Endothelin Converting Enzyme-1 Gene Expression in the Kidney of Spontaneously Hypertensive Rats

Disashi, Tumba G.; Nonoguchi, Hiroshi; Iwaoka, Taisuke; Naomi, Shojiro; Nakayama, Yushi; Shimada, Kohei; Tanzawa, Kazuhiko; Tomita, Kimio

doi:10.1161/01.hyp.30.6.1591

Cited by 30 publications

(37 citation statements)

References 33 publications

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“…Recently, the ECE-1 gene in the kidney has been reported to be involved in the pathogenesis of hypertension in spontaneously hypertensive rats. 35 The present findings that FK 506 increased the expression of ET-1 mRNA but not ECE-1 mRNA in the vasculature indicates that the production of ET by FK 506 is regulated at the transcription level of ET-1 mRNA rather than ECE-1. Abassi et al 36 also reported that the production of ET by CysA is regulated through the modulation of mRNA levels and not by regulation of ECE levels.…”

Section: Discussionmentioning

confidence: 57%

Mechanisms of FK 506–Induced Hypertension in the Rat

et al. 1999

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Abstract-Tacrolimus (FK 506) is a powerful, widely used immunosuppressant. The clinical utility of FK 506 is complicated by substantial hypertension and nephrotoxicity. To clarify the mechanisms of FK 506 -induced hypertension, we studied the chronic effects of FK 506 on the synthesis of endothelin-1 (ET-1), the expression of mRNA of ET-1 and endothelin-converting enzyme-1 (ECE-1), the endothelial nitric oxide synthase (eNOS) activity, and the expression of mRNA of eNOS and C-type natriuretic peptide (CNP) in rat blood vessels. In addition, the effect of the specific endothelin type A receptor antagonist FR 139317 on FK 506 -induced hypertension in rats was studied. FK 506, 5 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 given for 4 weeks, elevated blood pressure from 102Ϯ13 to 152Ϯ15 mm Hg and increased the synthesis of ET-1 and the levels of ET-1 mRNA in the mesenteric artery (240% and 230%, respectively). Little change was observed in the expression of ECE-1 mRNA and CNP mRNA. FK 506 decreased eNOS activity and the levels of eNOS mRNA in the aorta (48% and 55%, respectively). The administration of FR 139317 (10 mg ⅐ kg Ϫ1 ⅐ d Ϫ1) prevented FK 506 -induced hypertension in rats. These results indicate that FK 506 may increase blood pressure not only by increasing ET-1 production but also by decreasing NO synthesis in the vasculature. 1,2 FK 506 is 10 to 100 times more potent than cyclosporin (CysA). 3 The nephrotoxic side effects of CysA and the development of hypertension observed during CysA treatment also seem to be characteristic side effects of FK 506. 4 The incidence of hypertension in previously normotensive liver or heart transplant recipients treated with CysA has been reported to be 80% to 90%.5 A lower incidence (50% to 70%) of hypertension in FK 506 -treated recipients has been reported. 6 Although renal dysfunction is usually also present in transplant recipients treated with CysA or FK 506, blood pressure elevations have been observed in the absence of detectable renal dysfunction. 7,8 The exact mechanism of FK 506 -induced hypertension is unclear, but several researchers have suggested that the primary pathogenic mechanism may be vascular. 9 We have reported that CysA and FK 506 both increased the synthesis of endothelin-1 (ET-1) in cultured vascular endothelial cells. 10The natriuretic peptides organize a family of 3 distinct peptides (atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], and C-type natriuretic peptide [CNP]) and are involved in body fluid homeostasis and blood pressure control. CNP is reported to be synthesized in the vascular endothelial cells and to possess local effects of vascular tone and remodeling.11 Nitric oxide (NO) is synthesized from L-arginine by 2 enzymes. The generation of NO by constitutive, Ca 2ϩ -dependent NO synthase (NOS) from the vascular endothelium plays an important role in the homeostasis of the vascular system. Three isoforms of NOS have been cloned from rat brain (nNOS), vascular endothelium (eNOS), and inducible Ca 2ϩ -independent enzyme (iNOS). Vascular eNOS mainta...

