Renal failure · 2025
Tanshinone IIA alleviates LPS-induced acute kidney injury by inhibiting RIP3/Nrf2-mediated oxidative stress.
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Zhang Shu, Dong Xin, Chen Gangyi, Wang Chao
Аннотация
BACKGROUND: Oxidative stress is a critical pathological mechanism in septic acute kidney injury (AKI). Tanshinone IIA (Tan IIA), a bioactive compound derived from Salvia miltiorrhiza, exhibits antioxidative properties. This study aimed to explore the protective mechanisms of Tan IIA in septic AKI.
METHODS: A mouse model of lipopolysaccharide (LPS)-induced AKI was established, with Tan IIA administered prior to LPS injection. Renal function was assessed by serum creatinine and urea nitrogen levels, while histopathological damage and apoptosis were evaluated using PAS and TUNEL staining. Oxidative stress was assessed by SOD activity, ROS levels, and 8-OHdG staining. In vitro, LPS-stimulated HK-2 cells were treated with Tan IIA or RIP3 siRNA. The expression of RIP3, p-RIP3, Nrf2, HO-1, KEAP1, and downstream antioxidant genes (NQO1, GCLC) was analyzed by qRT-PCR, immunohistochemistry, and Western blot. Apoptosis was further evaluated by Annexin V-FITC/PI flow cytometry and detection of apoptosis-related proteins (Bax, cleaved caspase-3, Bcl-2). Co-immunoprecipitation was performed to examine RIP3-Nrf2 interaction.
RESULTS: In vivo, Tan IIA significantly improved renal function and alleviated tubular damage. It decreased ROS production and 8-OHdG positivity while restoring SOD activity. In vitro, Tan IIA or RIP3 silencing decreased ROS levels, enhanced SOD activity, promoted Nrf2 nuclear translocation, and upregulated antioxidant genes. Flow cytometry confirmed reduced apoptotic cell populations, and Western blot showed reversal of LPS-induced pro-apoptotic protein changes. The co-immunoprecipitation confirmed an interaction between RIP3 and Nrf2 under LPS stimulation.
CONCLUSION: These findings suggest that Tan IIA protects against LPS-induced AKI by inhibiting RIP3 expression and restoring Nrf2-mediated antioxidant defenses, thereby attenuating oxidative stress and apoptosis.
METHODS: A mouse model of lipopolysaccharide (LPS)-induced AKI was established, with Tan IIA administered prior to LPS injection. Renal function was assessed by serum creatinine and urea nitrogen levels, while histopathological damage and apoptosis were evaluated using PAS and TUNEL staining. Oxidative stress was assessed by SOD activity, ROS levels, and 8-OHdG staining. In vitro, LPS-stimulated HK-2 cells were treated with Tan IIA or RIP3 siRNA. The expression of RIP3, p-RIP3, Nrf2, HO-1, KEAP1, and downstream antioxidant genes (NQO1, GCLC) was analyzed by qRT-PCR, immunohistochemistry, and Western blot. Apoptosis was further evaluated by Annexin V-FITC/PI flow cytometry and detection of apoptosis-related proteins (Bax, cleaved caspase-3, Bcl-2). Co-immunoprecipitation was performed to examine RIP3-Nrf2 interaction.
RESULTS: In vivo, Tan IIA significantly improved renal function and alleviated tubular damage. It decreased ROS production and 8-OHdG positivity while restoring SOD activity. In vitro, Tan IIA or RIP3 silencing decreased ROS levels, enhanced SOD activity, promoted Nrf2 nuclear translocation, and upregulated antioxidant genes. Flow cytometry confirmed reduced apoptotic cell populations, and Western blot showed reversal of LPS-induced pro-apoptotic protein changes. The co-immunoprecipitation confirmed an interaction between RIP3 and Nrf2 under LPS stimulation.
CONCLUSION: These findings suggest that Tan IIA protects against LPS-induced AKI by inhibiting RIP3 expression and restoring Nrf2-mediated antioxidant defenses, thereby attenuating oxidative stress and apoptosis.