Angiotensin II stimulates endothelin-1 secretion in cultured rat mesangial cells

The prorenin receptor [(P)RR] is upregulated in the diabetic kidney and has been implicated in the high glucose (HG)-induced overproduction of profibrotic molecules by mesangial cells (MCs), which is mediated by ERK1/2 phosphorylation. The regulation of (P)RR gene transcription and the mechanisms by which HG increases (P)RR gene expression are not fully understood. Because intracellular levels of angiotensin II (AngII) are increased in MCs stimulated with HG, we used this in vitro system to evaluate the possible role of AngII in (P)RR gene expression and function by comparing the effects of AT1 receptor blockers (losartan or candesartan) and (P)RR mRNA silencing (siRNA) in human MCs (HMCs) stimulated with HG. HG induced an increase in (P)RR and fibronectin expression and in ERK1/2 phosphorylation. These effects were completely reversed by (P)RR siRNA and losartan but not by candesartan (an angiotensin receptor blocker that, in contrast to losartan, blocks AT1 receptor internalization). These results suggest that (P)RR gene activity may be controlled by intracellular AngII and that HG-induced ERK1/2 phosphorylation and fibronectin overproduction are primarily induced by (P)RR activation. This relationship between AngII and (P)RR may constitute an additional pathway of MC dysfunction in response to HG stimulation.

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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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P-450 Metabolites of Arachidonic Acid in the Control of Cardiovascular Function

Physiological Reviews ◽

10.1152/physrev.00021.2001 ◽

2002 ◽

Vol 82 (1) ◽

pp. 131-185 ◽

Cited By ~ 967

Author(s):

Richard J. Roman

Keyword(s):

Arachidonic Acid ◽

Angiotensin Ii ◽

Vascular Tone ◽

Mesangial Cells ◽

Cardiovascular Function ◽

Tubuloglomerular Feedback ◽

Peripheral Vasculature ◽

Therapeutic Benefits

Recent studies have indicated that arachidonic acid is primarily metabolized by cytochrome P-450 (CYP) enzymes in the brain, lung, kidney, and peripheral vasculature to 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) and that these compounds play critical roles in the regulation of renal, pulmonary, and cardiac function and vascular tone. EETs are endothelium-derived vasodilators that hyperpolarize vascular smooth muscle (VSM) cells by activating K+channels. 20-HETE is a vasoconstrictor produced in VSM cells that reduces the open-state probability of Ca2+-activated K+channels. Inhibitors of the formation of 20-HETE block the myogenic response of renal, cerebral, and skeletal muscle arterioles in vitro and autoregulation of renal and cerebral blood flow in vivo. They also block tubuloglomerular feedback responses in vivo and the vasoconstrictor response to elevations in tissue Po2both in vivo and in vitro. The formation of 20-HETE in VSM is stimulated by angiotensin II and endothelin and is inhibited by nitric oxide (NO) and carbon monoxide (CO). Blockade of the formation of 20-HETE attenuates the vascular responses to angiotensin II, endothelin, norepinephrine, NO, and CO. In the kidney, EETs and 20-HETE are produced in the proximal tubule and the thick ascending loop of Henle. They regulate Na+transport in these nephron segments. 20-HETE also contributes to the mitogenic effects of a variety of growth factors in VSM, renal epithelial, and mesangial cells. The production of EETs and 20-HETE is altered in experimental and genetic models of hypertension, diabetes, uremia, toxemia of pregnancy, and hepatorenal syndrome. Given the importance of this pathway in the control of cardiovascular function, it is likely that CYP metabolites of arachidonic acid contribute to the changes in renal function and vascular tone associated with some of these conditions and that drugs that modify the formation and/or actions of EETs and 20-HETE may have therapeutic benefits.

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