title: Autophagy influences glomerular disease   susceptibility and maintains podocyte   homeostasis in aging mice.
abstract: Injury and loss of podocytes are leading factors of glomerular disease and renal failure. The postmitotic podocyte is the primary glomerular target for toxic, immune, metabolic, and oxidant stress, but little is known about how this cell type copes with stress. Recently, autophagy has been identified as a major pathway that delivers damaged proteins and organelles to lysosomes in order to maintain cellular homeostasis. Here we report that podocytes exhibit an unusually high level of constitutive autophagy. Podocyte-specific deletion of autophagy-related 5 (Atg5) led to a glomerulopathy in aging mice that was accompanied by an accumulation of oxidized and ubiquitinated proteins, ER stress, and proteinuria. These changes resulted ultimately in podocyte loss and late-onset glomerulosclerosis. Analysis of pathophysiological conditions indicated that autophagy was substantially increased in glomeruli from mice with induced proteinuria and in glomeruli from patients with acquired proteinuric diseases. Further, mice lacking Atg5 in podocytes exhibited strongly increased susceptibility to models of glomerular disease. These findings highlight the importance of induced autophagy as a key homeostatic mechanism to maintain podocyte integrity. We postulate that constitutive and induced autophagy is a major protective mechanism against podocyte aging and glomerular injury, representing a putative target to ameliorate human glomerular disease and aging-related loss of renal function.
authors.affiliation: Renal Division, University Hospital Freiburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Hartleben
authors.forename: Markus
authors.initials: M
authors.lastname: Gödel
authors.forename: Catherine
authors.initials: C
authors.lastname: Meyer-Schwesinger
authors.forename: Shuya
authors.initials: S
authors.lastname: Liu
authors.forename: Theresa
authors.initials: T
authors.lastname: Ulrich
authors.forename: Sven
authors.initials: S
authors.lastname: Köbler
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wiech
authors.forename: Florian
authors.initials: F
authors.lastname: Grahammer
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Arnold
authors.forename: Maja T
authors.initials: MT
authors.lastname: Lindenmeyer
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.forename: Dontscho
authors.initials: D
authors.lastname: Kerjaschki
authors.forename: Noboru
authors.initials: N
authors.lastname: Mizushima
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Shaw
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D002478:Cells, Cultured; D004198:Disease Susceptibility; D006706:Homeostasis; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology*; D007678:Kidney Glomerulus / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000502:physiology; D050199:Podocytes / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D011507:Proteinuria / Q000209:etiology; D013312:Stress, Physiological; D054875:Ubiquitination
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D046988:Proteasome Endopeptidase Complex