title: Impaired Podocyte Autophagy Exacerbates Proteinuria in Diabetic Nephropathy.
abstract: Overcoming refractory massive proteinuria remains a clinical and research issue in diabetic nephropathy. This study was designed to investigate the pathogenesis of massive proteinuria in diabetic nephropathy, with a special focus on podocyte autophagy, a system of intracellular degradation that maintains cell and organelle homeostasis, using human tissue samples and animal models. Insufficient podocyte autophagy was observed histologically in patients and rats with diabetes and massive proteinuria accompanied by podocyte loss, but not in those with no or minimal proteinuria. Podocyte-specific autophagy-deficient mice developed podocyte loss and massive proteinuria in a high-fat diet (HFD)-induced diabetic model for inducing minimal proteinuria. Interestingly, huge damaged lysosomes were found in the podocytes of diabetic rats with massive proteinuria and HFD-fed, podocyte-specific autophagy-deficient mice. Furthermore, stimulation of cultured podocytes with sera from patients and rats with diabetes and massive proteinuria impaired autophagy, resulting in lysosome dysfunction and apoptosis. These results suggest that autophagy plays a pivotal role in maintaining lysosome homeostasis in podocytes under diabetic conditions, and that its impairment is involved in the pathogenesis of podocyte loss, leading to massive proteinuria in diabetic nephropathy. These results may contribute to the development of a new therapeutic strategy for advanced diabetic nephropathy.
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Tagawa
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Mako
authors.initials: M
authors.lastname: Yasuda
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan skume@belle.shiga-med.ac.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kume
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yamahara
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Nakazawa
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Chin-Kanasaki
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Hisazumi
authors.initials: H
authors.lastname: Araki
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Araki
authors.affiliation: Division of Diabetology and Endocrinology, Kanazawa Medical University, Kahoku-gun, Ishikawa, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
authors.affiliation: Laboratory for Kidney Research (TMK Project), Medical Innovation Center, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan Division of Nephrology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Asanuma
authors.affiliation: Division of Nephrology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan Osong Medical Innovation Foundation, Laboratory Animal Center, Cheongwon-gun, Chungbuk, Republic of Korea.
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Kim
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Hokkaido, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Haneda
authors.affiliation: Department of Nephrology, Ikeda City Hospital, Ikeda, Osaka, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kajiwara
authors.affiliation: Department of Nephrology, Ikeda City Hospital, Ikeda, Osaka, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Pathology, Ikeda City Hospital, Ikeda, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohashi
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ugi
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Uzu
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D015153:Blotting, Western; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D059305:Diet, High-Fat; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000069416:Intravital Microscopy; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D050199:Podocytes / Q000378:metabolism*; D011507:Proteinuria / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016601:RNA-Binding Proteins / Q000097:blood; D051381:Rats; D020318:Rats, Long-Evans; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; C407223:NPHS2 protein; C118585:P62 protein, human; D016601:RNA-Binding Proteins; C503968:Synpo protein, mouse; D000071193:Autophagy-Related Protein 7