Autophagy influences glomerular disease   susceptibility and maintains podocyte   homeostasis in aging mice.
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.
Hartleben
Björn
B
Renal Division, University Hospital Freiburg, Germany.
Gödel
Markus
M
Meyer-Schwesinger
Catherine
C
Liu
Shuya
S
Ulrich
Theresa
T
Köbler
Sven
S
Wiech
Thorsten
T
Grahammer
Florian
F
Arnold
Sebastian J
SJ
Lindenmeyer
Maja T
MT
Cohen
Clemens D
CD
Pavenstädt
Hermann
H
Kerjaschki
Dontscho
D
Mizushima
Noboru
N
Shaw
Andrey S
AS
Walz
Gerd
G
Huber
Tobias B
TB
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
C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D046988:Proteasome Endopeptidase Complex