Forkhead Box O3 (FoxO3) Regulates Kidney Tubular Autophagy Following Urinary Tract Obstruction [Cell Biology]

Autophagy has been shown to be important for normal homeostasis and adaptation to stress in the kidney. Yet, the molecular mechanisms regulating renal epithelial autophagy are not fully understood. Here, we explored the role of the stress-responsive transcription factor forkhead box O3 (FoxO3) in mediating injury-induced proximal tubular autophagy in mice with unilateral ureteral obstruction (UUO). We show that following UUO, FoxO3 is activated and displays nuclear expression in the hypoxic proximal tubules exhibiting high levels of autophagy. Activation of FoxO3 by mutating phosphorylation sites to enhance its nuclear expression induces profound autophagy in cultured renal epithelial cells. Conversely, deleting FoxO3 in mice results in fewer numbers of autophagic cells in the proximal tubules and reduced ratio of the autophagy-related protein LC3-II/I in the kidney post-UUO. Interestingly, autophagic cells deficient in FoxO3 contain lower numbers of autophagic vesicles per cell. Analyses of individual cells treated with autophagic inhibitors to sequentially block the autophagic flux suggest that FoxO3 stimulates the formation of autophagosomes to increase autophagic capacity but has no significant effect on autophagosome-lysosome fusion or autolysosomal clearance. Furthermore, in kidneys with persistent UUO for 7 days, FoxO3 activation increases the abundance of mRNA and protein levels of the core autophagy-related (Atg) proteins including Ulk1, Beclin-1, Atg9A, Atg4B and Bnip3, suggesting that FoxO3 may function to maintain components of the autophagic machinery that would otherwise be consumed during prolonged autophagy. Taken together, our findings indicate that FoxO3 activation can both induce and maintain autophagic activities in renal epithelial cells in response to injury from urinary tract obstruction.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2viEbzK
via IFTTT