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  3. Atorvastatin ameliorates diabetic nephropathy through inhibiting oxidative stress and ferroptosis signaling

Atorvastatin ameliorates diabetic nephropathy through inhibiting oxidative stress and ferroptosis signaling

  • Eur J Pharmacol. 2024 Aug 5:976:176699. doi: 10.1016/j.ejphar.2024.176699.
Yaoxia Zhang 1,  Yuanyuan Qu 2,  Ruiping Cai 3,  Junjia Gao 4,  Qian Xu 5,  Lu Zhang 5,  Mengjie Kang 2,  Hui Jia 6,  Qing Chen 7,  Yueyang Liu 7,  Fu Ren 8,  Ming-Sheng Zhou 9
Affiliations

Affiliations

  • 1 Science and Experiment Research Center & Shenyang Key Laboratory of Vascular Biology, Shenyang Medical College, Shenyang, 110034, China; Department of Physiology, Shenyang Medical College, Shenyang, 110034, China. Electronic address: zhangyx0875@163.com.
  • 2 Science and Experiment Research Center & Shenyang Key Laboratory of Vascular Biology, Shenyang Medical College, Shenyang, 110034, China; Department of Physiology, Shenyang Medical College, Shenyang, 110034, China.
  • 3 Department of Physiology, Shenyang Medical College, Shenyang, 110034, China.
  • 4 Department of Cardiology, 2nd Affiliated Hospital, Shenyang Medical College, 110000, China.
  • 5 Science and Experiment Research Center & Shenyang Key Laboratory of Vascular Biology, Shenyang Medical College, Shenyang, 110034, China.
  • 6 School of Traditional Chinese Medicine, Shenyang Medical College, Shenyang, 110034, China.
  • 7 Department of Pharmacy, Shenyang Medical College, Shenyang, 110034, China.
  • 8 Department of Anatomy, Shenyang Medical College, Shenyang, 110034, China. Electronic address: rf@symc.edu.cn.
  • 9 Science and Experiment Research Center & Shenyang Key Laboratory of Vascular Biology, Shenyang Medical College, Shenyang, 110034, China; Department of Physiology, Shenyang Medical College, Shenyang, 110034, China. Electronic address: zhoums@symc.edu.cn.
PMID: 38825302 DOI: 10.1016/j.ejphar.2024.176699
Abstract

Clinically, statins have long been used for the prevention and treatment of chronic renal diseases, however, the underlying mechanisms are not fully elucidated. The present study investigated the effects of atorvastatin on diabetes renal injury and Ferroptosis signaling. A mouse model of diabetes was established by the intraperitoneal injection of streptozotocin (50 mg/kg/day) plus a high fat diet with or without atorvastatin treatment. Diabetes mice manifested increased plasma glucose and lipid profile, proteinuria, renal injury and fibrosis, atorvastatin significantly lowered plasma lipid profile, proteinuria, renal injury in diabetes mice. Atorvastatin reduced renal Reactive Oxygen Species (ROS), iron accumulation and renal expression of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), Transferrin Receptor 1 (TFR1), and increased renal expression of Glutathione Peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor (NRF2) and ferritin heavy chain (FTH) in diabetes mice. Consistent with the findings in vivo, atorvastatin prevented high glucose-induced ROS formation and Fe2+ accumulation, an increase in the expression of 4-HNE, MDA and TFR1, and a decrease in cell viability and the expression of NRF2, GPX4 and FTH in HK2 cells. Atorvastatin also reversed Ferroptosis inducer erastin-induced ROS production, intracellular Fe2+ accumulation and the changes in the expression of above-mentioned Ferroptosis signaling molecules in HK2 cells. In addition, atorvastatin alleviated high glucose- or erastin-induced mitochondria injury. Ferroptosis inhibitor ferrostatin-1 and antioxidant N-acetylcysteine (NAC) equally reversed the expression of high glucose-induced Ferroptosis signaling molecules. Our data support the notion that statins can inhibit diabetes-induced renal oxidative stress and Ferroptosis, which may contribute to statins protection of diabetic nephropathy.

Keywords

Diabetes; Diabetic nephropathy; Ferroptosis; Oxidative stress; Renal diseases; Statins.

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