Evaluation of urinary and plasma endothelin-like domain peptide (ELDP) in chronic kidney disease
Jale YüzügülenPajaree LilitkarntakulElizabeth G. WoodRobert KimmittNeeraj DhaunJane GoddardDavid J. WebbRoger Corder
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The aim of the study was to evaluate the influence of endothelin-1 (ET-1) and endothelin receptor (ETA) blocker (BQ 123) on the content of white blood cells in the peripheral blood of rat.Experiments were performed on Wistar rats divided into following groups: group I (control) received saline; group II (ET-1) received endothelin-1 (3 microg/kg b.w.); group III (BQ 123) received ETA receptor blocker (1 mg/kg b.w.); group IV (BQ 123+ET-1) received BQ 123 (1 mg/kg b.w) and 30 minutes later ET-1 (3 microg/kg b.w.). Peripheral blood was collected from animals at three time intervals to determine the content of white blood cells using a hematology analyzer MICROS OT 45.Administration of ET-1 resulted in a statistically significant increase in the concentration of white blood cells after 1 hour after administration, compared with the control group. Contrast, administration of a specific blocker of ETA (BQ 123) reduced the leukocyte content after 1 and 5 hours after administration of ET-1.Intravenous administration of ET-1 significantly increased the content of white blood cells in peripheral blood of rat via the ETA receptor since reversed its blockage caused the change.
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To study the effect of endothelin-1 (ET-1) and its antagonists on the expression of endothelin and its receptors mRNA in HSC-T6 cells.Cultured HSC-T6 cells were randomly divided into 7 groups: Sham control group, ET-1 group (10 nmol/L ET-1), BQ-123 group [1 micromol/L BQ-123, a selective endothelin receptor A (ETRA) antagonist], BQ-788 group [1 micromol/L BQ-788, a selective endothelin receptor B (ETRB) antagonist], ET-1 + BQ123 group (10 nmol/L ET-1 + 1 micromol/L BQ-123), ET-1 + BQ-788 group (10 nmol/L ET-1 + 1 micromol/L BQ-788) and ET-1 + BQ-788 group (10 nmol/L ET-1 + 1 micromol/L BQ-123 + 1 micromol/L BQ-788). The expression of endothelin receptor mRNA of HSC-T6 cells was determined by reverse-transcription polymerase chain reaction (RT-PCR).The expression of ETRA mRNA in ET-1 + BQ123 + BQ788 and ET-1 + BQ788 group was significantly lower than ET-1 group (0.329 +/- 0.044 and 0.292 +/- 0.023 vs. 0.440 +/- 0.030 P < 0.05). Compared with ET-1 group, the expression of ETRB mRNA in ET-1 + BQ788 group was down regulated obviously (0.499 +/- 0.136 vs. 0.153 +/- 0.071, P < 0.05). There was no significant difference in ET-1 + BQ123 group and ET-1 + BQ123 + BQ788 group when compared with ET-1 group (0.499 +/- 0.136 vs. 0.496 +/- 0.103 and 0.299 +/- 0.129, P > 0.05).ET-1 has no obvious effect on the expression of ETRA mRNA in HSC-T6. ET-1 may up-regulate the expression of ETRB mRNA. Act on ETRA receptor, ET-1 can inhibit the expression of ETRB mRNA.
Endothelin receptor antagonist
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Objective:To investigate the levels of plasma endothelin and the expression of endothelin receptors gene in patients with congestive heart failure.Methods:The radio immunologic method was used to measure the plasma concentration of ET in 36 CHF pationts and 12 healthy (control). RT PCR was used to check the expression of CT recoptor gene in peripheral blood mononuclear cell. Results:Plasma endothelin of patients ( 4.90 ± 1.96 ) pmol/L was higher than that in healthy control ( 1.76 ± 0.82 ) pmol/L (P 0.01 ). There was no significant difference in the positive rate expression of endothelin receptor gene between patients and health control (P 0.05 ). There was no significant difference for ET receptor gene expression beween 2 groups ( 0.59 ± 0.17 ) (P 0.01 ).Conclusion:Plasma endothelin levels was elevated and endothelin A receptors were upregulated in patients with congestive heart failure. The ET system plays a key role in the pathogenesis of congestive heart failure.
