Kidney Institute of PLA, Department of Nephrology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, People's Republic of China.
Mol Cell Biochem. 2018 Dec;449(1-2):219-226. doi: 10.1007/s11010-018-3358-0. Epub 2018 Apr 19.
Autosomal dominant polycystic kidney disease (ADPKD) is a common heritable human disease. Recently, the role of repressed autophagy in ADPKD has drawn increasing attention. Here, we investigate the mechanism underlying the effect of Saikosaponin-d (SSd), a sarcoplasmic/endoplasmic reticulum Ca ATPase pump (SERCA) inhibitor. We show that SSd suppresses proliferation in ADPKD cells by up-regulating autophagy. We found that treatment with SSd results in the accumulation of intracellular calcium, which in turn activates the CaMKKβ-AMPK signalling cascade, inhibits mTOR signalling and induces autophagy. Conversely, we also found that treatment with an autophagy inhibitor (3-methyladenine), AMPK inhibitor (Compound C), CaMKKβ inhibitor (STO-609) and intracellular calcium chelator (BAPTA/AM) could reduce autophagy puncta formation mediated by SSd. Our results demonstrated that SSd induces autophagy through the CaMKKβ-AMPK-mTOR signalling pathway in ADPKD cells, indicating that SSd might be a potential therapy for ADPKD and that SERCA might be a new target for ADPKD treatment.
常染色体显性多囊肾病 (ADPKD) 是一种常见的遗传性人类疾病。最近，抑制自噬在 ADPKD 中的作用引起了越来越多的关注。在这里，我们研究了柴胡皂甙-d (SSd) 的作用机制，SSd 是肌浆/内质网 Ca ATP 酶泵 (SERCA) 的抑制剂。我们表明，SSd 通过上调自噬来抑制 ADPKD 细胞的增殖。我们发现，SSd 的处理导致细胞内钙的积累，进而激活 CaMKKβ-AMPK 信号级联，抑制 mTOR 信号并诱导自噬。相反，我们还发现，用自噬抑制剂 (3-甲基腺嘌呤)、AMPK 抑制剂 (Compound C)、CaMKKβ 抑制剂 (STO-609) 和细胞内钙螯合剂 (BAPTA/AM) 处理可以减少 SSd 介导的自噬斑点形成。我们的结果表明，SSd 通过 CaMKKβ-AMPK-mTOR 信号通路诱导 ADPKD 细胞中的自噬，表明 SSd 可能是 ADPKD 的一种潜在治疗方法，而 SERCA 可能是 ADPKD 治疗的新靶点。
