Liver X receptor activation induces podocyte injury via inhibiting autophagic activity
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ORIGINAL ARTICLE
Liver X receptor activation induces podocyte injury via inhibiting autophagic activity Ziyi Zhang 1 & Shengjie Tang 1 & Weiwei Gui 1 & Xihua Lin 1 & Fenping Zheng 1 & Fang Wu 1 & Hong Li 1 Received: 5 August 2019 / Accepted: 17 March 2020 # University of Navarra 2020
Abstract 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. Keywords Liver X receptors . Autophagy . Podocytes . Kidney . STZ
Introduction Proteinuria is a major characteristic of chronic kidney disease (CKD) and is caused by disruption of glomerular filtration barrier (GFB) which is consisted of three layers: the glomerular endothelium, the glomerular basement membrane, and podocytes. Podocytes are highly specialized and terminally differentiated. Abnormalities of podocytes including podocyte loss or podocyte foot process dysfunction lead to massive Key points 1. Liver X receptor activation gets involved in the progress of podocyte injury through suppressing the autophagic activity both in vivo and in vitro. 2. This effect was possibly achieved by affecting AMPK, mTOR, and SIRT1 signaling pathways. * Hong Li [email protected] 1
Department of Endocrinology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Hangzhou 310016, China
proteinuria and eventually glomerulosclerosis in CKD, including diabetic kidney disease (DKD) [23, 27]. Therefore, maintaining homeostasis and cell integrity of podocytes are essential in preventing progression of kidney diseases. Autophagy is a homeostatic cellular process through which aggregated cellular protein and damaged organelles are degraded via the lysosomal
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