of [125I]ET-1 in anesthetized rats, radioactivity was rapidly cleared from the circulation and trapped by the lungs, kidneys and liver. Tissue distribution of the radioactivity was significantly inhibited in the lungs and kidneys, but not in the liver by infusion of the ETB antagonist BQ-788 (0.1 mg/kg/min i.v.), and the ET-1 clearance rate was reduced, while the ETA antagonist BQ-123 had no such effect. Furthermore, in isolated perfused rat lungs, about 80% of bolus-injected [125I]ET-1 was retained by the lungs after one passage. The retention of ET-1 was significantly inhibited by infusion of 1 μM BQ-788, but not BQ-123. These results suggest that ETB receptors play an important role in the clearance of ET-1.
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The kidney is considered to be one of the most estrogen-responsive, not reproductive organs in the body. Different estrogen receptors (ERs) show sex-specific differences in expression along the nephron and the expression of different ERs also changes with the estrous cycle of the female. The kidney becomes more estrogen-sensitive when estradiol levels are at their highest, just prior to ovulation. This review discusses the different mechanisms by which estradiol can modify the salt and water conservation processes of the kidney through transporter regulation to support the fluid and electrolyte homeostasis changes required in mammalian reproduction. The kidney plays a critical role in regulating blood pressure by controlling fluid homeostasis, and so protects the female cardiovascular system from dramatic changes in whole body fluid volume that occur at critical points in the human menstrual cycle and in pregnancy. This is augmented by the direct actions of estradiol on the cardiovascular system, for example through the direct stimulation of endothelial nitric oxide (NO) synthase, which releases NO to promote vasodilation. This and other mechanisms are less evident in the male and give women a degree of cardiovascular protection up until menopause, when the risks of cardiovascular disease and chronic kidney disease begin to match the risks experienced by males.
Pericyte dysfunction and impaired vasomotion are hallmarks of islets during the pathogenesis of type 1 diabetes
2023, Cell ReportsPancreatic islets are endocrine organs that depend on their microvasculature to function. Along with endothelial cells, pericytes comprise the islet microvascular network. These mural cells are crucial for microvascular stability and function, but it is not known if/how they are affected during the development of type 1 diabetes (T1D). Here, we investigate islet pericyte density, phenotype, and function using living pancreas slices from donors without diabetes, donors with a single T1D-associated autoantibody (GADA+), and recent onset T1D cases. Our data show that islet pericyte and capillary responses to vasoactive stimuli are impaired early on in T1D. Microvascular dysfunction is associated with a switch in the phenotype of islet pericytes toward myofibroblasts. Using publicly available RNA sequencing (RNA-seq) data, we further found that transcriptional alterations related to endothelin-1 signaling and vascular and extracellular matrix (ECM) remodeling are hallmarks of single autoantibody (Aab)+ donor pancreata. Our data show that microvascular dysfunction is present at early stages of islet autoimmunity.
Endothelin-1 (ET-1) contributes to the development of kidney diseases. However, the underlying molecular mechanism is largely undefined. Here we sought to investigate the potential role of ET-1 receptors, ETA and ETB in the regulation of increased glomerular permeability and underlying signaling pathways post-ET-1 infusion. Male Sprague-Dawley rats were infused with ET-1 (2 pmol/kg per minute, i.v.) for four weeks, and the effect on glomerular permeability to albumin (Palb) and albuminuria was measured. The selective ROCK-1/2 inhibitor, Y-27632, was administered to a separate group of rats to determine its effect on ET-1-induced Palb and albuminuria. The role of ETA and ETB receptors in regulating RhoA/ROCK activity was determined by incubating isolated glomeruli from normal rats with ET-1 and with selective ETA and ETB receptor antagonists. ET-1 infusion for four weeks significantly elevated Palb and albuminuria. Y-27632 significantly reduced the elevation of Palb and albuminuria. The activities of both RhoA and ROCK-1/2 were increased by ET-1 infusion. Selective ETB receptor antagonism had no effect on the elevated activity of both RhoA and ROCK-1/2 enzymes. Selective ETA receptor and combined ETA/ETB receptors blockade restored the activity of RhoA and ROCK-1/2 to normal levels. In addition, chronic ET-1 infusion increased the levels of glomerular inflammatory and fibrotic markers. These effects were all attenuated in rats following ROCK-1/2 inhibition. These observations suggest that ET-1 contributes to increased albuminuria, inflammation, and fibrosis by modulating the activity of the ETA-RhoA/ROCK-1/2 pathway. Selective ETA receptor blockade may represent a potential therapeutic strategy to limit glomerular injury and albuminuria in kidney disease.