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Endothelin-1 (ET-1) is considered to be involved in the development and progression of heart failure. Therefore, we analysed the expression of endothelin-converting enzyme-1 (ECE-1), endothelin receptors A (ETA) and B (ETB) mRNAs by standard-calibrated, competitive reverse transcriptase-PCR using an internal-deleted in vitro-transcribed cRNA standard. ET-1 peptide levels were measured using isoform-specific rabbit antibodies against synthetic ET-1. mRNA and protein expression was determined in the right atrial myocardium of New York Heart Association class I patients and class IV patients undergoing aorto-coronary bypass surgery. ECE-1 mRNA was upregulated in failing atrial myocardium. Furthermore, ET-1 peptide levels were increased in failing atrial myocardium. Atrial ETA mRNA expression was not changed, while ETB mRNA was downregulated in the failing atrial myocardium. Our results support an upregulation of ET-1 synthesis by induction of ECE-1 in failing atrial myocardium. Pharmacological inhibition of augmented ECE-1 expression might provide a new therapeutic perspective in the treatment of heart failure.
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The mechanisms of blood pressure regulation by endothelin-1 produced by endothelial cells are complex and still unclear. Transgenic mice with endothelium-restricted human endothelin-1 ( EDN1 ) overexpression presented vascular damage but no significant change in blood pressure, which could be because of adaptation to life-long exposure to elevated endothelin-1 levels. We now generated a tamoxifen-inducible endothelium-restricted EDN1 overexpressing transgenic mouse (ieET-1) using Cre/loxP technology. Sixteen days after tamoxifen treatment, ieET-1 mice presented ≥10-fold increase in plasma endothelin-1 ( P <0.01) and ≥20 mm Hg elevation in systolic blood pressure ( P <0.01), which could be reversed by atrasentan ( P <0.05). Endothelin-1 overexpression did not cause vascular or kidney injury or changes in kidney perfusion or function. However, endothelin type A and B receptor expression was differentially regulated in the mesenteric arteries and the kidney. Our results demonstrate using this ieET-1 mouse model that 21 days of induction of endothelin-1 overexpression caused endothelin-1–dependent elevated blood pressure mediated by endothelin type A receptors.
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Spontaneously hypertensive stroke-prone rats (SHR-SP) suffer spontaneous stroke in part as a result of abnormal cerebrovascular development. Reduction of regional cerebral blood flow in this model has already been demonstrated. This model has three distinct stages of hypertension: pre-hypertensive, typical hypertensive and malignant hypertensive. We investigated the level of endothelin-1 and its receptor expression in the frontal cortex of SHR-SP at the malignant hypertensive stage (35-40 weeks of age), during which time the rats suffer strokes. The cerebral endothelin-1 level, as determined by enzyme-linked immunosorbent assay, was highly increased at this severely hypertensive stage compared to their genetic control, normotensive Wistar-Kyoto rats. This upregulation was associated with an increased expression of endothelin-A receptor, however, another endothelin-1 receptor, endothelin-B, was downregulated. The regional cerebral blood flow in the frontal cortex was reduced by 60% in 40-week-old malignantly SHR-SP as compared to age-matched Wistar-Kyoto rats. Thus, cerebral endothelin-1 expression increased in malignant hypertension in SHR-SP. The enhanced endothelin-1 may activate the endothelin-A receptor, which would, in turn, result in reduced cerebral blood flow. Downregulation of the endothelin-B receptor may cause suppression of endothelium-derived relaxing factors in the brain of SHR-SP and be an underlying factor in their stroke susceptibility.
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