Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China.
Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, China; Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China.
Biomed Pharmacother. 2023 Sep;165:115122. doi: 10.1016/j.biopha.2023.115122. Epub 2023 Jul 4.
Nephrotoxicity is a major side effect of cisplatin treatment of solid tumors in the clinical setting. Long-term low-dose cisplatin administration causes renal fibrosis and inflammation. However, few specific medicines with clinical application value have been developed to reduce or treat the nephrotoxic side effects of cisplatin without affecting its tumor-killing effect. The present study analyzed the potential reno-protective effect and mechanism of asiatic acid (AA) in long-term cisplatin-treated nude mice suffering from tumors. AA treatment significantly attenuated renal injury, inflammation, and fibrosis induced by long-term cisplatin injection in tumor-bearing mice. AA administration notably suppressed tubular necroptosis and improved the autophagy-lysosome pathway disruption caused by chronic cisplatin treatment in tumor-transplanted nude mice and HK-2 cells. AA promoted transcription factor EB (TFEB)-mediated lysosome biogenesis and reduced the accumulation of damaged lysosomes, resulting in enhanced autophagy flux. Mechanistically, AA increased TFEB expression by rebalancing Smad7/Smad3, whereas siRNA inhibition of Smad7 or TFEB abolished the effect of AA on autophagy flux in HK-2 cells. In addition, AA treatment did not weaken, but actually enhanced the anti-tumor effect of cisplatin, as evidenced by the promoted tumor apoptosis and inhibited proliferation in nude mice. In summary, AA alleviates cisplatin-induced renal fibrosis in tumor-bearing mice by improving the TFEB-mediated autophagy-lysosome pathway.
肾毒性是临床中顺铂治疗实体瘤的主要副作用。长期低剂量顺铂给药会导致肾纤维化和炎症。然而，开发出具有临床应用价值的特异性药物来减少或治疗顺铂的肾毒性副作用而不影响其肿瘤杀伤作用的却很少。本研究分析了齐墩果酸（AA）在长期顺铂治疗荷瘤裸鼠中潜在的肾保护作用及其机制。AA 治疗显著减轻了荷瘤小鼠长期顺铂注射引起的肾损伤、炎症和纤维化。AA 给药显著抑制了慢性顺铂处理引起的管状细胞坏死和自噬-溶酶体途径破坏，并改善了裸鼠和 HK-2 细胞中的自噬流。AA 通过重新平衡 Smad7/Smad3 来促进转录因子 EB（TFEB）介导的溶酶体生物发生，减少受损溶酶体的积累，从而增强自噬流。从机制上讲，AA 通过重新平衡 Smad7/Smad3 增加了 TFEB 的表达，而 Smad7 或 TFEB 的 siRNA 抑制消除了 AA 对 HK-2 细胞中自噬流的影响。此外，AA 治疗并没有削弱，反而增强了顺铂的抗肿瘤作用，这从裸鼠中促进肿瘤凋亡和抑制增殖得到了证实。总之，AA 通过改善 TFEB 介导的自噬-溶酶体途径缓解了荷瘤小鼠顺铂引起的肾纤维化。
