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Mulberrin Alleviates Renal Ischemia-Reperfusion by Inhibiting Ferroptosis and Oxidative Stress Through Sirt3
Qiangmin Qiu1,2, Zhan Chen1,2, Wenbin Yang3
1Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Abstract:
Background: Renal ischemia-reperfusion (I/R) injury represents a principal etiologic factor in acute kidney injury (AKI), in which ferroptosis plays a critical role. Mulberrin (Mul), a prenylated flavonoid with antioxidative properties, has an as-yet undefined role in renal I/R injury. Methods: We established a mouse renal IRI model and an HK-2 H/R system. Renal function, histological injury, oxidative stress, ferroptosis markers, and mitochondrial function were assessed. The role of Sirtuin 3 (Sirt3) in Mul-mediated effects was further examined using siRNA knockdown in HK-2 cells. Results: The administration of Mul led to a marked improvement in renal function, lessened tubular injury, and reduced apoptosis in IRI mice. Mul also restored GSH levels, decreased MDA and Fe2+ accumulation, and normalized expression of ferroptosis-related proteins, thereby suppressing ferroptosis. In H/R-injured HK-2 cells, Mul restored mitochondrial membrane potential, increased ATP production, and reduced ROS accumulation. Mechanistically, Mul markedly upregulated Sirt3 expression, and silencing Sirt3 abolished its antioxidant and anti-ferroptosis effects, confirming the essential role of Sirt3 in Mul-mediated protection. Conclusions: Our findings underscore Mul's therapeutic promise in acute kidney injury and provide a mechanistic foundation for interventions directed at the Sirt3-ferroptosis pathway to safeguard renal function.
Insights
Mulberrin (Mul) protects against kidney injury by suppressing ferroptosis, a cell death pathway. This effect is mediated by Sirtuin 3 (Sirt3), highlighting Mul
Area of Science:
- Nephrology
- Biochemistry
- Cell Biology
Background:
- Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury (AKI).
- Ferroptosis, a form of regulated cell death, is implicated in the pathogenesis of renal I/R injury.
- Mulberrin (Mul), an antioxidative flavonoid, has a potential but uncharacterized role in mitigating renal I/R injury.
Purpose of the Study:
- To investigate the therapeutic potential of Mulberrin (Mul) in a mouse model of renal ischemia-reperfusion (I/R) injury.
- To elucidate the underlying mechanisms of Mul's protective effects, particularly its role in ferroptosis and Sirtuin 3 (Sirt3) regulation.
Main Methods:
- Established a mouse model of renal I/R injury and an HK-2 cell hypoxia/reoxygenation (H/R) system.
- Assessed renal function, histological damage, oxidative stress, ferroptosis markers, and mitochondrial function.
- Utilized Sirtuin 3 (Sirt3) siRNA knockdown in HK-2 cells to examine its role in Mul-mediated protection.
Main Results:
- Mul administration improved renal function, reduced tubular injury and apoptosis in I/R mice.
- Mul suppressed ferroptosis by restoring GSH levels, decreasing MDA and Fe2+ accumulation, and normalizing ferroptosis-related proteins.
- Mul upregulated Sirt3 expression, and Sirt3 knockdown abolished Mul's protective effects against oxidative stress and ferroptosis in HK-2 cells.
Conclusions:
- Mulberrin demonstrates significant therapeutic promise for acute kidney injury (AKI) by protecting against renal I/R injury.
- The protective mechanisms involve the upregulation of Sirtuin 3 (Sirt3), which suppresses ferroptosis.
- Targeting the Sirt3-ferroptosis pathway presents a potential therapeutic strategy for safeguarding renal function.