The endothelin system as target for therapeutic interventions in cardiovascular and renal disease
2020, Clinica Chimica ActaEndothelins including its most abundant isoform, endothelin-1 (ET-1), are peptides acting as vasoconstrictors when binding to ETA and ETB receptors, and, in addition to their distinct roles in normal physiology, endothelins have a central role in the pathophysiology of many diseases including cardiovascular and renal diseases. Endothelin-1 (ET-1), the most potent vasoconstrictor in the cardiovascular system, regulates basal vascular tone and glomerular hemodynamics. ET-1 is involved also in vascular and cardiac hypertrophy, inflammation, and in the development and progression of cardiovascular diseases - e.g. essential hypertension, atherosclerosis, coronary artery disease, congestive heart failure, pulmonary arterial hypertension and cerebrovascular disease and renal diseases - e.g. acute renal failure, polycystic kidney disease and chronic kidney disease. Not surprisingly, the ET system has become a target for therapeutic interventions that now include a few already established and some new promising agents. In this narrative review, we summarize physiologic properties of the ET system, focusing especially on ET-1, and its role in the pathophysiology of ET system activated diseases, and discuss the potentials of therapeutic interventions targeting the ET system in cardiovascular and renal diseases. While ET receptor antagonists have already revolutionized the management of idiopathic pulmonary arterial hypertension, so far, this class of drugs have failed as medication for congestive heart failure. Clinical trials continue to explore new applications of endothelin receptor antagonists in treatment-resistant hypertension and chronic kidney disease and have shown some benefits in the latter group by reducing proteinuria; however, they have not been approved yet. We conclude that larger clinical trials are needed to validate the use of ET receptor antagonists in ET system activated diseases.
Endothelins (EDN1, EDN2, EDN3) and their receptors (EDNRA, EDNRB, EDNRB2) in chickens: Functional analysis and tissue distribution
2019, General and Comparative EndocrinologyCitation Excerpt :In chicken liver, both cEDNRB and cEDNRB2 are highly expressed, where EDNRB/B2 signaling may be an important regulator of sinusoid vascular resistance, as reported in mice (Ling et al., 2012). Since the three EDNs are weakly expressed in the liver, therefore, it is tempting to speculate that as in rats, liver EDNRBs may also function as clearing receptor(s) to remove circulating EDN in chickens (Fukuroda et al., 1994). Of particular interest to note is that EDN2 has the highest expression level in many parts of the GI tract, including the proventriculus, jejunum, ileum, cecum and colon (Fig. 7E).
Endothelins (EDNs) and their receptors (EDNRs) are reported to be involved in the regulation of many physiological/pathological processes, such as cardiovascular development and functions, pulmonary hypertension, neural crest cell proliferation, differentiation and migration, pigmentation, and plumage in chickens. However, the functionality, signaling, and tissue expression of avian EDN-EDNRs have not been fully characterized, thus impeding our comprehensive understanding of their roles in this model vertebrate species. Here, we reported the cDNAs of three EDN genes (EDN1, EDN2, EDN3) and examined the functionality and expression of the three EDNs and their receptors (EDNRA, EDNRB and EDNRB2) in chickens. The results showed that: 1) chicken (c-) EDN1, EDN2, and EDN3 cDNAs were predicted to encode bioactive EDN peptides of 21 amino acids, which show remarkable degree of amino acid sequence identities (91–95%) to their respective mammalian orthologs; 2) chicken (c-) EDNRA expressed in HEK293 cells could be preferentially activated by chicken EDN1 and EDN2, monitored by the three cell-based luciferase reporter assays, indicating that cEDNRA is a functional receptor common for both cEDN1 and cEDN2. In contrast, both cEDNRB and cEDNRB2 could be activated by all three EDN peptides with similar potencies, indicating that both receptors can function as common receptors for the three EDNs and share functional similarity. Moreover, activation of three EDNRs could stimulate intracellular calcium, MAPK/ERK, and cAMP/PKA signaling pathways. 3) qPCR assay revealed that cEDNs and cEDNRs are widely, but differentially, expressed in adult chicken tissues. Taken together, our data establishes a clear molecular basis to uncover the physiological/pathological roles of EDN-EDNR system in birds and helps to reveal the conserved actions of EDN-EDNR signaling across vertebrates.
Role of endothelin-1 clearance in the haemodynamic responses to endothelin-1 in the pulmonary and hindquarter vasculature of anaesthetised rats.
2019, European Journal of PharmacologyIn the pulmonary vasculature there is clearance of endothelin-1 from the circulation mediated by endothelin ETB receptors. This study explored the haemodynamic effects of endothelin-1 and its clearance in the pulmonary and hindquarter vasculature in anaesthetised rats. Carotid and pulmonary artery pressures and pulmonary and hindquarter blood flows were measured. In each rat, a single endothelin-1 or sarafotoxin S6C cumulative dose-response curve was generated with or without antagonist pretreatment (i.v.). Endothelin-1 caused an acute fall in MAP and rise in hindquarter vascular conductance (HVC) followed by a marked increase in MAP at 5 min with falls in HVC and pulmonary vascular conductance (PVC). Bosentan (10, 20 & 30 mg/kg) pretreatment caused dose-dependent inhibition of the MAP increase as well as PVC and HVC decreases to endothelin-1. Similarly, macitentan (30 mg/kg) or ambrisentan (10 mg/kg) caused significant block of responses to endothelin-1. Sarafotoxin S6C caused acute falls in MAP and increases in HVC and then small falls in PVC and HVC, all prevented by pretreatment with ETB antagonist BQ788 (1 mg/kg). Pretreatment with BQ788 enhanced endothelin-1 potency by 2.5-fold in PVC and 2.4-fold in HVC. With BQ788 and bosentan, the fall in HVC response was completely blocked, but there were residual MAP rises and PVC falls at the highest endothelin-1 dose. Our work confirms the role of ETB receptors in the pulmonary vasculature that decrease the circulating levels of endothelin-1. This has important consequences in selecting an appropriate ETA and ETB dual receptor antagonist to effectively block endothelin-1-mediated pulmonary vasoconstriction.