Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments.
Evidence suggests that autophagy promotes the development of cellular senescence. Because cellular senescence contributes to renal aging and promotes the progression from AKI to CKD, we investigated the potential effect of tubular autophagy on senescence induction. Compared with kidneys from control mice, kidneys from mice with conditional deletion of autophagy-related 5 (Atg5) for selective ablation of autophagy in proximal tubular S3 segments (Atg5(Δ) (flox/) (Δ) (flox)) presented with significantly less tubular senescence, reduced interstitial fibrosis, and superior renal function 30 days after ischemia/reperfusion injury. To correlate this long-term outcome with differences in the early injury process, kidneys were analyzed 2 hours and 3 days after reperfusion. Notably, compared with kidneys of control mice, Atg5(Δ) (flox/) (Δ) (flox) kidneys showed more cell death in outer medullary S3 segments at 2 hours but less tubular damage and inflammation at day 3. These data suggest that the lack of autophagy prevents early survival mechanisms in severely damaged tubular cells. However, if such compromised cells persist, then they may lead to maladaptive repair and proinflammatory changes, thereby facilitating the development of a senescent phenotype and CKD.
Department of Nephrology and Department of Kidney, Liver and Metabolic Diseases, Children's Hospital, Hannover, Germany;
Arpita
A
Baisantry
Department of Nephrology and.
Sagar
S
Bhayana
Department of Nephrology and.
Song
S
Rong
Department of Nephrology and Department of Kidney, Liver and Metabolic Diseases, Children's Hospital, Hannover, Germany;
Esther
E
Ermeling
Institute of Functional and Applied Anatomy and Cluster of Excellence REBIRTH (Regenerative Biology to Reconstructive Therapy), Hannover Medical School, Hannover, Germany; and.
Christoph
C
Wrede
Institute of Functional and Applied Anatomy and Cluster of Excellence REBIRTH (Regenerative Biology to Reconstructive Therapy), Hannover Medical School, Hannover, Germany; and.
Jan
J
Hegermann
Children's Hospital, University of Munster, Munster, Germany.
Petra
P
Pennekamp
Department of Nephrology and.
Inga
I
Sörensen-Zender
Department of Nephrology and.
Hermann
H
Haller
Department of Kidney, Liver and Metabolic Diseases, Children's Hospital, Hannover, Germany;
Anette
A
Melk
Department of Nephrology and schmitt.roland@mh-hannover.de.
Roland
R
Schmitt
D000818:Animals; D001343:Autophagy; D016922:Cellular Senescence; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D008297:Male; D051379:Mice
acute renal failure; fibrosis; ischemia/reperfusion; pathophysiology of renal disease and progression; progression of renal failure; proximal tubule