title: The impact of autophagy on the development of senescence in primary tubular epithelial cells.
abstract: Autophagy and senescence are 2 distinct pathways that are importantly involved in acute kidney injury and renal repair. Recent data indicate that the 2 processes might be interrelated. To investigate the potential link between autophagy and senescence in the kidney we isolated primary tubular epithelial cells (PTEC) from wild-type mice and monitored the occurrence of cellular senescence during autophagy activation and inhibition. We found that the process of cell isolation and transfer into culture was associated with a strong basal autophagic activation in PTEC. Specific inhibition of autophagy by silencing autophagy-related 5 (Atg5) counteracted the occurrence of senescence hallmarks under baseline conditions. Reduced senescent features were also observed in Atg5 silenced PTEC after γ-irradiation and during H-Ras induced oncogenic senescence, but the response was less uniform in these stress models. Senescence inhibition was paralleled by better preservation of a mature epithelial phenotype in PTEC. Interestingly, treatment with rapamycin, which acts as an activator of autophagy, also counteracted the occurrence of senescence features in PTEC. While we interpret the anti-senescent effect of rapamycin as an autophagy-independent effect of mTOR-inhibition, the more specific approach of Atg5 silencing indicates that overactivated autophagy can have pro-senescent effects in PTEC. These results highlight the complex interaction between cell culture dependent stress mechanisms, autophagy and senescence.
authors.affiliation: a Department of Nephrology , Children's Hospital , Hannover , Germany.|b Department of Kidney , Liver and Metabolic Diseases, Children's Hospital , Hannover , Germany.
authors.forename: Arpita
authors.initials: A
authors.lastname: Baisantry
authors.affiliation: a Department of Nephrology , Children's Hospital , Hannover , Germany.
authors.forename: Sagar
authors.initials: S
authors.lastname: Bhayana
authors.affiliation: c Institute of Functional and Applied Anatomy, Hannover Medical School , Hannover , Germany.|d Cluster of Excellence REBIRTH (Regenerative Biology to Reconstructive Therapy), Hannover Medical School , Hannover , Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wrede
authors.affiliation: c Institute of Functional and Applied Anatomy, Hannover Medical School , Hannover , Germany.|d Cluster of Excellence REBIRTH (Regenerative Biology to Reconstructive Therapy), Hannover Medical School , Hannover , Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Hegermann
authors.affiliation: a Department of Nephrology , Children's Hospital , Hannover , Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.affiliation: b Department of Kidney , Liver and Metabolic Diseases, Children's Hospital , Hannover , Germany.
authors.forename: Anette
authors.initials: A
authors.lastname: Melk
authors.affiliation: a Department of Nephrology , Children's Hospital , Hannover , Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Schmitt
mesh_terms: D000818:Animals; D001343:Autophagy; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D007684:Kidney Tubules / Q000166:cytology*; D008810:Mice, Inbred C57BL; D010641:Phenotype; D013312:Stress, Physiological
chemical_list: D015415:Biomarkers
keywords: Autophagy; chloroquine; p16INK4a; rapamycin; senescence; tubular epithelial cells