2. Academic Validation
  3. Sirtuin 7 mitigates renal ferroptosis, fibrosis and injury in hypertensive mice by facilitating the KLF15/Nrf2 signaling

Sirtuin 7 mitigates renal ferroptosis, fibrosis and injury in hypertensive mice by facilitating the KLF15/Nrf2 signaling

  • Free Radic Biol Med. 2022 Nov 3;193(Pt 1):459-473. doi: 10.1016/j.freeradbiomed.2022.10.320.
Xue-Ting Li 1,  Jia-Wei Song 1,  Zhen-Zhou Zhang 1,  Mi-Wen Zhang 2,  Li-Rong Liang 3,  Ran Miao 3,  Ying Liu 2,  Yi-Hang Chen 2,  Xiao-Yan Liu 4,  Jiu-Chang Zhong 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Clinical Epidemiology, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
  • 4 Heart Center and Beijing Key Laboratory of Hypertension, 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.
  • 5 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. Electronic address: [email protected].
PMID: 36334846 DOI: 10.1016/j.freeradbiomed.2022.10.320
Abstract

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.

Keywords

Epithelial-mesenchymal transition; Ferroptosis; Hypertension; Renal fibrosis; Sirtuin 7.

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