title: In vivo and in vitro analysis of age-associated changes and somatic cellular senescence in renal epithelial cells.
abstract: Acute kidney injury is a major clinical problem and advanced age is associated with ineffective renal regeneration and poor functional outcome. Data from kidney injury models suggest that a loss of tubular epithelial proliferation contributes to a decrease in renal repair capacity with aging, but aging can also lead to a higher severity of inflammation and damage which may influence repair. In this study we tested intrinsic age-dependent changes in tubular epithelial proliferation in young and old mice, by injecting low-dose lead acetate as a non-injurious mitogen. In parallel, we explored in vitro techniques of studying cellular senescence in primary tubular epithelial cells (PTEC). Lead acetate induced tubular epithelial proliferation at a significantly higher rate in young as compared to old mice. Old kidneys showed significantly more senescence as demonstrated by increased p16 (INK4a), senescence associated β-galactosidase, and γH2AX(+)/Ki-67(-) cells. This was paralleled in old kidneys by a higher number of Cyclin D1 positive tubular cells. This finding was corroborated by a positive correlation between Cyclin D1 positivity and age in human renal biopsies. When tubular cells were isolated from mouse kidneys they rapidly lost their age-associated differences under culture conditions. However, senescence was readily induced in PTEC by γ-irradiation representing a future model for study of cellular senescence in the renal epithelium. Together, our data indicate that the tubular epithelium of aged kidney has an intrinsically reduced proliferative capacity probably due to a higher load of senescent cells. Moreover, stress induced models of cellular senescence are preferable for study of the renal epithelium in vitro. Finally, the positive correlation of Cyclin D1 with age and cellular senescence in PTEC needs further evaluation as to a functional role of renal epithelial aging.
authors: Department of Pediatric Nephrology and Gastroenterology, Medical School Hannover, Hannover, Lower Saxony, Germany.
authors: Birgit
authors: B
authors: Berkenkamp
authors: Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Lower Saxony, Germany.
authors: Nathan
authors: N
authors: Susnik
authors: Department of Pediatric Nephrology and Gastroenterology, Medical School Hannover, Hannover, Lower Saxony, Germany.
authors: Arpita
authors: A
authors: Baisantry
authors: Department of Pediatric Nephrology and Gastroenterology, Medical School Hannover, Hannover, Lower Saxony, Germany ; Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Lower Saxony, Germany.
authors: Inna
authors: I
authors: Kuznetsova
authors: Department of Pediatric Nephrology and Gastroenterology, Medical School Hannover, Hannover, Lower Saxony, Germany.
authors: Christoph
authors: C
authors: Jacobi
authors: Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Lower Saxony, Germany.
authors: Inga
authors: I
authors: Sörensen-Zender
authors: Department of Pathology, Medical School Hannover, Hannover, Lower Saxony, Germany.
authors: Verena
authors: V
authors: Broecker
authors: Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Lower Saxony, Germany.
authors: Hermann
authors: H
authors: Haller
authors: Department of Pediatric Nephrology and Gastroenterology, Medical School Hannover, Hannover, Lower Saxony, Germany.
authors: Anette
authors: A
authors: Melk
authors: Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Lower Saxony, Germany.
authors: Roland
authors: R
authors: Schmitt
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000503:physiopathology; D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D019938:Cyclin D1 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004847:Epithelial Cells / Q000502:physiology*; D004848:Epithelium / Q000502:physiology; D006657:Histones / Q000235:genetics; D019394:Ki-67 Antigen / Q000235:genetics; D007684:Kidney Tubules / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012038:Regeneration / Q000235:genetics / Q000502:physiology; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: C530105:Ccnd1 protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; C475961:gamma-H2AX protein, mouse; D019938:Cyclin D1; D001616:beta-Galactosidase