Age-Dependent Loss of N-Cadherin in Rat Proximal Tubules

Texas A&M University Health Science Ctr, College Station TX

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Abstract

DESCRIPTION (provided by applicant): PA-01-127; "Studies on age-related changes in the biology of the kidney and kidney function, and propensity for diseases of the kidney relevant to older subjects" Aging is associated with a significant loss of renal reserve function, and is linked to an increased susceptibility of the kidney to ischemia and toxic insult. Since the maintenance of membrane polarity and transport properties is critical for normal renal function, it is not surprising that several human nephropathies are associated with the loss of cell-cell adhesion. However, the impact of aging on critical cell adhesion complexes in the kidney has not been investigated. The cadherin/catenin complex is the predominant regulator of cell-cell adhesion, and a functional complex is required for normal organ homeostasis. Based on preliminary data generated from completion of an RO3 from the NIA which demonstrates that N-cadherin expression is decreased as a function of age in the rat kidney, but not other organs, we have developed two Specific Aims to determine the mechanism underlying the loss of N-cadherin. In aim I, we will determine specific sequences and corresponding transcription factors that regulate N-cadherin promoter activity in proximal tubular epithelial cells. At this time, little is known about N-cadherin regulation, due to the lack of information on the promoter. Therefore, the experiments will have a significant impact. The studies proposed in aim II will determine the mechanism underlying the loss of N-cadherin. Increased understanding of molecular pathways leading to age-dependent renal dysfunction is a requisite for the development of therapeutic strategies for prevention or treatment. The proposed studies will begin to establish a role for disruption of the cadherin/catenin complex as an important feature of aging in the kidney.