title: The renoprotective role of autophagy activation in proximal tubular epithelial cells in diabetic nephropathy.
abstract: With intensive investigations recently, autophagy is hoped to be a potential therapeutic target to prevent or alleviate diabetic nephropathy (DN). Our previous study revealed that lipotoxicity participated in epithelial-to-mesenchymal transition (EMT) of proximal tubular epithelial cells (PTECs) under diabetic conditions. Based on evidences that autophagy and lipid metabolism are closely related, we investigated autophagy under diabetic conditions and how it contributed in the lipotoxicity and EMT. In high-glucose-cultured PTECs, we found that Beclin1 and LC3-II were elevated, while p62 was decreased. These results indicate that autophagy activity was elevated under diabetic conditions. Autophagy deficiency induced by autophagy inhibitors, chloroquine diphosphate (CQ) and 3-Methyladenine (3-MA), and by Atg5 siRNA transfection exacerbated lipid accumulation and EMT. This supports that the elevated autophagy activity acts as a renoprotective response under diabetic conditions. Treatment of rapamycin, which is a mammalian target of rapamycin (mTOR) receptor-specific inhibitor and a known autophagy activator, attenuated high-glucose-induced lipid accumulation and EMT. The Atg5 silence counteracted the protective effect of rapamycin. The present study deepens our understanding of the role of autophagy in DN, suggesting a complex interplay of autophagy, metabolic pathways, lipotoxicity and EMT.
authors: Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors: Ying
authors: Y
authors: Xu
authors: School of Medicine, Shandong University, Jinan, China.
authors: Lei
authors: L
authors: Liu
authors: Center Lab of Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors: Wei
authors: W
authors: Xin
authors: School of Medicine, Shandong University, Jinan, China.
authors: Xu
authors: X
authors: Zhao
authors: Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China.
authors: Liyong
authors: L
authors: Chen
authors: Department of Pathology, Shandong University School of Medicine, Jinan, Shandong, China.
authors: Junhui
authors: J
authors: Zhen
authors: Department of Nephrology, Shandong Provincial Qianfoshan Hospital Affiliated to Shandong University, Jinan, China. Electronic address: wanyanshaoqiang@163.com.
authors: Qiang
authors: Q
authors: Wan
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D015415:Biomarkers / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000031:analogs & derivatives / Q000494:pharmacology; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D007202:Indicators and Reagents / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008565:Membrane Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C502778:ATG5 protein, human; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; D015415:Biomarkers; D007202:Indicators and Reagents; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C118585:P62 protein, human; D047428:Protein Kinase Inhibitors; D016601:RNA-Binding Proteins; C025946:3-methyladenine; C023676:chloroquine diphosphate; D002738:Chloroquine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000225:Adenine; D020123:Sirolimus
keywords: Autophagy; Diabetic nephropathy; Epithelial-to-mesenchymal transition; Lipotoxicity; Rapamycin