Alterations in the ubiquitin proteasome system in persistent but not reversible proteinuric diseases.
Podocytes are the key cells affected in nephrotic glomerular kidney diseases, and they respond uniformly to injury with cytoskeletal rearrangement. In nephrotic diseases, such as membranous nephropathy and FSGS, persistent injury often leads to irreversible structural damage, whereas in minimal change disease, structural alterations are mostly transient. The factors leading to persistent podocyte injury are currently unknown. Proteolysis is an irreversible process and could trigger persistent podocyte injury through degradation of podocyte-specific proteins. We, therefore, analyzed the expression and functional consequence of the two most prominent proteolytic systems, the ubiquitin proteasome system (UPS) and the autophagosomal/lysosomal system, in persistent and transient podocyte injuries. We show that differential upregulation of both proteolytic systems occurs in persistent human and rodent podocyte injury. The expression of specific UPS proteins in podocytes differentiated children with minimal change disease from children with FSGS and correlated with poor clinical outcome. Degradation of the podocyte-specific protein α-actinin-4 by the UPS depended on oxidative modification in membranous nephropathy. Notably, the UPS was overwhelmed in podocytes during experimental glomerular disease, resulting in abnormal protein accumulation and compensatory upregulation of the autophagosomal/lysosomal system. Accordingly, inhibition of both proteolytic systems enhanced proteinuria in persistent nephrotic disease. This study identifies altered proteolysis as a feature of persistent podocyte injury. In the future, specific UPS proteins may serve as new biomarkers or therapeutic targets in persistent nephrotic syndrome.
Departments of Internal Medicine, Nephrology.
Maire
M
Beeken
Institute of Physiology and Division of Nephrology, University of Zurich, Zurich, Switzerland;
Maja T
MT
Lindenmeyer
Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan; and.
Simone M
SM
Blattner
Departments of Internal Medicine, Nephrology.
Victoria
V
Radón
Pediatrics, Nephrology.
Jun
J
Oh
Department of Internal Medicine, Nephrology, University Affiliated Asklepios Clinic Hamburg Barmbek, Hamburg, Germany.
Tobias N
TN
Meyer
Clinical Chemistry, Mass Spectrometry and Proteome Analysis, and.
Diana
D
Hildebrand
Clinical Chemistry, Mass Spectrometry and Proteome Analysis, and.
Hartmut
H
Schlüter
Departments of Internal Medicine, Nephrology.
Anna T
AT
Reinicke
Departments of Internal Medicine, Nephrology.
Jan-Hendrik
JH
Knop
Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan; and.
Anuradha
A
Vivekanandan-Giri
Departments of Internal Medicine, Nephrology.
Silvia
S
Münster
Departments of Internal Medicine, Nephrology.
Marlies
M
Sachs
Pathology, Division of Renal Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
Thorsten
T
Wiech
Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan; and.
Subramaniam
S
Pennathur
Institute of Physiology and Division of Nephrology, University of Zurich, Zurich, Switzerland;
Clemens D
CD
Cohen
Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan; and.
Matthias
M
Kretzler
Departments of Internal Medicine, Nephrology.
Rolf A K
RA
Stahl
Departments of Internal Medicine, Nephrology, c.meyer-schwesinger@uke.uni-hamburg.de.
Catherine
C
Meyer-Schwesinger
D000185:Actinin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000502:physiology; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017208:Rats, Wistar; D059467:Transcriptome; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
C111453:ACTN4 protein, human; C491751:Actn4 protein, rat; D025801:Ubiquitin; D000185:Actinin; D046988:Proteasome Endopeptidase Complex