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 autophagyrelated 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.

Dietary fat composition influences glomerular and proximal convoluted tubule cell structure and autophagic processes in kidneys from calorie-restricted mice

“…Electron microscopy images showing typical structures of autophagy (see, for example, Hartleben et al ., 2010 and Kume et al ., 2010) were found in podocytes (Fig. 5A,B) and in PCT epithelial cells (Fig.…”

“…Moreover, our results show a negative correlation between GBM thickness and FS width in our animal model. On the other hand, it has been shown that aging induces expansion of podocyte processes (Wiggins et al ., 2005; Hartleben et al ., 2010), a phenomenon that could result in the reduction of FS width. In our control animals, aging also induced podocyte processes expansion, a phenomenon that was partially prevented by CR.…”

“…Furthermore, our results show a negative correlation between PFP and FS width indicating that the narrowed FS found during aging can be due to PFP expansion. We also found a positive correlation between PFP width and GBM thickness during aging, two phenomena considered as hallmarks of glomerular aging (Wiggins et al ., 2005; McKiernan et al ., 2007; Hartleben et al ., 2010; Bolignano et al ., 2014). To our best knowledge, this is the first report showing a narrowing in FS which correlated with increased GBM thickness and PFP expansion during aging.…”

“…In kidney, decreased autophagy has been related to glomerulosclerosis, tubular atrophy, and interstitial fibrosis, and two different renal cell types have been reported to display autophagic activity depending on the physiological conditions: podocytes and PCT cells (Hartleben et al ., 2010; Kume et al ., 2010). In rodent kidney, aging has been shown to decrease phagocytic activity, a phenomenon that can be partially reverted by CR (Kume et al ., 2010; Cui et al ., 2012, 2013).…”

Autophagy supports survival and phototransduction protein levels in rod photoreceptors

“…6 Induced autophagy maintains the amino acid pool inside cells to adapt to starvation while constitutive autophagy has been shown to function as a cell-repair mechanism that is important for long-lived postmitotic cells. [7][8][9][10][11] Defects in autophagy have been associated with neurodegenerative diseases, [12][13][14][15] diabetes, 16,17 lysosomal storage disease 18 and the loss of vision. 19 In addition to macroautophagy, microautophagy and chaperone-mediated autophagy (CMA) have been described.…”