Angiotensin II sensitivity of afferent glomerular arterioles in endothelin-1 transgenic mice

Abstract. Transgenic mice are useful tools to investigate the mechanisms of the renal profibrotic actions of endothelin and angiotensin II. The overexpression of angiotensinogen and renin genes induces renal sclerosis independently of changes in systemic hemodynamics. The same results are observed when the endothelin-1 gene is overexpressed. Transgenic mice harboring the luciferase gene, under the control of the collagen I α2 chain promoter, and made hypertensive by induction of a nitric oxide (NO) deficiency have been studied. In this strain of mice, luciferase activity is an early index of renal and vascular fibrosis. Luciferase activity was increased in preglomerular arterioles and glomeruli when mice were treated with Nω-nitro-L-arginine methyl ester, an inhibitor of NO synthases. Bosentan (an endothelin receptor antagonist) was as efficient as losartan (an AT1 receptor antagonist) in preventing renal fibrosis, although it did not decrease BP. In short-term experiments, angiotensin II produced an increase in luciferase activity that was entirely prevented by losartan but also by bosentan. It can be concluded that, during chronic inhibition of NO, the collagen I gene is activated, which contributes to the development of nephroangiosclerosis and glomerulosclerosis. Angiotensin II plays a major role in this fibrogenic process, and its effect is at least partly independent of systemic hemodynamics and mediated by the profibrotic action of endothelin-1.

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Protein kinase C inhibitors enhance endothelin-1 and attenuate vasopressin and angiotensin II evoked [Ca2+]i elevation in the rat cardiomyocyte

British Journal of Pharmacology ◽

10.1111/j.1476-5381.1993.tb13430.x ◽

1993 ◽

Vol 108 (1) ◽

pp. 6-8 ◽

Cited By ~ 21

Author(s):

Yanjun Xu ◽

L. Sandirasegarane ◽

Venkat Gopalakrishnan

Keyword(s):

Protein Kinase C ◽

Angiotensin Ii ◽

Protein Kinase ◽

Endothelin 1 ◽

Protein Kinase C Inhibitors ◽

Kinase C

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Leptin Induces Vascular Smooth Muscle Cell Hypertrophy through Angiotensin II- and Endothelin-1-Dependent Mechanisms and Mediates Stretch-Induced Hypertrophy

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.105.091561 ◽

2005 ◽

Vol 315 (3) ◽

pp. 1075-1084 ◽

Cited By ~ 63

Author(s):

Asad Zeidan ◽

Daniel M. Purdham ◽

Venkatesh Rajapurohitam ◽

Sabzali Javadov ◽

Subrata Chakrabarti ◽

...

Keyword(s):

Smooth Muscle ◽

Angiotensin Ii ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Vascular Smooth Muscle Cell ◽

Endothelin 1 ◽

Cell Hypertrophy

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Interleukin-8 Synthesis, Regulation, and Steroidogenic Role in H295R Human Adrenocortical Cells

Endocrinology ◽

10.1210/en.2005-0951 ◽

2006 ◽

Vol 147 (2) ◽

pp. 891-898 ◽

Cited By ~ 22

Author(s):

Damian G. Romero ◽

Gaston R. Vergara ◽

Zheng Zhu ◽

Gina S. Covington ◽

Maria W. Plonczynski ◽

...

Keyword(s):

Immune System ◽

Angiotensin Ii ◽

Adrenal Gland ◽

Interferon Γ ◽

Cell Culture Supernatant ◽

Adrenocortical Cells ◽

Adrenal Cells ◽

Endothelin 1 ◽

H295r Cells ◽

First Time

The adrenal gland secretes several cytokines, and cytokines modulate steroid secretion by this gland. In this study, a survey of cytokine production by H295R human adrenocortical cells demonstrated that these cells secreted IL-2, IL-4, IL-8, IL-10, IL-13, and TNFα but not IL-5, IL-12, or interferon-γ. IL-8 was the IL secreted at higher concentration. IL-8 secretion, its regulation, and role in steroidogenesis were further studied. Secreted ILs and steroids were measured by ELISA in cell culture supernatant. IL-8 mRNA was quantified by real-time RT-PCR. H295R cells and human adrenal gland expressed IL-8 mRNA. Angiotensin II, potassium, endothelin-1, IL-1α, IL-1β, TNFα, and Escherichia coli lipopolysaccharide dose-dependently increase IL-8 secretion by H295R cells after 24 h incubation. IL-6 had no effect on IL-8 secretion. Angiotensin II time-dependently increased IL-8 secretion by H295R cells up to 48 h. Angiotensin II caused a biphasic increase in IL-8 mRNA expression with a peak 6 h after stimulation. TNFα synergized angiotensin II, potassium, and IL-1α-mediated IL-8 secretion. IL-8 did not modify aldosterone or cortisol secretion by H295R cells under basal or stimulated (angiotensin II or potassium) conditions. In conclusion, it is demonstrated for the first time that human adrenal cells expressed and secreted IL-8 under the regulation of angiotensin II, potassium, endothelin-1, and immune peptides. Adrenal-secreted IL-8 is one point of convergence between the adrenal gland and the immune system and may have relevance in physiological and pathophysiological conditions associated with increased levels of aldosterone secretagogues and the immune system.

