title: Autophagy inhibition induces podocyte apoptosis by activating the pro-apoptotic pathway of endoplasmic reticulum stress.
abstract: Podocyte apoptosis is a major factor inducing podocyte depletion that predicts the progressive course of glomerulosclerosis. However, the molecular mechanisms underlying podocyte apoptosis are still not well understood. Autophagy is a lysosomal degradation system involving the degradation and recycling of obsolete, damaged, or harmful cytoplasmic materials and organelles. Recent advances in the understanding of the molecular processes contributing to autophagy have provided insight into the relationship between autophagy and apoptosis. However, their cross-talk remains largely obscure until now. Here, we found that podocytes both in vivo and in vitro always exhibited high basal levels of autophagy, whereas autophagy inhibition could induce podocyte apoptosis, suggesting the pro-survival role of autophagy in podocytes. Besides, we found that autophagy inhibition by 3-methyladenine (3-MA) could induce the activation of endoplasmic reticulum stress even without any external stimulations, whereas knockdown of CHOP could effectively improve podocyte apoptosis and down-regulated expression of slit-diaphragm proteins induced by autophagy inhibition. Collectively, this study demonstrated that autophagy might act as a crucial regulatory mechanism of apoptotic cell death by modulating the balance between the pro-survival pathway and the pro-apoptotic pathway of endoplasmic reticulum stress, which might provide a novel mechanistic insight into the interface between autophagy and apoptosis in the progression of podocyte injury.
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing 210003, Jiangsu Province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Fang
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing 210003, Jiangsu Province, China.
authors.forename: Xiurong
authors.initials: X
authors.lastname: Li
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing 210003, Jiangsu Province, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing 210003, Jiangsu Province, China.
authors.forename: Weichun
authors.initials: W
authors.lastname: He
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing 210003, Jiangsu Province, China.
authors.forename: Chunsun
authors.initials: C
authors.lastname: Dai
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing 210003, Jiangsu Province, China. Electronic address: jwyang@njmu.edu.cn.
authors.forename: Junwei
authors.initials: J
authors.lastname: Yang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005921:Glomerulonephritis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D050199:Podocytes / Q000187:drug effects / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C497249:DDIT3 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051742:Transcription Factor CHOP; C025946:3-methyladenine; D000225:Adenine
keywords: Apoptosis; Autophagy; Endoplasmic reticulum stress; Podocyte