Chemotherapy and radiation regimens to breast cancer treatment induce changes in mRNA levels of renin–angiotensin system related genes in cardiac tissue

An activated renin-angiotensin system (RAS) within the central nervous system has been implicated in sympathoexcitation during various disease conditions including congestive heart failure (CHF). In particular, activation of the RAS in the paraventricular nucleus (PVN) of the hypothalamus has been recognized to augment sympathoexcitation in CHF. We observed a 2.6-fold increase in angiotensinogen (AGT) in the PVN of CHF. To elucidate the molecular mechanism for increased expression of AGT, we performed in silico analysis of the 3′-untranslated region (3′-UTR) of AGT and found a potential binding site for microRNA (miR)-133a. We hypothesized that decreased miR-133a might contribute to increased AGT in the PVN of CHF rats. Overexpression of miR-133a in NG108 cells resulted in 1.4- and 1.5-fold decreases in AGT and angiotensin type II (ANG II) type 1 receptor (AT1R) mRNA levels, respectively. A luciferase reporter assay performed on NG108 cells confirmed miR-133a binding to the 3′-UTR of AGT. Consistent with these in vitro data, we observed a 1.9-fold decrease in miR-133a expression with a concomitant increase in AGT and AT1R expression within the PVN of CHF rats. Furthermore, restoring the levels of miR-133a within the PVN of CHF rats with viral transduction resulted in a significant reduction of AGT (1.4-fold) and AT1R (1.5-fold) levels with a concomitant decrease in basal renal sympathetic nerve activity (RSNA). Restoration of miR-133a also abrogated the enhanced RSNA responses to microinjected ANG II within the PVN of CHF rats. These results reveal a novel and potentially unique role for miR-133a in the regulation of ANG II within the PVN of CHF rats, which may potentially contribute to the commonly observed sympathoexcitation in CHF. NEW & NOTEWORTHY Angiotensinogen (AGT) expression is upregulated in the paraventricular nucleus of the hypothalamus through posttranscriptional mechanism interceded by microRNA-133a in heart failure. Understanding the mechanism of increased expression of AGT in pathological conditions leading to increased sympathoexcitation may provide the basis for the possible development of new therapeutic agents with enhanced specificity.

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Synergistic Expression of Angiotensin-Converting Enzyme (ACE) and ACE2 in Human Renal Tissue and Confounding Effects of Hypertension on the ACE to ACE2 Ratio

Endocrinology ◽

10.1210/en.2006-1287 ◽

2007 ◽

Vol 148 (5) ◽

pp. 2453-2457 ◽

Cited By ~ 68

Author(s):

Shigeyuki Wakahara ◽

Tadashi Konoshita ◽

Shinichi Mizuno ◽

Makoto Motomura ◽

Chikako Aoyama ◽

...

Keyword(s):

Renal Function ◽

Angiotensin Converting Enzyme ◽

Pairwise Comparison ◽

Renin Angiotensin System ◽

Mrna Levels ◽

Converting Enzyme ◽

Gene Expressions ◽

Angiotensin System ◽

Renin Angiotensin ◽

Clinicopathological Variables

Angiotensin-converting enzyme (ACE) 2, a newly emerging component of the renin-angiotensin system, is presumed to be a counterregulator against ACE in generating and degrading angiotensin II. It remains to be elucidated how mRNA levels of these two genes are quantitatively regulated in the kidney and also what kind of clinicopathological characteristics could influence the gene expressions in humans. Seventy-eight cases of biopsy-proven renal conditions were examined in detail. Total RNA from a small part of each renal cortical biopsy specimen was reverse transcribed, and the resultant cDNA was amplified for ACE, ACE2, and glyceraldehyde-3-phosphate dehydrogenase with a real-time PCR system. Then we investigated the relationship between clinicopathological variables and mRNA levels adjusted for glyceraldehyde-3-phosphate dehydrogenase. Statistically significant correlation was not observed between any clinicopathological variables and either of the gene expressions by pairwise comparison. However, a strong correlation was observed between the gene expressions of ACE and those of ACE2. Moreover, the ACE to ACE2 ratio was significantly higher in subjects with hypertension (HT) than that in subjects without HT. Whereas parameters of renal function, e.g. urinary protein excretion (UPE) and creatinine clearance (Ccr), are not significantly related to the ACE to ACE2 ratio as a whole, the HT status may reflect disease-induced deterioration of renal function. That is, UPE and Ccr of subjects with HT are significantly different from those without HT, in which a significant correlation is also observed between UPE and Ccr. Finally, stepwise regression analysis further revealed that only the HT status is an independent confounding determinant of the ACE to ACE2 ratio among the variables tested. Our data suggest that ACE2 might play an important role in maintaining a balanced status of local renin-angiotensin system synergistically with ACE by counterregulatory effects confounded by the presence of hypertension. Thus, ACE2 may exert pivotal effects on cardiovascular and renal conditions.

