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HDAC9 is an epigenetic repressor of kidney angiotensinogen establishing a sex difference

Overview of attention for article published in Biology of Sex Differences, May 2017
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Title
HDAC9 is an epigenetic repressor of kidney angiotensinogen establishing a sex difference
Published in
Biology of Sex Differences, May 2017
DOI 10.1186/s13293-017-0140-z
Pubmed ID
Authors

Camille T. Bourgeois, Ryousuke Satou, Minolfa C. Prieto

Abstract

Sexual difference has been shown in the pathogenesis of chronic kidney disease induced by hypertension. Females are protected from hypertension and related end-organ damage. Augmentation of renal proximal tubular angiotensinogen (AGT) expression can promote intrarenal angiotensin formation and the development of associated hypertension and kidney injury. Female rodents exhibit lower intrarenal AGT levels than males under normal conditions, suggesting that the suppressed intrarenal AGT production by programmed mechanisms in females may provide protection from these diseases. This study was performed to examine whether epigenetic mechanisms serve as repressors of AGT. Male and female Sprague Dawley rats were used to investigate sex differences of systemic, hepatic, and intrarenal AGT levels. All histone deacetylase (HDAC) mRNA levels in the kidneys were determined using a PCR array. HDAC9 protein expression in the kidneys and cultured renal proximal tubular cells (PTC) was analyzed by Western blot analysis and immunohistochemistry. The effects of HDAC9 on AGT expression were evaluated by using an inhibitor and siRNA. ChIP assay was performed to investigate the interaction between the AGT promoter and HDAC9. Plasma and liver AGT levels did not show differences between male and female Sprague-Dawley rats. In contrast, females exhibited lower AGT levels than males in the renal cortex and urine. In the absence of supplemented sex hormones, primary cultured renal cortical cells isolated from female rats sustained lower AGT levels than those from males, suggesting that the kidneys have a unique mechanism of AGT regulation controlled by epigenetic factors rather than sex hormones. HDAC9 mRNA and protein levels were higher in the renal cortex of female rats versus male rats (7.09 ± 0.88, ratio to male) while other HDACs did not exhibit a sex difference. HDAC9 expression was localized in PTC which are the primary source of intrarenal AGT. Importantly, HDAC9 knockdown augmented AGT mRNA (1.92 ± 0.35-fold) and protein (2.25 ± 0.50-fold) levels, similar to an HDAC9 inhibitor. Furthermore, an interaction between HDAC9 and a distal 5' flanking region of AGT via a histone complex containing H3 and H4 was demonstrated. These results indicate that HDAC9 is a novel suppressing factor involved in AGT regulation in PTC, leading to low levels of intrarenal AGT in females. These findings will help to delineate mechanisms underlying sex differences in the development of hypertension and renin-angiotensin system (RAS) associated kidney injury.

Mendeley readers

The data shown below were compiled from readership statistics for 8 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 8 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 2 25%
Student > Master 2 25%
Student > Ph. D. Student 1 13%
Student > Bachelor 1 13%
Unspecified 1 13%
Other 1 13%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 4 50%
Medicine and Dentistry 2 25%
Agricultural and Biological Sciences 1 13%
Unspecified 1 13%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 07 June 2017.
All research outputs
#10,051,398
of 11,332,834 outputs
Outputs from Biology of Sex Differences
#161
of 176 outputs
Outputs of similar age
#222,995
of 267,454 outputs
Outputs of similar age from Biology of Sex Differences
#9
of 10 outputs
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