A reciprocal regulation of spermidine and autophagy in podocytes maintains the filtration barrier
A reciprocal regulation of spermidine and autophagy in podocytes maintains the filtration barrier
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DOI：
10.1016/j.kint.2020.06.016
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发表时间：
2020-12-01
影响因子：
19.6
通讯作者：
Bork, Tillmann
中科院分区：
文献类型：
--
作者：
Liang, Wei;Yamahara, Kosuke;Bork, Tillmann
足细胞的维持和抗逆性是建立在高基础自噬率的基础上的，这使得足细胞成为揭示自噬调节机制的独特模型。多胺具有重要的细胞功能，如增殖、核酸生物合成和自噬。在这里，我们通过遗传学和药理学方法来测试内源性亚精胺信号是否驱动足细胞的基础和动态自噬，以干扰多胺代谢的不同步骤。转化研究揭示了局灶节段性肾小球硬化中亚精胺信号的改变。外源亚精胺补充成为一种新的治疗策略，通过抑制EP300成功激活体内自噬，EP300是一种在控制细胞生长、细胞分裂和促使细胞分化以承担特殊功能中起重要作用的蛋白质。令人惊讶的是，基于气相色谱-质谱的野生型和自噬缺陷的初级足细胞的非靶向代谢组学揭示了自噬本身维持多胺代谢和亚精胺合成的正反馈机制。转录因子MAFB是多胺代谢的上游调控因子。因此，我们的数据强调了一种新的自噬和亚精胺信号的正反馈回路，它允许维持高基础水平的自噬，作为维持过滤屏障的关键机制。因此，补充亚精胺可能成为恢复肾小球疾病自噬的一种新的治疗方法。
Podocyte maintenance and stress resistance are exquisitely based on high basal rates of autophagy making these cells a unique model to unravel mechanisms of autophagy regulation. Polyamines have key cellular functions such as proliferation, nucleic acid biosynthesis and autophagy. Here we test whether endogenous spermidine signaling is a driver of basal and dynamic autophagy in podocytes by using genetic and pharmacologic approaches to interfere with different steps of polyamine metabolism. Translational studies revealed altered spermidine signaling in focal segmental glomerulosclerosis in vivo and in vitro. Exogenous spermidine supplementation emerged as new treatment strategy by successfully activating autophagy in vivo via inhibition of EP300, a protein with an essential role in controlling cell growth, cell division and prompting cells to differentiate to take on specialized functions. Surprisingly, gas chromatography-mass spectroscopy based untargeted metabolomics of wild type and autophagy deficient primary podocytes revealed a positive feedback mechanism whereby autophagy itself maintains polyamine metabolism and spermidine synthesis. The transcription factor MAFB acted as an upstream regulator of polyamine metabolism. Thus, our data highlight a novel positive feedback loop of autophagy and spermidine signaling allowing maintenance of high basal levels of autophagy as a key mechanism to sustain the filtration barrier. Hence, spermidine supplementation may emerge as a new therapeutic to restore autophagy in glomerular disease.