Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 294, Issue 1, Pages F170-F176Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00285.2007
Keywords
aging; caloric restriction; adherens junction
Categories
Funding
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [P30ES009106] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R21AG024179] Funding Source: NIH RePORTER
- NIA NIH HHS [AG-024179] Funding Source: Medline
- NIEHS NIH HHS [P30-ES09106] Funding Source: Medline
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The cadherins are cell adhesion molecules required for cellular homeostasis, and N-cadherin is the predominant cadherin expressed in proximal tubular epithelial cells in humans and rats. Our laboratory previously reported an age-dependent decrease in renal N-cadherin expression; the levels of N-cadherin mRNA and protein expression decreased in parallel, implicating a transcriptional mechanism in the age-dependent loss of expression (19). In this study, we examined the hypothesis that promoter hypermethylation underlies the loss of N-cadherin expression in aging rat kidney. We cloned the 5' flanking region of the rat N-cadherin gene and observed basic promoter activity in a 3,992-bp region localized immediately upstream of the ATG start site. Nucleotide analysis revealed 87% identity with the human N-cadherin minimal promoter region. Consistent with a role for regulation by DNA methylation, we found that a dense CpG island, which spans 1,104 bp (-1,158 to -55), flanks the rat N-cadherin gene; a similar CpG profile was found in the human N-cadherin 5' flanking region. Methylation-specific PCR analysis demonstrated that the promoter region of N-cadherin is heavily methylated in aged, but not young, rat kidney. Interestingly, the promoter is not methylated in age-matched, calorically restricted animals. In contrast, the promoter region is not methylated in either young or aged rat liver; this corresponds to the finding that aging is not associated with decreased N-cadherin expression in the liver. In addition, N-cadherin expression is markedly induced in NRK-52E cells treated with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine, further suggesting that methylation at CpG in the promoter region may underlie the age-dependent decrease in renal N- cadherin expression.
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