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From the Department of Medicine,* Vascular Biology Institute, University of Miami School of Medicine, Miami, Florida; the Gene Core Facility, Pulmonary and Critical Care Medicine, The Johns Hopkins University, Baltimore, Maryland; and the Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee
Age-associated renal changes may be an important cause of renal failure. We recently found that aged female B6 mice developed progressive glomerular lesions. This was associated with macrophage infiltration, a frequent finding in glomerulosclerosis. We used these mice as a model for studying the mechanisms of glomerular aging. We compared the gene expression profile of intact glomeruli from late postmenopausal (28-month-old) mice to that of intact glomeruli from premenopausal (5-month-old) mice. We found that inflammation-related genes, especially those expressed by activated macrophages, were up-regulated in the glomeruli of 28-month-old mice, a result correlating with the histological observation of glomerular macrophage infiltration. The mechanism for macrophage recruitment could have been stable phenotypic changes in mesangial cells because we found that mesangial cells isolated from 28-month-old mice expressed higher levels of RANTES and VCAM-1 than cells from 5-month-old mice. The elevated serum tumor necrosis factor (TNF)-
levels present in aged mice may contribute to increased RANTES and VCAM-1 expression in mesangial cells. Furthermore, cells from 28-month-old mice were more sensitive to TNF--induced RANTES and VCAM-1 up-regulation. The effect of TNF- on RANTES expression was mediated by TNF receptor 1. Interestingly, mesangial cells isolated from 28-month-old mice had increased nuclear factor-
B transcriptional activity. Inhibition of nuclear factor-B activity decreased baseline as well as TNF--induced RANTES and VCAM-1 expression in mesangial cells isolated from 28-month-old mice. Thus, phenotypic changes in mesangial cells may predispose them to inflammatory stimuli, such as TNF-, which would contribute to glomerular macrophage infiltration and inflammatory lesions in aging.
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