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Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice
Björn Hartleben, … , Gerd Walz, Tobias B. Huber
Björn Hartleben, … , Gerd Walz, Tobias B. Huber
Published March 1, 2010
Citation Information: J Clin Invest. 2010;120(4):1084-1096. https://doi.org/10.1172/JCI39492.
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Research Article Nephrology

Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice

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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

Björn Hartleben, Markus Gödel, Catherine Meyer-Schwesinger, Shuya Liu, Theresa Ulrich, Sven Köbler, Thorsten Wiech, Florian Grahammer, Sebastian J. Arnold, Maja T. Lindenmeyer, Clemens D. Cohen, Hermann Pavenstädt, Dontscho Kerjaschki, Noboru Mizushima, Andrey S. Shaw, Gerd Walz, Tobias B. Huber

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Figure 3

Functional cross-talk between the ubi­quitin proteasome pathway and autophagy in podocytes.

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Functional cross-talk between the ubi­quitin proteasome pathway and auto...
(A) Results from a 12-month follow-up of Atg5Δpodocyte mice for proteinuria (2- to 4-month-old mice: n = 6 control mice, n = 8 Atg5Δpodocyte mice; 8- to 12-month-old mice: n = 34 control mice, n = 33 Atg5Δpodocyte mice; ***P < 0.0001 by 1-tailed Mann-Whitney U test, z = 4.16). (B) No obvious histological phenotype in 2- to 4-month-old mice or in 8- to 12-month-old mice. (C and D) Electron microscopy analysis identified significant changes including vacuolar degeneration and ER extension (arrows indicate vacuoles) in 8- to 12-month-old Atg5Δpodocyte mice. (E) There was no accumulation of ubiquitinated proteins in glomerulus lysate of 8-month-old Atg5Δpodocyte mice. (F) Significant increase of proteasome activity in glomerulus lysate of 8-month-old Atg5Δpodocyte mice (***P < 0.001, by ANOVA/Scheffe test; glomeruli from n = 3 control mice and n = 3 Atg5Δpodocyte mice). (G) Significant decrease of proteasome activity in total kidney lysate of wild-type mice 24 hours after intravenous injection with the proteasome inhibitor bortezomib compared with control mice injected with 0.9% NaCl (**P < 0.01, by 2-tailed Student’s t test, kidney lysates from n = 3 control and n = 6 bortezomib mice). (H) Significant albuminuria of Atg5Δpodocyte mice 24 hours after bortezomib injection (*P < 0.05, by 2-tailed Student’s t test; n = 4 control and n = 3 Atg5Δpodocyte mice). (I and J) Inhibition of the proteasome with MG132 in differentiated podocytes resulted in an increase of converted LC3-II protein and an accumulation of GFP-LC3–positive autophagosomes. Scale bars: 20 μm (B and J), 1 μm (C, top), 200 nm (C, bottom), 2 μm (D); 10 μm (J, insets).

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