Abstract
BackgroundRenal aging is characterized by functional and structural changes like decreased glomerular filtration rate, and glomerular, tubular and interstitial damage. To gain insight in pathways involved in renal aging, we studied aged mouse strains and used genetic analysis to identify genes associated with aging phenotypes.MethodsUpon morphological screening in kidneys from 20-month-old mice from 26 inbred strains we noted intracapillary PAS-positive deposits. The severity of these deposits was quantified by scoring of a total of 50 glomeruli per section (grade 0–4). Electron microscopy and immunohistochemical staining for apoE, apoB, apoA-IV and perilipin-2 was performed to further characterize the lesions. To identify loci associated with these PAS-positive intracapillary glomerular deposits, we performed haplotype association mapping.ResultsSix out of 26 mouse strains showed glomerular PAS-positive deposits. The severity of these deposits varied: NOD(0.97), NZW(0.41), NON(0.30), B10(0.21), C3 H(0.9) and C57BR(0.7). The intracapillary deposits were strongly positive for apoE and weakly positive for apoB and apoA-IV. Haplotype association mapping showed a strong association with a 30-Kb haplotype block on Chr 1 within the Esrrg gene. We investigated 1 Mb on each site of this region, which includes the genes Spata17, Gpatch2, Esrrg, Ush2a and Kctd3.ConclusionsBy analyzing 26 aged mouse strains we found that some strains developed an intracapillary PAS and apoE-positive lesion and identified a small haplotype block on Chr 1 within the Esrrg gene to be associated with these lipoprotein deposits. The region spanning this haplotype block contains the genes Spata17, Gpatch2, Esrrg, Ush2a and Kctd3, which are all highly expressed in the kidney. Esrrg might be involved in the evolvement of these glomerular deposits by influencing lipid metabolism and possibly immune reponses.
Highlights
Aging is characterized by a gradual loss of normally functioning cell mass and requisite cell functions
Histology Morphological evaluation was performed on a periodic acid-Schiff (PAS) staining for all the 20-month-old male mice of 26 inbred strains
The analysis identified a small 30-Kb haplotype block of six single-nucleotide polymorphisms (SNP) within the Estrogen related receptor gamma (Esrrg) gene with a P-values were transformed using – log10 (P-value) of 9.5961028, which is different between strains with glomerular deposits and without glomerular deposits
Summary
Aging is characterized by a gradual loss of normally functioning cell mass and requisite cell functions. Age-related decline in renal function and structure predicts shorter lifespan. Physiological aging and/or stress-induced premature senescence of the kidney sets off a process leading to renal cellular senescence and increased risk for chronic kidney disease. Ethnicity and comorbidities play an important role in the rate of renal decline. Renal aging is considered a physiological phenomenon, it affects organ homeostasis as well as responses to acute and chronic injury. Decreased regeneration capacity makes aging individuals more vulnerable to superimposed stress factors and end-stage renal failure [1,2]. Understanding age related renal damage may provide tools for preventive and therapeutic means. Renal aging is characterized by functional and structural changes like decreased glomerular filtration rate, and glomerular, tubular and interstitial damage. To gain insight in pathways involved in renal aging, we studied aged mouse strains and used genetic analysis to identify genes associated with aging phenotypes
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