title: Thioredoxin interacting protein (TXNIP) regulates tubular autophagy and mitophagy in diabetic nephropathy through the mTOR signaling pathway.
abstract: Hyperglycemia upregulates thioredoxin interacting protein (TXNIP) expression, which in turn induces ROS production, inflammatory and fibrotic responses in the diabetic kidney. Dysregulation of autophagy contributes to the development of diabetic nephropathy. However, the interaction of TXNIP with autophagy/mitophagy in diabetic nephropathy is unknown. In this study, streptozotocin-induced diabetic rats were given TXNIP DNAzyme or scrambled DNAzyme for 12 weeks respectively. Fibrotic markers, mitochondrial function and mitochondrial reactive oxygen species (mtROS) were assessed in kidneys. Tubular autophagy and mitophagy were determined in kidneys from both human and rats with diabetic nephropathy. TXNIP and autophagic signaling molecules were examined. TXNIP DNAzyme dramatically attenuated extracellular matrix deposition in the diabetic kidneys compared to the control DNAzyme. Accumulation of autophagosomes and reduced autophagic clearance were shown in tubular cells of human diabetic compared to non-diabetic kidneys, which was reversed by TXNIP DNAzyme. High glucose induced mitochondrial dysfunction and mtROS production, and inhibited mitophagy in proximal tubular cells, which was reversed by TXNIP siRNA. TXNIP inhibition suppressed diabetes-induced BNIP3 expression and activation of the mTOR signaling pathway. Collectively, hyperglycemia-induced TXNIP contributes to the dysregulation of tubular autophagy and mitophagy in diabetic nephropathy through activation of the mTOR signaling pathway.
authors.affiliation: Kolling Institute, Sydney Medical School Northern, University of Sydney, Royal North Shore Hospital, St Leonards, Sydney, NSW, 2065, Australia.
authors.forename: Chunling
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, VIC, 3065, Australia.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, VIC, 3065, Australia.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.affiliation: Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, VIC, 3065, Australia.
authors.forename: Christina Y R
authors.initials: CY
authors.lastname: Tan
authors.affiliation: Department of Anatomical Pathology, Australia and Cancer Diagnosis and Pathology Group, Kolling Institute, Royal North Shore Hosptial, St Leonards, Sydney, NSW, 2065, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Gill
authors.affiliation: School of Medical Sciences (Discipline of Anatomy and Histology)-The Bosch Institute, University of Sydney,Sydney, NSW, 2006, Australia.
authors.forename: Delfine
authors.initials: D
authors.lastname: Cheng
authors.affiliation: School of Medical Sciences (Discipline of Anatomy and Histology)-The Bosch Institute, University of Sydney,Sydney, NSW, 2006, Australia.|Australian Centre for Microscopy &Microanalysis, Madsen Building, University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: Filip
authors.initials: F
authors.lastname: Braet
authors.affiliation: Department of Neurogenetics, Kolling Institute, Northern Sydney Local Health District, Sydney Medical School - Northern, University of Sydney, St Leonards, Sydney, NSW, 2065, Australia.
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Neurogenetics, Kolling Institute, Northern Sydney Local Health District, Sydney Medical School - Northern, University of Sydney, St Leonards, Sydney, NSW, 2065, Australia.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Sue
authors.affiliation: Kolling Institute, Sydney Medical School Northern, University of Sydney, Royal North Shore Hospital, St Leonards, Sydney, NSW, 2065, Australia.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Pollock
authors.affiliation: Kolling Institute, Sydney Medical School Northern, University of Sydney, Royal North Shore Hospital, St Leonards, Sydney, NSW, 2065, Australia.
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Chen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D005947:Glucose / Q000633:toxicity; D007684:Kidney Tubules / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism; D063306:Mitophagy / Q000187:drug effects; D051381:Rats; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D024042:Collagen Type I; D005947:Glucose; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D000071456:Sequestosome-1 Protein; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C505650:BNIP3 protein, rat; C526109:Anxa3 protein, rat; C491079:Sqstm1 protein, rat; C486715:TXNIP protein, human; C493796:TXNIP protein, rat