表观遗传机制对雌雄 Npr1 单倍型小鼠的血压和肾功能障碍具有不同的调节作用。

IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY FASEB Journal Pub Date : 2024-08-07 DOI:10.1096/fj.202400714R
Prerna Kumar, Kandasamy Neelamegam, Chandramohan Ramasamy, Ramachandran Samivel, Huijing Xia, Daniel R. Kapusta, Kailash N. Pandey
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引用次数: 0

摘要

我们确定了调节鸟苷酸环化酶/利尿肽受体-A(GC-A/NPRA)基因靶向小鼠平均动脉压(MAP)和肾功能障碍的表观遗传学机制。用1类特异性组蛋白去乙酰化酶抑制剂(HDACi)莫西司他(MGCD)处理Npr1(编码NPRA)基因靶向小鼠,以确定性别特异性的表观遗传学变化。成年雄性和雌性 Npr1 单倍型(1-拷贝;Npr1+/-)、野生型(2-拷贝;Npr1+/+)和基因重复杂合型(3-拷贝;Npr1++/+)小鼠腹腔注射 MGCD(2 mg/kg)14 天。对血压、肾功能、组织病理学和表观遗传学变化进行了测量。与双拷贝和三拷贝小鼠相比,单拷贝雄性小鼠的 MAP、肾功能障碍和纤维化明显增加。此外,与双拷贝对照组相比,单拷贝小鼠的 HDAC1/2、胶原 1α-2(Col1α-2)和α平滑肌肌动蛋白(α-SMA)明显增加。抗纤维化 microRNA-133a 的表达在 1 拷贝小鼠中减弱,但雄性小鼠的减弱程度大于雌性小鼠。在 1 拷贝小鼠中,NF-κB 在细胞质中的定位水平明显低于在细胞核中的定位水平,DNA 结合活性更强。MGCD 能明显降低血压、改善肌酐清除率并修复肾脏组织病理学。对 I 类 HDACs 的抑制导致 Npr1 1-copy 小鼠中乙酰化阳性组蛋白标记的刺激和甲基化抑制性组蛋白标记的抑制具有性别依赖性;然而,它在表观遗传学上降低了 MAP,修复了肾脏纤维化和蛋白尿,并在雄性和雌性之间不同程度地抑制了 NF-kB。我们的研究结果表明,表观遗传靶点以性别特异性的方式影响着高血压和肾功能障碍。
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Epigenetic mechanisms differentially regulate blood pressure and renal dysfunction in male and female Npr1 haplotype mice

We determined the epigenetic mechanisms regulating mean arterial pressure (MAP) and renal dysfunction in guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene-targeted mice. The Npr1 (encoding NPRA) gene-targeted mice were treated with class 1 specific histone deacetylase inhibitor (HDACi) mocetinostat (MGCD) to determine the epigenetic changes in a sex-specific manner. Adult male and female Npr1 haplotype (1-copy; Npr1+/−), wild-type (2-copy; Npr1+/+), and gene-duplicated heterozygous (3-copy; Npr1++/+) mice were intraperitoneally injected with MGCD (2 mg/kg) for 14 days. BP, renal function, histopathology, and epigenetic changes were measured. One-copy male mice showed significantly increased MAP, renal dysfunction, and fibrosis than 2-copy and 3-copy mice. Furthermore, HDAC1/2, collagen1alpha-2 (Col1α-2), and alpha smooth muscle actin (α-SMA) were significantly increased in 1-copy mice compared with 2-copy controls. The expression of antifibrotic microRNA-133a was attenuated in 1-copy mice but to a greater extent in males than females. NF-κB was localized at significantly lower levels in cytoplasm than in the nucleus with stronger DNA binding activity in 1-copy mice. MGCD significantly lowered BP, improved creatinine clearance, and repaired renal histopathology. The inhibition of class I HDACs led to a sex-dependent distinctive stimulation of acetylated positive histone marks and inhibition of methylated repressive histone marks in Npr1 1-copy mice; however, it epigenetically lowered MAP, repaired renal fibrosis, and proteinuria and suppressed NF-kB differentially in males versus females. Our results suggest a role for epigenetic targets affecting hypertension and renal dysfunction in a sex-specific manner.

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来源期刊
FASEB Journal
FASEB Journal 生物-生化与分子生物学
CiteScore
9.20
自引率
2.10%
发文量
6243
审稿时长
3 months
期刊介绍: The FASEB Journal publishes international, transdisciplinary research covering all fields of biology at every level of organization: atomic, molecular, cell, tissue, organ, organismic and population. While the journal strives to include research that cuts across the biological sciences, it also considers submissions that lie within one field, but may have implications for other fields as well. The journal seeks to publish basic and translational research, but also welcomes reports of pre-clinical and early clinical research. In addition to research, review, and hypothesis submissions, The FASEB Journal also seeks perspectives, commentaries, book reviews, and similar content related to the life sciences in its Up Front section.
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