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Renin–Angiotensin System Inhibitors to Mitigate Cancer Treatment–Related Adverse Events

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-18-0236 ◽

2018 ◽

Vol 24 (16) ◽

pp. 3803-3812 ◽

Cited By ~ 14

Author(s):

Matthias Pinter ◽

Wilhelmus J. Kwanten ◽

Rakesh K. Jain

Keyword(s):

Adverse Events ◽

Cancer Treatment ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin

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Synergistic association of six well-characterized polymorphisms in three genes of the renin-angiotensin system with breast cancer among Han Chinese women

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/1470320314542828 ◽

2014 ◽

Vol 16 (4) ◽

pp. 1232-1239 ◽

Cited By ~ 5

Author(s):

Peijian Ding ◽

Yang Yang ◽

Shuangjian Ding ◽

Baoxin Sun

Keyword(s):

Breast Cancer ◽

Chinese Women ◽

Renin Angiotensin System ◽

Han Chinese ◽

Angiotensin System ◽

Renin Angiotensin

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Comparative expression analysis of the renin–angiotensin system components between white and brown perivascular adipose tissue

Journal of Endocrinology ◽

10.1677/joe-07-0284 ◽

2008 ◽

Vol 197 (1) ◽

pp. 55-64 ◽

Cited By ~ 90

Author(s):

B Gálvez-Prieto ◽

J Bolbrinker ◽

P Stucchi ◽

A I de las Heras ◽

B Merino ◽

...

Keyword(s):

Adipose Tissue ◽

Renin Angiotensin System ◽

Receptor Expression ◽

Mrna Levels ◽

Ang Ii ◽

Perivascular Adipose Tissue ◽

Angiotensin System ◽

Renin Angiotensin ◽

Vascular Bed ◽

Brown Adipose

Recent studies have demonstrated that the rat adipose tissue expresses some of the components necessary for the production of angiotensin II (Ang II) and the receptors mediating its actions. The aim of this work is to characterize the expression of the renin–angiotensin system (RAS) components in perivascular adipose tissue and to assess differences in the expression pattern depending on the vascular bed and type of adipose tissue. We analyzed Ang I and Ang II levels as well as mRNA levels of RAS components by a quantitative RT-PCR method in periaortic (PAT) and mesenteric adipose tissue (MAT) of 3-month-old male Wistar–Kyoto rats. PAT was identified as brown adipose tissue expressing uncoupling protein-1 (UCP-1). It had smaller adipocytes than those from MAT, which was identified as white adipose tissue. All RAS components, except renin, were detected in both PAT and MAT. Levels of expression of angiotensinogen, Ang-converting enzyme (ACE), and ACE2 were similar between PAT and MAT. Renin receptor expression was five times higher, whereas expression of chymase, AT1a, and AT2 receptors were significantly lower in PAT compared with MAT respectively. In addition, three isoforms of the AT1a receptor were found in perivascular adipose tissue. The AT1b receptor was found at very a low expression level. Ang II levels were higher in MAT with no differences between tissues in Ang I. The results show that the RAS is differentially expressed in white and brown perivascular adipose tissues implicating a different role for the system depending on the vascular bed and the type of adipose tissue.

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Regulation of nonclassical renin-angiotensin system receptor gene expression in the adrenal medulla by acute and repeated immobilization stress

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00130.2014 ◽

2015 ◽

Vol 308 (6) ◽

pp. R517-R529 ◽

Cited By ~ 5

Author(s):

Regina Nostramo ◽

Lidia Serova ◽

Marcela Laukova ◽

Andrej Tillinger ◽

Chandana Peddu ◽

...

