Department of Physiology, School of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
FASEB J. 2024 Aug 15;38(15):e23858. doi: 10.1096/fj.202400714R.
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.
我们确定了调节平均动脉压（MAP）和鸟苷酸环化酶/利钠肽受体-A（GC-A/NPRA）基因靶向小鼠肾功能障碍的表观遗传机制。通过使用 1 类特异性组蛋白去乙酰化酶抑制剂（HDACi）莫西他汀（MGCD）以性别特异性方式处理 NPR1（编码 NPRA）基因靶向小鼠，确定表观遗传变化。成年雄性和雌性 NPR1 单倍型（1 拷贝；Npr1）、野生型（2 拷贝；Npr1）和基因重复杂合子（3 拷贝；Npr1）小鼠经腹腔注射 MGCD（2mg/kg）14 天。测量血压、肾功能、组织病理学和表观遗传变化。与 2 拷贝和 3 拷贝小鼠相比，1 拷贝雄性小鼠的 MAP、肾功能障碍和纤维化显著增加。此外，与 2 拷贝对照相比，1 拷贝小鼠中的 HDAC1/2、胶原 1alpha-2（Col1α-2）和α平滑肌肌动蛋白（α-SMA）显著增加。与雌性相比，1 拷贝小鼠的抗纤维化 microRNA-133a 表达减弱。NF-κB 在细胞质中的定位明显低于细胞核，并且在 1 拷贝小鼠中的 DNA 结合活性更强。MGCD 显著降低血压，改善肌酐清除率，修复肾脏组织病理学。抑制 I 类 HDACs 导致 1 拷贝 NPR1 小鼠中乙酰化阳性组蛋白标记的性别依赖性独特刺激和甲基化抑制性组蛋白标记的抑制；然而，它在性别之间以不同的方式降低 MAP、修复肾纤维化和蛋白尿，并抑制 NF-kB。我们的研究结果表明，表观遗传靶标在性别特异性方式下影响高血压和肾功能障碍的作用。
