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Lack of Ku86 and water restriction both increase P16 INK4 expression in renal inner medullary cells in vivo.
Author(s) -
Dmitrieva Natalia I.,
Zhou Xiaoming,
Nussenzweig André,
Burg Maurice B.
Publication year - 2007
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.21.6.a962-c
Subject(s) - medulla , biology , renal medulla , kidney , in vivo , chromatin , downregulation and upregulation , cortex (anatomy) , dna damage , microbiology and biotechnology , dna , cancer research , medicine , endocrinology , genetics , neuroscience , gene
High NaCl increases the number of DNA breaks in renal cells in culture and in the kidney inner medulla in vivo (Dmitrieva, PNAS, 2004). Ku86 is a DNA end binding protein that normally aligns the ends of broken DNA while it is being repaired. High NaCl disrupts chromatin, which leads to chromosomal aberrations. These are particularly pronounced in Ku86 −/− cells (Dmitrieva, PNAS, 2005). P16 INK4 is a member of INK4‐class of cell cycle inhibitors. It is upregulated in cells whose DNA is damaged, preventing them from growing aberrantly. It is also upregulated in senescent cells and in cells that have exhausted their regenerative ability in the course of aging. In the present studies we show by immunohistochemical staining that the P16 INK4 level in kidneys increases with age, and is highest in the inner medulla. Thus, in wild type mice the level of P16 INK4 is higher in inner medulla than in the cortex, and is much greater at 12 months than at 3–4 months. Further, restricting water intake for two days increases renal p16 INK4 level in wild type mice, and the greatest increase is in the inner medulla. In Ku86 −/− mice, renal medullary p16 INK4 is already high at 4 months, and the mice have damaged glomeruli. We speculate that the p16 INK4 level is elevated in renal medullas because of the normally high level of DNA breaks that occurs there and that deficiency of the DNA repair protein Ku86 exacerbates the response. The role and consequences of the high level of p16 INK4 remains to be established.