title: Doxorubicin-induced glomerulosclerosis with proteinuria in GFP-GABARAP transgenic mice.
abstract: Autophagy is a process of cellular degradation, and its dysfunction elicits many pathological symptoms. However, the contribution of autophagy to kidney glomerular function has not been fully clarified. We previously reported that LC3, a promising executor of autophagy, played an important role in recovery from podocyte damage in an experimental nephrosis model (Asanuma K, Tanida I, Shirato I, Ueno T, Takahara H, Nishitani T, Kominami E, Tomino Y. FASEB J 17: 1165-1167, 2003). γ-Aminobutyric acid A receptor-associated protein (GABARAP), has recently been characterized as another homolog of LC3, although its precise role in autophagy remains unclear. We recently generated green fluorescent protein (GFP)-GABARAP transgenic mice, in which GFP-GABARAP is abundantly expressed in glomerular podocytes. We found that the transgenic mice showed no obvious phenotype, and podocytes isolated from these mice manifested autophagic activity almost equivalent to that of wild-type mice when measured in vitro. Surprisingly, a single injection of doxorubicin caused a greater increase in proteinuria and sclerotic glomeruli in transgenic mice compared with wild-type mice. Under these conditions, neither GFP-GABARAP nor endogenous GABARAP appeared to be recruited to autophagosomes, and both remained in the cytosol. Moreover, the cytosolic GFP-GABARAP was significantly colocalized with p62 to form aggregates. These results indicate that the GFP-GABARAP/p62 complex is responsible for impairment of glomerular function and that it retards recovery from the effects of doxorubicin.
authors: Div. of Nephrology, Dept. of Internal Medicine, Juntendo Univ., Hongo, Bunkyo-ku, Tokyo, Japan.
authors: Miyuki
authors: M
authors: Takagi-Akiba
authors: Katsuhiko
authors: K
authors: Asanuma
authors: Isei
authors: I
authors: Tanida
authors: Norihiro
authors: N
authors: Tada
authors: Juan Alejandro
authors: JA
authors: Oliva Trejo
authors: Kanae
authors: K
authors: Nonaka
authors: Etsuko
authors: E
authors: Asanuma
authors: Eiki
authors: E
authors: Kominami
authors: Takashi
authors: T
authors: Ueno
authors: Yasuhiko
authors: Y
authors: Tomino
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins; D050199:Podocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D011247:Pregnancy; D011507:Proteinuria / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D003598:Cytoskeletal Proteins; C480861:GABARAP protein, mouse; C490981:Gtf2h1 protein, mouse; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D051758:Transcription Factor TFIIH; D004317:Doxorubicin