A new LKB1 activator, piericidin analogue S14, retards renal fibrosis through promoting autophagy and mitochondrial homeostasis in renal tubular epithelial cells.
A new LKB1 activator, piericidin analogue S14, retards renal fibrosis through promoting autophagy and mitochondrial homeostasis in renal tubular epithelial cells.
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一种新的 LKB1 激活剂，杀粉粉菌素类似物 S14，通过促进肾小管上皮细胞的自噬和线粒体稳态来延缓肾纤维化
作者：
Liu C;Wang X;Wang X;Zhang Y;Min W;Yu P;Miao J;Shen W;Chen S;Zhou S;Li X;Meng P;Wu Q;Hou FF;Liu Y;Yang P;Wang C;Lin X;Tang L;Zhou X;Zhou L
背景：肝激酶B1(LKB1)是能量代谢和细胞内稳态的关键调节因子。LKB1功能障碍在肾纤维化中起关键作用。然而，LKB1激活剂目前在商业上很少见。本研究旨在发现一种新的药物分子PERICIDIN类似物S14(PA-S14)，作为LKB1的一种新的激活剂来预防肾纤维化。方法：本课题组从一株海洋来源的链霉菌的肉汤培养物中分离到PA-S14并鉴定其结合部位。我们采用了不同的CKD模型或AKI-CKD模型(5/6肾切除、UUO、UIRI和阿霉素肾病模型)。同时检测转化生长因子-β刺激的肾小管上皮细胞培养。结果：我们鉴定了PA-S14与LKB1激活区的D176残基结合，然后通过其磷酸化和与MO25、STRAD形成复合体来诱导LKB1的激活。因此，PA-S14促进AMPK激活，触发自噬小体成熟，增加自噬通量。PA-S14通过激活LKB1/AMPK信号通路抑制肾小管细胞衰老，延缓肾小管纤维化形成。转录组测序和突变分析进一步证实了我们的结果。结论：PA-S14是一种新型的LKB1激活剂先导化合物。PA-S14可能通过LKB1/AMPK介导的自噬和线粒体内稳态途径治疗肾纤维化。
Background: Liver kinase B1 (LKB1) is the key regulator of energy metabolism and cell homeostasis. LKB1 dysfunction plays a key role in renal fibrosis. However, LKB1 activators are scarce in commercial nowadays. This study aims to discover a new drug molecule, piericidin analogue S14 (PA-S14), preventing renal fibrosis as a novel activator to LKB1. Methods: Our group isolated PA-S14 from the broth culture of a marine-derived Streptomyces strain and identified its binding site. We adopted various CKD models or AKI-CKD model (5/6 nephrectomy, UUO, UIRI and adriamycin nephropathy models). TGF-β-stimulated renal tubular cell culture was also tested. Results: We identified that PA-S14 binds with residue D176 in the kinase domain of LKB1, and then induces the activation of LKB1 through its phosphorylation and complex formation with MO25 and STRAD. As a result, PA-S14 promotes AMPK activation, triggers autophagosome maturation, and increases autophagic flux. PA-S14 inhibited tubular cell senescence and retarded fibrogenesis through activation of LKB1/AMPK signaling. Transcriptomics sequencing and mutation analysis further demonstrated our results. Conclusion: PA-S14 is a novel leading compound of LKB1 activator. PA-S14 is a therapeutic potential to renal fibrosis through LKB1/AMPK-mediated autophagy and mitochondrial homeostasis pathways.
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
DOI：
10.1073/pnas.0705070104
发表时间：
2007-07-17
影响因子：
11.1
作者：
Jaeger, Sibylle;Handschin, Christoph;Spiegelman, Bruce M.
通讯作者：
Spiegelman, Bruce M.
影响因子：
29
作者：
Hardie DG
通讯作者：
Hardie DG
肾上腺髓质素通过 ROS-AMPK-mTOR 轴促进自噬，减轻 Leydig 细胞焦亡
影响因子：
9
作者：
Li, Ming-yong;Zhu, Xia-lian;Liu, Bo-long
通讯作者：
Liu, Bo-long
DOI：
10.1111/apha.12852
发表时间：
2017-06
期刊：
Acta physiologica (Oxford, England)
影响因子：
--
作者：
Lin F
通讯作者：
Lin F