International immunopharmacology · 2026
Sarsasapogenin attenuates renal ischemia-reperfusion injury by inhibiting the NF-κB pathway and NLRP3 inflammasome-mediated pyroptosis.
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Yuan Qiang, Li Yaoke, Shen Kaiwen, Zhang Ruibo, Wang Qiang, Xia Shasha, Shen Jun
Аннотация
BACKGROUND: Renal ischemia-reperfusion injury (RIRI) contributes significantly to acute kidney injury (AKI), which is associated with high morbidity and mortality rates. Currently, therapeutic options for RIRI remain limited. Sarsasapogenin (Sar), a steroidal saponin from Anemarrhena asphodeloides, exhibits strong anti-inflammatory properties. However, its renoprotective effects, dose-response characteristics, and tissue-specific benefits in acute RIRI have not been thoroughly explored. This study aimed to determine whether Sar provides protection against RIRI-induced AKI and to investigate the potential signaling pathways involved.
METHODS: Rats underwent 45 min of renal ischemia followed by reperfusion. Sar (20 or 60 mg/kg) was administered daily via gavage for one week prior to surgery. As a positive control, INF39 (7.5 mg/kg), an NLRP3 inhibitor, was injected intraperitoneally 2 h before surgery. Renal function was assessed through serum creatinine and BUN levels, while histopathology was evaluated using H&E and TEM. Tubular injury markers, such as KIM-1, were also assessed. Total cell death was determined using the TUNEL assay, which detects DNA fragmentation but does not specifically identify pyroptosis. The expression of inflammatory factors (IL-1β, IL-6, TNF-α) and key proteins of the NF-κB pathway (p-p65/p65) and NLRP3 inflammasome (NLRP3, Caspase-1, GSDMD) were measured using ELISA, immunohistochemistry, immunofluorescence, and Western blotting.
RESULTS: RIRI led to severe renal dysfunction, structural damage, and increased KIM-1 expression. These pathological changes were linked to significant activation of the NF-κB pathway, upregulation of NLRP3 inflammasome components, and increased pyroptosis, indicated by elevated levels of cleaved Caspase-1, GSDMD-N, and mature IL-1β. Pretreatment with Sar dose-dependently improved renal function and reduced histopathological injury. Sar provided tissue-specific protection by maintaining mitochondrial integrity in renal tubular epithelial cells. These beneficial effects were accompanied by decreased phosphorylation of p65, reduced expression of NLRP3, cleaved Caspase-1, and GSDMD-N, as well as lower IL-1β production. High-dose Sar exhibited renoprotective effects comparable to INF39, acting as a multi-stage regulator that inhibits both NF-κB priming and NLRP3 inflammasome activation, suggesting advantages over single-target inhibitors.
CONCLUSION: Sar effectively attenuated RIRI-induced AKI, demonstrating favorable dose-dependent and tissue-specific renoprotective effects. This protective effect was associated with suppression of the NF-κB/NLRP3 inflammasome axis and reduced pyroptosis, highlighting its potential as a safe, multi-stage, natural candidate for treating ischemia-related renal injury.
METHODS: Rats underwent 45 min of renal ischemia followed by reperfusion. Sar (20 or 60 mg/kg) was administered daily via gavage for one week prior to surgery. As a positive control, INF39 (7.5 mg/kg), an NLRP3 inhibitor, was injected intraperitoneally 2 h before surgery. Renal function was assessed through serum creatinine and BUN levels, while histopathology was evaluated using H&E and TEM. Tubular injury markers, such as KIM-1, were also assessed. Total cell death was determined using the TUNEL assay, which detects DNA fragmentation but does not specifically identify pyroptosis. The expression of inflammatory factors (IL-1β, IL-6, TNF-α) and key proteins of the NF-κB pathway (p-p65/p65) and NLRP3 inflammasome (NLRP3, Caspase-1, GSDMD) were measured using ELISA, immunohistochemistry, immunofluorescence, and Western blotting.
RESULTS: RIRI led to severe renal dysfunction, structural damage, and increased KIM-1 expression. These pathological changes were linked to significant activation of the NF-κB pathway, upregulation of NLRP3 inflammasome components, and increased pyroptosis, indicated by elevated levels of cleaved Caspase-1, GSDMD-N, and mature IL-1β. Pretreatment with Sar dose-dependently improved renal function and reduced histopathological injury. Sar provided tissue-specific protection by maintaining mitochondrial integrity in renal tubular epithelial cells. These beneficial effects were accompanied by decreased phosphorylation of p65, reduced expression of NLRP3, cleaved Caspase-1, and GSDMD-N, as well as lower IL-1β production. High-dose Sar exhibited renoprotective effects comparable to INF39, acting as a multi-stage regulator that inhibits both NF-κB priming and NLRP3 inflammasome activation, suggesting advantages over single-target inhibitors.
CONCLUSION: Sar effectively attenuated RIRI-induced AKI, demonstrating favorable dose-dependent and tissue-specific renoprotective effects. This protective effect was associated with suppression of the NF-κB/NLRP3 inflammasome axis and reduced pyroptosis, highlighting its potential as a safe, multi-stage, natural candidate for treating ischemia-related renal injury.