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

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 5

ER stress and the accumulation of oxidized and ubiquitinated protein aggregates result in a loss of podocytes in Atg5Δpodocyte mice.

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ER stress and the accumulation of oxidized and ubiquitinated protein agg...
(A) Vacuolized podocytes stained positive for the ER marker calnexin (arrows indicate podocytes). (B) ER stress was confirmed by the increased detection of the ER stress marker GRP94 from lysates of isolated glomeruli. (C) The proteasomal activity of glomerular lysates of 22-month-old Atg5Δpodocyte mice was significantly reduced compared with control mice (***P < 0.001, by ANOVA/Scheffe test: glomeruli from n = 3 control and n = 3 Atg5Δpodocyte mice). (D) Short exposures of Western blots with glomerular lysates from 22-month-old control and Atg5Δpodocyte mice showed a significant accumulation of poly-ubiquitinated proteins. (E and F) Accumulation of the ubiquitin-associated protein p62 in Atg5Δpodocyte mice (arrows indicate podocytes). (G and H) Glomeruli from 22-month-old Atg5Δpodocyte mice accumulated oxidized proteins (*P = 0.0186, by 2-tailed Student’s t test, glomeruli from n = 3 control and n = 3 Atg5Δpodocyte mice) and significantly upregulated the podocyte stress marker UCH-L1. (I) Loss of podocytes was reflected by reduced podocyte numbers per glomeruli in non-sclerosed glomeruli of 22-month-old Atg5Δpodocyte mice compared with control mice (**P = 0.0026, by 2-tailed Student’s t test, glomeruli from n = 3 control and n = 3 Atg5Δpodocyte mice; 30 glomeruli for each mouse were analyzed). Scale bars: 5 μm (A), 5 μm (E).