Renal phenotype of young and old telomerase-deficient mice.
Telomere shortening in the kidney explains the impaired regenerative capacity, but may not drive the ageing phenotype itself. We investigated kidneys from young and old Terc(+/+) and Terc(-/-) mice of early (G1) and late (G4, G5) generations. Functional parameters declined and age-related morphological changes increased in late generation Terc(-/-) mice and with further age. Podocyte loss was only seen in old G4 Terc(-/-). Whereas p21(CIP1/WAF1) was highest in old G1 and G4 Terc(-/-), telomere shortening and p16(INK4a) expression, also significantly associated with later generation young Terc(-/-), were not further induced in old Terc(-/-) mice. Both, young and old late generation Terc(-/-), showed increased pro-inflammatory cytokine levels. Young late generation Terc(-/-) animals show mild functional and histological abnormalities, the presence of cellular senescence explains their kidneys' limited regenerative capacity. While these aspects resemble the situation seen in aged human kidneys, the lack of telomere shortening and p16(INK4a) induction in older Terc(-/-) animals differs from observations in old human kidneys and may result from clearance of senescent cells. This animal model is well suited to investigate the mechanisms of impaired renal regeneration in aged human kidney, but may not fully explain the natural course of the human renal ageing phenotype.
Department of Pediatric Nephrology, Gastroenterology and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover, Germany.
Carolin
C
Schildhorn
Department of Pediatric Nephrology, Gastroenterology and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover, Germany.
Christoph
C
Jacobi
Department of Pediatric Nephrology, Gastroenterology and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover, Germany.
Andrea
A
Weissbrodt
Department of Pediatric Nephrology, Gastroenterology and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover, Germany.
Christine
C
Hermstedt
Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany.
Jens Hendrik
JH
Westhoff
Department of Pediatric Nephrology, Gastroenterology and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover, Germany.
Meike
M
Hömme
Department of Pediatric Nephrology, Gastroenterology and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover, Germany.
Raj
R
Bhayadia
Medical Research Center, University of Heidelberg, Mannheim, Germany.
Norbert
N
Gretz
Institute of Transplant Immunology, IFB-Tx Hannover Medical School, Hannover, Germany.
Christine Susanne
CS
Falk
Department of Nephrology, Hannover Medical School, Hannover, Germany.
Roland
R
Schmitt
Department of Pathology, Hannover Medical School, Hannover, Germany.
Verena
V
Bröcker
Medical Research Center, University of Heidelberg, Mannheim, Germany.
Bettina
B
Kränzlin
Department of Pediatric Nephrology, Gastroenterology and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover, Germany. Electronic address: melk.anette@mh-hannover.de.
Anette
A
Melk
D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D012313:RNA; D012038:Regeneration; D019098:Telomerase / Q000172:deficiency*
C493957:Cdkn1a protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase
Kidney; Knockout-mouse; Senescence; Telomerase; Telomere