title: Autophagy Inhibits the Accumulation of Advanced Glycation End Products by Promoting Lysosomal Biogenesis and Function in the Kidney Proximal Tubules.
abstract: Advanced glycation end products (AGEs) are involved in the progression of diabetic nephropathy. AGEs filtered by glomeruli or delivered from the circulation are endocytosed and degraded in the lysosomes of kidney proximal tubular epithelial cells (PTECs). Autophagy is a highly conserved degradation system that regulates intracellular homeostasis by engulfing cytoplasmic components. We have recently demonstrated that autophagic degradation of damaged lysosomes is indispensable for cellular homeostasis in some settings. In this study, we tested the hypothesis that autophagy could contribute to the degradation of AGEs in the diabetic kidney by modulating lysosomal biogenesis. Both a high-glucose and exogenous AGE overload gradually blunted autophagic flux in the cultured PTECs. AGE overload upregulated lysosomal biogenesis and function in vitro, which was inhibited in autophagy-deficient PTECs because of the impaired nuclear translocation of transcription factor EB. Consistently, streptozotocin-treated, PTEC-specific, autophagy-deficient mice failed to upregulate lysosomal biogenesis and exhibited the accumulation of AGEs in the glomeruli and renal vasculature as well as in the PTECs, along with worsened inflammation and fibrosis. These results indicate that autophagy contributes to the degradation of AGEs by the upregulation of lysosomal biogenesis and function in diabetic nephropathy. Strategies aimed at promoting lysosomal function hold promise for treating diabetic nephropathy.
authors.affiliation: Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan takaba@kid.med.osaka-u.ac.jp.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Takabatake
authors.affiliation: Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Laboratory of Molecular Traffic, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Maejima
authors.affiliation: Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Namba
authors.affiliation: Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Matsuda
authors.affiliation: Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Minami
authors.affiliation: Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Jun-Ya
authors.initials: JY
authors.lastname: Kaimori
authors.affiliation: Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Matsui
authors.affiliation: Institute of Medical Science and Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.affiliation: Department of Pediatrics, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Niimura
authors.affiliation: Department of Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Yoshimori
authors.affiliation: Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Isaka
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D000071187:Autophagy-Related Protein 5 / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D004705:Endocytosis; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D001678:Organelle Biogenesis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D001786:Blood Glucose; D017127:Glycation End Products, Advanced; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D005947:Glucose