Possible mechanism of PNS protection against cisplatin-induced nephrotoxicity in rat models
Possible mechanism of PNS protection against cisplatin-induced nephrotoxicity in rat models
复制标题
PNS 对抗顺铂诱导的大鼠模型肾毒性的可能机制
DOI：
10.3109/15376516.2015.1006492
复制
发表时间：
2015-06-13
影响因子：
3.2
通讯作者：
Wen, Yan
中科院分区：
文献类型：
--
作者：
Liu, Xinwen;Huang, Zhenguang;Wen, Yan
本研究探讨三七总皂甙（PNS）通过缺氧诱导因子1（HIF-1）/Bcl-2/腺病毒E1 B19 kDa相互作用蛋白3（BNIP 3）自噬途径对顺铂肾毒性的保护作用机制。大鼠腹腔注射顺铂，部分大鼠腹腔注射三七总皂苷31.35mg/kg，每日1次。顺铂染毒24 h后，测定尿N-乙酰-β-D-氨基葡萄糖苷酶（NAG）、血尿素氮（BUN）和血肌酐（Scr）。用H& E染色法观察大鼠肾组织，透射电镜观察肾小管上皮细胞线粒体。采用免疫印迹法检测大鼠肾组织中微管相关蛋白1轻链（LC）3、自噬相关基因（Atg）5、Beclin-1和BNIP 3的表达。免疫组化法检测HIF-1的表达。结果表明，三七总皂甙能显著降低顺铂肾毒性大鼠血BUN和Scr浓度，减轻肾组织病理学改变，减轻肾细胞线粒体损伤，增加肾小管上皮细胞线粒体自噬体。PNS还能显著增加大鼠肾组织中LC 3的表达及LC 3 II/LC 3 I的比值。PNS还能显著增加大鼠肾组织中HIF-1、BNIP 3、Atg 5和Beclin-1的表达。综上所述，三七总皂苷对顺铂肾毒性的保护作用主要是通过HIF-1/BNIP 3途径增强肾组织线粒体自噬，本文首次证实了这一点。
This study investigates the mechanism of the protective effect of Panax notoginsenosides (PNS) against cisplatin-induced nephrotoxicity via the hypoxia inducible factor 1 (HIF-1)/Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) pathway of autophagy. The rats underwent intraperitoneal injection with a single dose of cisplatin and a subset of rats were also intraperitoneally injected with 31.35mg/kg PNS once a day. After 24h exposure to cisplatin, the concentrations of urinary N-acetyl--d-glucosaminidase (NAG), blood urea nitrogen (BUN) and serum creatinine (Scr) were determined. The rat renal tissue was examined using H&E-staining, and the mitochondria of renal tubular epithelial cells were observed using transmission electron microscopy. The expressions of microtubule-associated protein-1 light chain (LC)3, autophagy-related gene (Atg)5, Beclin-1 and BNIP3 in rat renal tissue were detected using western blotting. The expression of HIF-1 was detected by immunohistochemistry. The results showed that PNS significantly protected against cisplatin-induced nephrotoxicity, as evidenced by decreasing the concentration of blood BUN and Scr, the attenuation of renal histopathological changes and the mitochondrial damages of renal cells, and the increase of mitochondria autophagosome in renal tubular epithelial cells. Additionally, PNS significantly increased the expression of LC3 and the ratio of LC3II/LC3I in rat renal tissue. Moreover, PNS significantly increased the expression of HIF-1, BNIP3, Atg5 and Beclin-1 in rat renal tissue. In conclusion, the protective effect of PNS on cisplatin-induced nephrotoxicity was mainly due to its ability to enhancing the mitochondrial autophagy of renal tissue via the HIF-1/BNIP3 pathway, and here is the first demonstration about it.