ABSTRACT
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.
Subject(s)
Aging/metabolism , Kidney/metabolism , Regeneration , Telomerase/deficiency , Aging/genetics , Animals , Cyclin-Dependent Kinase Inhibitor p16/biosynthesis , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p21/biosynthesis , Cyclin-Dependent Kinase Inhibitor p21/genetics , Gene Expression Regulation , Humans , Kidney/pathology , Mice , Mice, Knockout , RNAABSTRACT
BACKGROUND: Recipient death is a leading cause for renal allograft loss. Cardiovascular mortality is the most important cause of death among this patient group. Single nucleotide polymorphisms (SNPs) in a noncoding region close to the CDKN2a/b senescence genes have been associated with higher cardiovascular morbidity and mortality in nontransplant populations. METHODS: We selected 2064 renal transplant recipients: 688 with a known cardiovascular cause of death and 1376 matched controls. DNA specimens were genotyped for the three SNPs with known risk allele (rs10757274, rs2383206, and rs10757278) and one SNP without risk allele (rs518394). Genotyping results were analyzed according to the frequency of risk alleles in the two groups. RESULTS: The risk allele for three SNPs was detected significantly more often in patients with a known cardiovascular cause of death than in matched controls (all P<0.05). Diabetes and time on dialysis were modifiers of this effect with the presence of high-risk alleles having a stronger impact in diabetic patients and those with longer dialysis time. There was no difference between groups for the investigated SNP without risk allele. CONCLUSIONS: Our results support data from large cohort studies in normal nontransplant populations, which suggested a higher risk for cardiovascular events in individuals carrying certain SNPs in senescence-associated genes. Notably, this finding was obtained in a population known to be at increased risk of cardiovascular death.
Subject(s)
Cardiovascular Diseases/genetics , Cardiovascular Diseases/mortality , Chromosomes, Human, Pair 9 , Kidney Transplantation/mortality , Polymorphism, Single Nucleotide , Adolescent , Adult , Aged , Case-Control Studies , Cause of Death , Chi-Square Distribution , Diabetes Mellitus/mortality , Female , Gene Frequency , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Odds Ratio , Phenotype , Renal Dialysis/mortality , Risk Assessment , Risk Factors , Time Factors , Young AdultABSTRACT
Telomeres of most somatic cells progressively shorten, compromising the regenerative capacity of human tissues during aging and chronic diseases and after acute injury. Whether telomere shortening reduces renal regeneration after acute injury is unknown. Here, renal ischemia-reperfusion injury led to greater impairment of renal function and increased acute and chronic histopathologic damage in fourth-generation telomerase-deficient mice compared with both wild-type and first-generation telomerase-deficient mice. Critically short telomeres, increased expression of the cell-cycle inhibitor p21, and more apoptotic renal cells accompanied the pronounced damage in fourth-generation telomerase-deficient mice. These mice also demonstrated significantly reduced proliferative capacity in tubular, glomerular, and interstitial cells. These data suggest that critical telomere shortening in the kidney leads to increased senescence and apoptosis, thereby limiting regenerative capacity in response to injury.
