title: Deficient Autophagy Results in Mitochondrial Dysfunction and FSGS.
abstract: FSGS is a heterogeneous fibrosing disease of the kidney, the cause of which remains poorly understood. In most cases, there is no effective treatment to halt or retard progression to renal failure. Increasing evidence points to mitochondrial dysfunction and the generation of reactive oxygen species in the pathogenesis of CKD. Autophagy, a major intracellular lysosomal degradation system, performs homeostatic functions linked to metabolism and organelle turnover. We prevented normal autophagic pathways in nephrons of mice by mutating critical autophagy genes ATG5 or ATG7 during nephrogenesis. Mutant mice developed mild podocyte and tubular dysfunction within 2 months, profound glomerular and tubular changes bearing close similarity to human disease by 4 months, and organ failure by 6 months. Ultrastructurally, podocytes and tubular cells showed vacuolization, abnormal mitochondria, and evidence of endoplasmic reticulum stress, features that precede the appearance of histologic or clinical disease. Similar changes were observed in human idiopathic FSGS kidney biopsy specimens. Biochemical analysis of podocytes and tubules of 2-month-old mutant mice revealed elevated production of reactive oxygen species, activation of endoplasmic reticulum stress pathways, phosphorylation of p38, and mitochondrial dysfunction. Furthermore, cultured proximal tubule cells isolated from mutant mice showed marked mitochondrial dysfunction and elevated mitochondrial reactive oxygen species generation that was suppressed by a mitochondrial superoxide scavenger. We conclude that mitochondrial dysfunction and endoplasmic reticulum stress due to impaired autophagic organelle turnover in podocytes and tubular epithelium are sufficient to cause many of the manifestations of FSGS in mice.
authors.affiliation: Division of Nephrology, Departments of Medicine & Pathology, and Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; Division of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan;
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kawakami
authors.affiliation: Division of Nephrology, Departments of Medicine & Pathology, and Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; Division of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan;
authors.forename: Ivan G
authors.initials: IG
authors.lastname: Gomez
authors.affiliation: Division of Nephrology, Departments of Medicine & Pathology, and Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; Biogen Idec, Inc., Cambridge, Massachusetts; and.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Ren
authors.affiliation: Division of Nephrology, Departments of Medicine & Pathology, and.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hudkins
authors.affiliation: Division of Nephrology, Departments of Medicine & Pathology, and Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; Biogen Idec, Inc., Cambridge, Massachusetts; and.
authors.forename: Allie
authors.initials: A
authors.lastname: Roach
authors.affiliation: Division of Nephrology, Departments of Medicine & Pathology, and.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Alpers
authors.affiliation: Division of Nephrology, Departments of Medicine & Pathology, and.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Shankland
authors.affiliation: Department of Pathology, Columbia University, New York, New York.
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
authors.affiliation: Division of Nephrology, Departments of Medicine & Pathology, and Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; Biogen Idec, Inc., Cambridge, Massachusetts; and jeremy.duffield@biogenidec.com.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
mesh_terms: D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency* / Q000235:genetics; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D009154:Mutation; D050199:Podocytes / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012189:Retrospective Studies; D019459:Urothelium / Q000378:metabolism
chemical_list: C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D000071193:Autophagy-Related Protein 7
keywords: Autophagy; focal segmental glomerulosclerosis; mitochondria