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Biology of Sex Differences

, 8:18

First Online: 30 May 2017Received: 13 January 2017Accepted: 22 May 2017DOI: 10.1186-s13293-017-0140-z

Cite this article as: Bourgeois, C.T., Satou, R. & Prieto, M.C. Biol Sex Differ 2017 8: 18. doi:10.1186-s13293-017-0140-z

Abstract

BackgroundSexual 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.

MethodsMale 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.

ResultsPlasma 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.

ConclusionsThese 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.

KeywordsHistone deacetylase 9 Angiotensinogen Kidney Sex differences Renin-angiotensin system Epigenetics AbbreviationsAGTAngiotensinogen

Ang IIAngiotensin II

HDAC9Histone deacetylase 9

PTCProximal tubular cells

RASRenin-angiotensin system





Autor: Camille T. Bourgeois - Ryousuke Satou - Minolfa C. Prieto

Fuente: https://link.springer.com/







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