Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Clinical Epidemiology, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
Free Radic Biol Med. 2022 Nov 20;193(Pt 1):459-473. doi: 10.1016/j.freeradbiomed.2022.10.320. Epub 2022 Nov 3.
Hypertension is one of the leading causes of chronic kidney disease characterized with renal fibrosis. This study aimed to investigate roles and mechanisms of sirtuin 7 (SIRT7) in hypertensive renal injury. Mini-pumps were implanted to male C57BL/6 mice to deliver angiotensin (Ang) Ⅱ (1.5 mg/kg/d) or saline for 2 weeks. Ang Ⅱ infusion resulted in marked increases in systolic blood pressure levels, renal ferroptosis and interstitial fibrosis in hypertensive mice, concomitantly with downregulated SIRT7 and Krüppel-like factor 15 (KLF15) levels. Notably, administration of recombinant adeno-associated virus-SIRT7 or ferroptosis inhibitor ferrostatin-1 effectively mitigated Ang Ⅱ-triggered renal ferroptosis, epithelial-mesenchymal transition (EMT), interstitial fibrosis, renal functional and structural injury in hypertensive mice by blunting the KIM-1/NOX4 signaling and enforcing the KLF15/Nrf2 and xCT/GPX4 signaling, respectively. In primary cultured mouse renal tubular epithelial cells (TECs), Ang Ⅱ pretreatment led to repressed SIRT7 expression and augmented ferroptosis as well as partial EMT, which were substantially antagonized by rhSIRT7 or ferrostatin-1 administration. Additionally, both Nrf2 inhibitor ML385 and KLF15 siRNA strikingly abolished the rhSIRT7-mediated beneficial roles in mouse renal TECs in response to Ang Ⅱ with reduced expression of Nrf2, xCT and GPX4. More importantly, ML385 administration remarkably amplified Ang Ⅱ-mediated ROS generation, lipid peroxidation and ferroptosis in renal TECs, which were significantly reversed by ferrostatin-1. In conclusion, SIRT7 alleviates renal ferroptosis, lipid peroxidation, and partial EMT under hypertensive status by facilitating the KLF15/Nrf2 signaling, thereby mitigating renal fibrosis, injury and dysfunction. Targeting SIRT7 signaling serves as a promising strategy for hypertension and hypertensive renal injury.
高血压是慢性肾脏病的主要病因之一，其特征为肾纤维化。本研究旨在探讨 Sirtuin 7（SIRT7）在高血压肾损伤中的作用和机制。雄性 C57BL/6 小鼠植入微量泵，以输注血管紧张素（Ang）Ⅱ（1.5mg/kg/d）或生理盐水 2 周。AngⅡ输注导致高血压小鼠的收缩压显著升高，肾铁死亡和间质纤维化，同时 SIRT7 和 Krüppel 样因子 15（KLF15）水平下调。值得注意的是，给予重组腺相关病毒-SIRT7 或铁死亡抑制剂 ferrostatin-1 可通过抑制 KIM-1/NOX4 信号通路和增强 KLF15/Nrf2 和 xCT/GPX4 信号通路，有效减轻 AngⅡ引发的肾铁死亡、上皮-间充质转化（EMT）、间质纤维化、高血压小鼠的肾功能和结构损伤。在原代培养的小鼠肾小管上皮细胞（TECs）中，AngⅡ预处理导致 SIRT7 表达下调和铁死亡增加以及部分 EMT，给予 rhSIRT7 或 ferrostatin-1 可明显拮抗。此外，Nrf2 抑制剂 ML385 和 KLF15 siRNA 显著消除了 rhSIRT7 对 AngⅡ刺激的小鼠肾 TECs 的有益作用，导致 Nrf2、xCT 和 GPX4 的表达减少。更重要的是，ML385 给药显著增强了肾 TECs 中 AngⅡ介导的 ROS 生成、脂质过氧化和铁死亡，而 ferrostatin-1 可显著逆转这一过程。总之，SIRT7 通过促进 KLF15/Nrf2 信号减轻高血压状态下的肾铁死亡、脂质过氧化和部分 EMT，从而减轻肾纤维化、损伤和功能障碍。靶向 SIRT7 信号可能是高血压和高血压肾损伤的一种有前途的治疗策略。
