Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, India.
Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, India.
Toxicol Appl Pharmacol. 2019 Jan 1;362:95-104. doi: 10.1016/j.taap.2018.10.004. Epub 2018 Oct 2.
Hypertension is associated with major cardiovascular (CV) and renal complications. The molecular intricacy by which hypertension leads to end organ damage is not known. To address this, we aimed to determine the effect of deoxycorticosterone acetate (DOCA) -salt (sodium chloride)-induced hypertension on the alterations in renin-angiotensin system, leading to CV and renal dysfunction in uninephrectomized male Sprague Dawley rats. MicroRNAs involved in this were also not yet explored. Metformin was used to delineate the role of AMPK in mitigating the hypertension-induced CV and renal dysfunction. Administering DOCA and offering saline to uninephrectomized rats, induced hypertension and associated abnormalities of diastolic dysfunction, CV and renal hypertrophy and fibrosis via activating local renin angiotensin system. Western blotting and RT-qPCR analysis of diseased heart revealed decreased SERCA2, p-AMPK, miR-146a, miR-99b and increased miR-155 and metformin administered, at dose of 300 mg/kg/day, for a period of 8 weeks prevented CV and renal damage. To our knowledge, we are the first to show that involvement of epigenetic alterations at microRNA level might be responsible for hypertension-induced cardiac dysfunction and metformin reverses these alterations.
高血压与主要心血管（CV）和肾脏并发症有关。目前尚不清楚高血压导致终末器官损伤的分子复杂性。为了解决这个问题，我们旨在确定醛固酮（DOCA）-盐（氯化钠）诱导的高血压对肾素-血管紧张素系统改变的影响，导致单侧肾切除雄性 Sprague Dawley 大鼠的 CV 和肾功能障碍。涉及的 microRNA 也尚未探索。二甲双胍用于描绘 AMPK 在减轻高血压引起的 CV 和肾功能障碍中的作用。给单侧肾切除大鼠施用 DOCA 和生理盐水，通过激活局部肾素血管紧张素系统，诱导高血压和相关的舒张功能障碍、CV 和肾脏肥大和纤维化异常。对患病心脏进行的 Western 印迹和 RT-qPCR 分析显示，SERCA2、p-AMPK、miR-146a、miR-99b 减少，miR-155 增加，给予剂量为 300mg/kg/天的二甲双胍 8 周可预防 CV 和肾脏损伤。据我们所知，我们是第一个表明，在 microRNA 水平的表观遗传改变可能是导致高血压引起的心脏功能障碍的原因，而二甲双胍可以逆转这些改变。
