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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-35305

Hartleben, B; Gödel, M; Meyer-Schwesinger, C; Liu, S; Ulrich, T; Köbler, S; Wiech, T; Grahammer, F; Arnold, S J; Lindenmeyer, M T; Cohen, C D; Pavenstädt, H; Kerjaschki, D; Mizushima, N; Shaw, A S; Walz, G; Huber, T B (2010). Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. Journal of Clinical Investigation, 120(4):1084-1096.

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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.


202 citations in Web of Science®
226 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Nephrology
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Deposited On:03 Aug 2010 12:01
Last Modified:05 Apr 2016 14:13
Publisher:American Society for Clinical Investigation
Publisher DOI:10.1172/JCI39492
PubMed ID:20200449

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