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Atorvastatin ameliorates diabetic nephropathy through inhibiting oxidative stress and ferroptosis signaling
Yaoxia Zhang1, Yuanyuan Qu1, Ruiping Cai2
1Science 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.
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.
Insights
Atorvastatin, a statin, protects against diabetic kidney disease by reducing oxidative stress and ferroptosis. This study reveals its mechanism in inhibiting renal injury and fibrosis in diabetic mice.
Area of Science:
- Nephrology
- Pharmacology
- Biochemistry
Background:
- Statins are clinically utilized for managing chronic kidney diseases, but their precise mechanisms remain unclear.
- Diabetic nephropathy is a significant complication of diabetes, characterized by renal injury and fibrosis.
- Ferroptosis, a form of regulated cell death driven by iron accumulation and lipid peroxidation, is implicated in diabetic kidney injury.
Purpose of the Study:
- To investigate the protective effects of atorvastatin on diabetes-induced renal injury and ferroptosis signaling.
- To elucidate the molecular mechanisms by which atorvastatin mitigates oxidative stress and ferroptosis in diabetic nephropathy.
Main Methods:
- A mouse model of diabetes was established using streptozotocin and a high-fat diet, with or without atorvastatin treatment.
- Renal injury, fibrosis, oxidative stress markers (ROS, MDA, 4-HNE), iron accumulation, and ferroptosis-related proteins (TFR1, GPX4, NRF2, FTH) were assessed in vivo and in vitro.
- Experiments utilized human kidney cells (HK-2) exposed to high glucose or erastin, with or without atorvastatin, ferrostatin-1, or N-acetylcysteine.
Main Results:
- Atorvastatin treatment significantly reduced plasma glucose, lipid profiles, proteinuria, and renal injury in diabetic mice.
- Atorvastatin decreased oxidative stress, iron accumulation, and expression of MDA, 4-HNE, and TFR1, while increasing GPX4, NRF2, and FTH in diabetic kidneys.
- In vitro, atorvastatin inhibited high glucose- and erastin-induced ROS production, iron accumulation, ferroptosis markers, and mitochondrial damage in HK-2 cells.
Conclusions:
- Atorvastatin effectively inhibits diabetes-induced renal oxidative stress and ferroptosis.
- The findings suggest that atorvastatin's renoprotective effects in diabetic nephropathy are mediated through the modulation of ferroptosis signaling pathways.
- Statins may represent a therapeutic strategy to combat diabetic kidney disease by targeting ferroptosis.
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