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Section: Discussionmentioning

confidence: 57%

Mechanisms of FK 506–Induced Hypertension in the Rat

et al. 1999

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“…Elevated ECE-1 mRNA levels have been found in the kidneys of spontaneously hypertensive rats, and it has been proposed that ECE-1 could contribute to the development and maintenance of the elevated blood pressure through an increase in ET-1 production. 37 In our model, FR901533, an ECE inhibitor at least 3 times more potent than phosphoramidon, 38 decreased AP only in the telomerase-deficient group, stressing the importance of this mechanism in the hypertension of these animals.…”

Section: Discussionmentioning

confidence: 64%

Mice Deficient in Telomerase Activity Develop Hypertension Because of an Excess of Endothelin Production

et al. 2006

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Background-Telomere shortening has been related to vascular dysfunction and hypertension. In the present study, we analyzed the influence of telomerase deficiency and telomere shortening on arterial pressure (AP). Methods and Results-AP was evaluated in 6-month-old mice lacking the RNA component of the telomerase (terc Ϫ/Ϫ ) at the first generation and third generation (G3). First generation and G3 mice showed higher AP than wild-type (WT) mice. To analyze the mechanisms involved, mean AP and vascular resistance in response to vasoactive substances were measured in G3 and WT mice. These mice showed similar responses to acetylcholine, N G -nitro-L-arginine methyl ester, angiotensin II, and losartan administration. Mean AP did not increase after endothelin-1 (ET-1) administration in G3 mice, but it did in WT animals. Bosentan treatment decreased mean AP only in G3 mice. Serum and urine concentrations of ET-1 were higher in terc Ϫ/Ϫ than in WT mice. Endothelin-converting enzyme (ECE-1) mRNA expression was higher in terc Ϫ/Ϫ animals than in the WT group. FR901533, an ECE antagonist, decreased blood pressure in conscious G3 mice. Studies in mouse embryonic fibroblasts from G3 mice suggest that ECE-1 overexpression could be mediated by reactive oxygen species in an AP-1-dependent mechanism, in which some kinases such as PI3-kinase, Akt, erk1/2, and Jun Kinase could be involved. An increased activity of nicotinamide adenine dinucleotide phosphate oxidase seems to be the main source of reactive oxygen species. Conclusions-Mice lacking telomerase activity show hypertension as a result of an increase in plasma ET-1 levels, which is a consequence of ECE-1 overexpression. A direct link between telomerase activity and hypertension is reported.

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“…ET-1 also mediates, at least in part, the chronic effects of Ang II on blood pressure [9,10]. Conversely, ACE-inhibitors (ACE-i) and Ang II receptor type 1 blockers (AT1) diminish ET-1 expression [11,12,13]. In theory these findings would provide a strong rationale for the combination of endothelin receptor blockers (ET A -RB) with ACE-i or AT1 receptor blockers.…”

Section: Immunohistologymentioning

confidence: 99%

ACE-inhibition is superior to endothelin A receptor blockade in preventing abnormal capillary supply and fibrosis of the heart in experimental diabetes

et al. 2004

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Aims/hypothesis. There is little information whether cardiac capillary supply is deranged in diabetes. Hyperglycaemia is a potent stimulus for endothelin-1 (ET-1) production. We therefore hypothesised that increased ET-1 production in Streptozotocin-induced Type 1 diabetes causes abnormalities of cardiac capillaries and the aorta. To this end we compared the effects of an ET receptor A blocker (ET A -RB) with that of an ACE-inhibitor (ACE-i) or their combination in rats with Streptozotocin (STZ) diabetes. Methods. Sprague Dawley rats were injected with 65 mg STZ i.v. and subsequently developed diabetes. Rats were left untreated or received daily either the ACE-i Trandolapril, the ET A -RB Darusentan or a combination of both. After 6 months the experiment was terminated and the heart and the aorta were investigated using quantitative morphological techniques. Results. ACE-i but not ET A -RB lowered blood pressure in STZ Type 1 diabetic rats. Capillary length density was lower in untreated STZ diabetic rats (2932±128 mm/mm 3 ) compared to non-diabetic control rats (3410±252 mm/mm 3 ). Treatment with ACE-i (3568±431 mm/mm 3 ), but not with ET A -RB (2893±192 mm/mm 3 ), prevented the decrease in capillary supply. Volume density of the myocardial interstitium was higher in untreated STZ diabetic rats (0.86±0.04%) compared to non-diabetic control rats (0.36±0.06%). In all three intervention groups the values were lower (ACE-i: 0.53±0.05%, ET A -RB: 0.7±0.08% and combination: 0.69±0.1). Conclusion/interpretation. Our study identifies a capillary defect of the heart in STZ diabetes, i.e. decreased capillary supply. This abnormality was reversed by ACE-i, but not by ET A -R blockade. A similar trend, although not complete normalisation, was seen in cardiac fibrosis. [Diabetologia (2004) 47:316-324]

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Endothelin Converting Enzyme-1 Gene Expression in the Kidney of Spontaneously Hypertensive Rats

Cited by 30 publications

References 33 publications

Mechanisms of FK 506–Induced Hypertension in the Rat

Mechanisms of FK 506–Induced Hypertension in the Rat

Mice Deficient in Telomerase Activity Develop Hypertension Because of an Excess of Endothelin Production

ACE-inhibition is superior to endothelin A receptor blockade in preventing abnormal capillary supply and fibrosis of the heart in experimental diabetes

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