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A mouse model of accelerated aging due to a defect in DNA repair
Author(s) -
Wack Kathryn E.,
Gregg Siobhan Q.,
Robinson Andria Rasile,
Ross Mark A.,
Rigatti Lora,
Stolz Donna Beer,
Niedernhofer Laura J
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.705.9
Subject(s) - ercc1 , dna damage , dna repair , kidney , kidney disease , fibrosis , medicine , biology , endocrinology , premature aging , endogeny , senescence , progeria , podocyte , pathology , nucleotide excision repair , dna , genetics , proteinuria , gene
Aging results in the loss of kidney function, leading to increased risk of chronic kidney disease in the elderly. With this demographic rapidly rising, it is critical to understand the molecular basis for age‐associated kidney dysfunction. To address this, we utilize a murine model ( Ercc1 −/Δ mice) of human progeria, an accelerated aging disease, caused by reduced ERCC1‐XPF DNA repair endonuclease expression. These mice accumulate endogenous DNA damage faster than normal organisms and develop premature onset of aging‐related degenerative diseases over their 28‐wk lifespan. To determine if renal changes that occur with normal aging occur in Ercc1 −/Δ mice, we compared kidneys from Ercc1 −/Δ mice to old (24–36 month) wild‐type (WT) mice. 23 wk Ercc1 −/Δ mice exhibited glomerulopathies similar to that observed in old WT kidneys including albuminuria, fibrosis, podocyte effacement and GBM thickening, indicating glomerular sensitivity to endogenous DNA damage. Endothelial activation, macrophage infiltration, increased smooth muscle actin expression, and decreased Klotho expression were comparable between old WT and the 23 wk Ercc 1 −/Δ mice. These data demonstrate that endogenous DNA damage drives age‐related renal degeneration, and therefore the utility of the Ercc1 −/Δ model for discovering the molecular mechanism by which damage drives aging and for testing therapeutic strategies to delay renal pathology.