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1 Systems Biology and Translational Medicine, College of Medicine Texas A&M Health Science Center, College Station, Texas, United States
2 Integrated Veterinary Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States
3 Medical Pharmacology and Toxicology, Texas A&M University, College Station, Texas, United States; Systems Biology and Translational Medicine, College of Medicine Texas A&M Health Science Center, College Station, Texas, United States
4 Veterinary Integrated Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States
* To whom correspondence should be addressed. E-mail: parrish{at}medicine.tamhsc.edu.
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 3992-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 1214-bp, 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. 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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