Ding Yanping, Liu Shuning, Zhang Mengqing, Su Meile, Shao Baoping
School of Life Science, Northwest Normal University, Lanzhou, China.
School of Life Science, Lanzhou University, Lanzhou, China.
Transl Androl Urol. 2024 Jan 31;13(1):25-41. doi: 10.21037/tau-23-323. Epub 2024 Jan 23.
Irradiation (IR) promotes inflammation and apoptosis by inducing oxidative stress and/or mitochondrial dysfunction (MD). The kidneys are rich in mitochondria, and mitophagy maintains normal renal function by eliminating damaged mitochondria and minimizing oxidative stress. However, whether astragaloside IV (AS-IV) can play a protective role through the mitophagy pathway is not known.
We constructed a radiation injury model using hematoxylin and eosin (HE) staining, blood biochemical analysis, immunohistochemistry, TdT-mediated dUTP nick end labeling (TUNEL) staining, ultrastructural observation, and Western blot analysis to elucidate the AS-IV resistance mechanism for IR-induced renal injury.
IR induced mitochondrial damage; the increase of creatinine (SCr), blood urea nitrogen (BUN) and uric acid (UA); and the activation of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome and apoptosis in renal tissue. AS-IV administration attenuated the IR-induced MD and reactive oxygen species (ROS) levels in the kidney; enhanced the levels of mitophagy-associated protein [PTEN-induced putative kinase 1 (PINK1)], parkin proteins, and microtubule-associated protein 1 light 3 (LC3) II/I ratio in renal tissues; diminished NLRP3 inflammasome activation-mediated proteins [cleaved cysteinyl aspartate-specific proteinase-1 (caspase-1), interleukin-1β (IL-1β)] and apoptosis-related proteins [cleaved caspase-9, cleaved caspase-3, BCL2-associated X (Bax)]; reduced SCr, BUN, and UA levels; and attenuated the histopathological alterations in renal tissue. Conversely, mitophagy inhibitor cyclosporin A (CsA) suppressed the AS-IV-mediated protection of renal tissue.
AS-IV can strongly diminish the activation and apoptosis of NLRP3 inflammasome, thus attenuating the renal injury induced by radiation by promoting the PINK1/parkin-mediated mitophagy. These findings suggest that AS-IV is a promising drug for treating IR-induced kidney injury.
辐射（IR）通过诱导氧化应激和/或线粒体功能障碍（MD）促进炎症和细胞凋亡。肾脏富含线粒体，线粒体自噬通过清除受损线粒体和最小化氧化应激来维持正常肾功能。然而，黄芪甲苷IV（AS-IV）是否能通过线粒体自噬途径发挥保护作用尚不清楚。
我们使用苏木精-伊红（HE）染色、血液生化分析、免疫组织化学、TdT介导的dUTP缺口末端标记（TUNEL）染色、超微结构观察和蛋白质印迹分析构建辐射损伤模型，以阐明AS-IV对IR诱导的肾损伤的抵抗机制。
IR诱导线粒体损伤；肌酐（SCr）、血尿素氮（BUN）和尿酸（UA）升高；肾组织中NOD样受体热蛋白结构域相关蛋白3（NLRP3）炎性小体激活和细胞凋亡。给予AS-IV可减轻IR诱导的肾脏MD和活性氧（ROS）水平；提高肾组织中线粒体自噬相关蛋白[PTEN诱导的假定激酶1（PINK1）]、帕金蛋白和微管相关蛋白1轻链3（LC3）II/I比值；减少NLRP3炎性小体激活介导的蛋白[裂解的半胱天冬酶-1（caspase-1）、白细胞介素-1β（IL-1β）]和凋亡相关蛋白[裂解的caspase-9、裂解的caspase-3、BCL2相关X蛋白（Bax）]；降低SCr、BUN和UA水平；减轻肾组织的组织病理学改变。相反，线粒体自噬抑制剂环孢素A（CsA）抑制了AS-IV介导的肾组织保护作用。
AS-IV可强烈减少NLRP3炎性小体的激活和细胞凋亡，从而通过促进PINK1/帕金介导的线粒体自噬减轻辐射诱导的肾损伤。这些发现表明AS-IV是治疗IR诱导的肾损伤的一种有前景的药物。
