雷公藤甲素通过抑制NLRP3介导的焦亡改善 单侧输尿管梗阻小鼠肾间质纤维化

Objective To investigate the effect of triptolide(TPL)on renal interstitial fibrosis in mice with unilateral ureteral obstruction(UUO)and its mechanism.Methods Six male C57 BL/6J mice were randomly selected as the sham group, and 12 mice with UUO modeling were randomly divided into the model group(UUO)and the triptolide group(TPL).Changes in serum creatinine(SCr), blood urea nitrogen(BUN), and body weight were compared among the groups.Renal tissue specimens were collected at 14d after UUO for HE and Masson staining.Immunohistochemistry staining was performed to observe the expression of α-smooth muscle actin(α-SMA)and fibronectin(Fn)in kidney tissues.Western blotting analysis was used to detect the protein expression levels of nucleotide combined with structure of oligomerization domain receptor protein 3(NLRP3), GSDMD, cGSDMD, IL-1βand IL-18.Results At week 1, the body weight of mice in the UUO and TPL groups significantly decreased compared with that in the sham group(P＜0.05).Body weight reduced in the TPL group compared with that in the Sham group at week 2(P＜0.01).There was no significant difference in body weight between the TPL and UUO groups.BUN levels did not differ significantly between the three groups.Compared with the sham group, the SCr level in the UUO group significantly increased [(15.680±1.508)μmol/L](P＜0.01).A reduction in SCr level was observed following TPL administration [(12.550±3.004)μmol/L](P＜0.05).HE staining showed that the renal tubules of mice in the UUO group were significantly dilated and atrophic, with interstitial edema and increased inflammatory cell infiltration, while the pathological damage of renal tissues was significantly alleviated after TPL treatment.Masson staining revealed that interstitial collagen deposition significantly increased in the UUO group(36.350±5.183)%(P＜0.01)and reduced after TPL administration(20.820±3.290)%(P＜0.01).Immunohistochemistry results demonstrated that the IOD levels of α-SMA(1.233±0.045)and Fn(1.337±0.045)were higher in UUO group mice than in the sham group, while the IOD levels of α-SMA(1.047±0.025)and Fn(1.113±0.021)were lower in the TPL group than in the UUO group(P＜0.05).Western blotting analysis indicated that the expression levels of NLRP3, cGSDMD, IL-1βand IL-18 in the UUO group mice were higher than those in the sham group, while the protein expression levels of the above-mentioned indicators significantly decreased after TPL treatment(P＜0.05).Conclusion TPL ameliorates renal interstitial fibrosis in mice with UUO by inhibiting NLRP3-mediated pyroptosis.