Podocyte injury plays a key role in the occurrence and development of kidney diseases. Decreased autophagic activity in podocyte is closely related to its injury and the occurrence of proteinuria. Liver X receptors (LXRs), as metabolic nuclear receptors, participate in multiple pathophysiological processes and express in several tissues, including podocytes. Although the functional roles of LXRs in the liver, adipose tissue and intestine are well established; however, the effect of LXRs on podocytes function remains unclear. In this study, we used mouse podocytes cell line to investigate the effects of LXR activation on podocytes autophagy level and related signaling pathway by performing Western blotting, RT-PCR, GFP-mRFP-LC3 transfection, and immunofluorescence staining. Then, we tested this effect in STZ-induced diabetic mice. Transmission electron microscopy and immunohistochemistry were employed to explore the effects of LXR activation on podocytes function and autophagic activity. We found that LXR activation could inhibit autophagic flux through blocking the formation of autophagosome in podocytes in vitro which was possibly achieved by affecting AMPK, mTOR, and SIRT1 signaling pathways. Furthermore, LXR activation in vivo induced autophagy suppression in glomeruli, leading to aggravated podocyte injury. In summary, our findings indicated that activation of LXRs induced autophagy suppression, which in turn contributed to the podocyte injury.

中文翻译：

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肝X受体的激活通过抑制自噬活性诱导足细胞损伤。

足细胞损伤在肾脏疾病的发生和发展中起关键作用。足细胞自噬活性的降低与其损伤和蛋白尿的发生密切相关。肝脏X受体（LXR）作为代谢核受体，参与多种病理生理过程并在包括足细胞在内的多个组织中表达。尽管LXRs在肝脏，脂肪组织和肠中的功能作用已得到很好的确立；但是，LXR对足细胞功能的影响尚不清楚。在这项研究中，我们使用小鼠足细胞细胞系通过进行Western印迹，RT-PCR，GFP-mRFP-LC3转染和免疫荧光染色来研究LXR激活对足细胞自噬水平和相关信号通路的影响。然后，我们在STZ诱导的糖尿病小鼠中测试了这种作用。透射电镜和免疫组织化学被用来探讨LXR激活对足细胞功能和自噬活性的影响。我们发现，LXR激活可通过阻断体外足细胞中自噬体的形成来抑制自噬通量，这可能是通过影响AMPK，mTOR和SIRT1信号通路来实现的。此外，体内LXR激活诱导肾小球自噬抑制，导致严重的足细胞损伤。总之，我们的发现表明LXRs的激活诱导自噬抑制，进而导致足细胞损伤。我们发现，LXR激活可通过阻断体外足细胞中自噬体的形成来抑制自噬通量，这可能是通过影响AMPK，mTOR和SIRT1信号通路来实现的。此外，体内LXR激活诱导肾小球自噬抑制，导致严重的足细胞损伤。总之，我们的发现表明LXRs的激活诱导自噬抑制，进而导致足细胞损伤。我们发现，LXR激活可通过阻断体外足细胞中自噬体的形成来抑制自噬通量，这可能是通过影响AMPK，mTOR和SIRT1信号通路来实现的。此外，体内LXR激活诱导肾小球自噬抑制，导致足细胞损伤加重。总之，我们的发现表明LXRs的激活诱导自噬抑制，进而导致足细胞损伤。