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Angiotensin II Enhances Responses to Endothelin-1 in Bovine Bronchial Smooth Muscle

Pulmonary Pharmacology ◽

10.1006/pulp.1994.1048 ◽

1994 ◽

Vol 7 (6) ◽

pp. 409-413 ◽

Cited By ~ 22

Author(s):

J.E. Nally ◽

R.A. Clayton ◽

M.J.O. Wakelam ◽

N.C. Thomson ◽

J.C. McGrath

Keyword(s):

Smooth Muscle ◽

Angiotensin Ii ◽

Bronchial Smooth Muscle ◽

Endothelin 1

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Regulation of endothelin-1 release from human endothelial cells by sex steroids and angiotensin-II

Peptides ◽

10.1016/j.peptides.2008.02.003 ◽

2008 ◽

Vol 29 (6) ◽

pp. 1057-1061 ◽

Cited By ~ 22

Author(s):

Lachlan J. Pearson ◽

Timothy G. Yandle ◽

M. Gary Nicholls ◽

John J. Evans

Keyword(s):

Endothelial Cells ◽

Angiotensin Ii ◽

Sex Steroids ◽

Human Endothelial Cells ◽

Endothelin 1

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Embryonic lethality in Dear gene-deficient mice: new player in angiogenesis

Physiological Genomics ◽

10.1152/physiolgenomics.00144.2005 ◽

2005 ◽

Vol 23 (3) ◽

pp. 257-268 ◽

Cited By ~ 11

Author(s):

Victoria L. M. Herrera ◽

Lorenz R. B. Ponce ◽

Pia D. Bagamasbad ◽

Benjamin D. VanPelt ◽

Tamara Didishvili ◽

...

Keyword(s):

Angiotensin Ii ◽

Embryonic Lethality ◽

Female Rats ◽

Ang Ii ◽

Sprague Dawley ◽

Angiotensin Ii Receptor ◽

Endothelin 1 ◽

Receptor Isoforms ◽

Age Range ◽

Deficient Mice

The dual endothelin-1/angiotensin II receptor (Dear) binds endothelin-1 (ET-1) and angiotensin II (ANG II) with equal affinities in the Dahl S/JRHS rat strain. To elucidate its physiological significance within the context of multiple receptor isoforms and diverse ET-1 and ANG II functions spanning blood pressure regulation, tumor proliferation, and angiogenesis, we characterized mouse Dear and Dear-deficient mice. Unlike null mutant models of ET-1, ANG II, and all other ET-1 and ANG II receptors, Dear−/− deficiency results in impaired angiogenesis, dysregulated neuroepithelial development, and embryonic lethality by embryonic day 12.5. Interestingly, mouse Dear does not bind ANG II, similar to Dahl R/JRHS rat Dear, but binds ET-1 and vascular endothelial growth factor (VEGF) signal peptide (VEGFsp) with equal affinities, suggesting a putative novel multifunction for VEGFsp and a parsimonious mechanism for coordination of VEGF-induced and Dear-mediated pathways. Consistent with its developmental angiogenic role, Dear inhibition results in decreased tumor growth in B16-F10 melanoma cell-induced subcutaneous tumor in female Dear+/−/C57BL6BC10 mice, but not in males (age 3.5 mo), and in 127Cs radiation-induced orthotopic mammary tumors in Sprague-Dawley female rats (age range 3–6.5 mo). Altogether, the data identify Dear as a new player in angiogenesis during development downstream to, and nonredundant with, VEGF-mediated pathways, as well as a putative modulator of tumor angiogenesis acting within a gender-specific paradigm.

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Aortic blood flow subtraction: an alternative method for measuring total renal blood flow in conscious dogs

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00494.2001 ◽

2002 ◽

Vol 282 (5) ◽

pp. R1528-R1535 ◽

Cited By ~ 6

Author(s):

N. C. F. Sandgaard ◽

J. L. Andersen ◽

N.-H. Holstein-Rathlou ◽

P. Bie

Keyword(s):

Blood Flow ◽

Angiotensin Ii ◽

Renal Blood Flow ◽

Aortic Blood Flow ◽

Excretory Function ◽

Endothelin 1 ◽

Arterial Blood ◽

Aortic Blood ◽

Bilateral Carotid ◽

Total Renal Blood Flow

We have measured total renal blood flow (TRBF) as the difference between signals from ultrasound flow probes implanted around the aorta above and below the renal arteries. The repeatability of the method was investigated by repeated, continuous infusions of angiotensin II and endothelin-1 seven times over 8 wk in the same dog. Angiotensin II decreased TRBF (350 ± 16 to 299 ± 15 ml/min), an effect completely blocked by candesartan (TRBF 377 ± 17 ml/min). Subsequent endothelin-1 infusion reduced TRBF to 268 ± 20 ml/min. Bilateral carotid occlusion (8 sessions in 3 dogs) increased arterial blood pressure by 49% and decreased TRBF by 12%, providing an increase in renal vascular resistance of 69%. Dynamic analysis showed autoregulation of renal blood flow in the frequency range <0.06–0.07 Hz, with a peak in the transfer function at 0.03 Hz. It is concluded that continuous measurement of TRBF by aortic blood flow subtraction is a practical and reliable method that allows direct comparison of excretory function and renal blood flow from two kidneys. The method also allows direct comparison between TRBF and flow in the caudal aorta.

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