Keyword(s):

Gene Expression ◽

Adrenal Medulla ◽

Immobilization Stress ◽

Receptor Gene ◽

Renin Angiotensin System ◽

Mrna Levels ◽

Angiotensin System ◽

Renin Angiotensin ◽

Catecholamine Biosynthesis ◽

Receptor Mrna

The involvement of the nonclassical renin-angiotensin system (RAS) in the adrenomedullary response to stress is unclear. Therefore, we examined basal and immobilization stress (IMO)-triggered changes in gene expression of the classical and nonclassical RAS receptors in the rat adrenal medulla, specifically the angiotensin II type 2 (AT2) and type 4 (AT4) receptors, (pro)renin receptor [(P)RR], and Mas receptor (MasR). All RAS receptors were identified, with AT2 receptor mRNA levels being the most abundant, followed by the (P)RR, AT1A receptor, AT4 receptor, and MasR. Following a single IMO, AT2 and AT4 receptor mRNA levels decreased by 90 and 50%, respectively. Their mRNA levels were also transiently decreased by repeated IMO. MasR mRNA levels displayed a 75% transient decrease as well. Conversely, (P)RR mRNA levels were increased by 50% following single or repeated IMO. Because of its abundance, the function of the (P)RR was explored in PC-12 cells. Prorenin activation of the (P)RR increased phosphorylation of extracellular signal-regulated kinase 1/2 and tyrosine hydroxylase at Ser31, likely increasing its enzymatic activity and catecholamine biosynthesis. Together, the broad and dynamic changes in gene expression of the nonclassical RAS receptors implicate their role in the intricate response of the adrenomedullary catecholaminergic system to stress.

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Mammary renin–angiotensin system-regulating aminopeptidase activities are modified in rats with breast cancer

Tumor Biology ◽

10.1007/s13277-010-0072-2 ◽

2010 ◽

Vol 31 (6) ◽

pp. 583-588 ◽

Cited By ~ 7

Author(s):

Maria del Pilar Carrera ◽

Maria Jesus Ramírez-Expósito ◽

Maria Dolores Mayas ◽

Maria Jesus García ◽

Jose Manuel Martínez-Martos

Keyword(s):

Breast Cancer ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin

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G-protein coupled receptors of the renin-angiotensin system: new targets against breast cancer?

Frontiers in Pharmacology ◽

10.3389/fphar.2015.00024 ◽

2015 ◽

Vol 6 ◽

Cited By ~ 17

Author(s):

Sylvie Rodrigues-Ferreira ◽

Clara Nahmias

Keyword(s):

Breast Cancer ◽

G Protein ◽

Renin Angiotensin System ◽

G Protein Coupled Receptors ◽

Angiotensin System ◽

Renin Angiotensin ◽

New Targets ◽

G Protein Coupled

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Fetal Sex Affects Expression of Renin-Angiotensin System Components in Term Human Decidua

Endocrinology ◽

10.1210/en.2011-1316 ◽

2012 ◽

Vol 153 (1) ◽

pp. 462-468 ◽

Cited By ~ 31

Author(s):

Yu Wang ◽

Kirsty G. Pringle ◽

Shane D. Sykes ◽

Francine Z. Marques ◽

Brian J. Morris ◽

...

Keyword(s):

Angiotensin Ii ◽

Real Time ◽

Renin Angiotensin System ◽

Mrna Levels ◽

Rt Pcr ◽

Female Fetus ◽

Angiotensin System ◽

Renin Angiotensin ◽

Prorenin Receptor ◽

Human Decidua

The maternal decidua expresses the genes of the renin-angiotensin system (RAS). Human decidua was collected at term either before labor (i.e. cesarean delivery) or after spontaneous labor. The mRNA for prorenin (REN), prorenin receptor (ATP6AP2), angiotensinogen (AGT), angiotensin-converting enzymes 1 and 2 (ACE1 and ACE2), angiotensin II type 1 receptor (AGTR1), and angiotensin 1–7 receptor (MAS1) were measured by quantitative real-time RT-PCR. Decidual explants were cultured in duplicate for 24 and 48 h, and all RAS mRNA, and the secretion of prorenin, angiotensin II, and angiotensin 1–7 was measured using quantitative real-time RT-PCR, ELISA, and radioimmunoassay, respectively. In the decidua collected before labor, REN mRNA levels were higher if the fetus was female. In addition, REN, ATP6AP2, AGT, and MAS1 mRNA abundance was greater in decidual explants collected from women carrying a female fetus, as was prorenin protein. After 24 h, ACE1 mRNA was higher in the decidual explants from women with a male fetus, whereas after 48 h, both ACE1 and ACE2 mRNA was higher in decidual explants from women with a female fetus. Angiotensin II was present in all explants, but angiotensin 1–7 levels often registered below the lower limits of sensitivity for the assay. After labor, decidua, when compared with nonlaboring decidua, demonstrated lower REN expression when the fetus was female. Therefore, the maternal decidual RAS is regulated in a sex-specific manner, suggesting that it may function differently when the fetus is male than when it is female.

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