NFκB promotes inflammation, coagulation, and fibrosis in the aging glomerulus

Abstract

The peak prevalence of ESRD from glomerulosclerosis occurs at 70 to 79 years. To understand why old glomeruli are prone to failure, we analyzed the Fischer 344 rat model of aging under ad libitum-fed (rapid aging) and calorie-restricted (slowed aging) conditions. All glomerular cells contained genes whose expression changed "linearly" during adult life from 2 to 24 months: mesangial cells (e.g., MMP9), endothelial cells (e.g., ICAM and VCAM), parietal epithelial cells (e.g., ceruloplasmin), and podocytes (e.g., nephrin and prepronociceptin). Patterns of aging glomerular gene expression closely resembled atherosclerosis, including activation of endothelial cells, epithelial cells, and macrophages, as well as proinflammatory pathways related to cell adhesion, chemotaxis, blood coagulation, oxidoreductases, matrix metalloproteinases, and TGF-κactivation. We used a nonbiased data-mining approach to identify NFκB as the likely transcriptional regulator of these events. We confirmed NFκB activation by two independent methods: translocation of NFκB p50 to glomerular nuclei and ChIP assays demonstrating NFκB p50 binding to the κB motif of target genes in old versus young glomeruli. These data suggest that old glomeruli exhibit NFκB-associated up-regulation of a proinflammatory, procoagulable, and profibrotic phenotype compared with young glomeruli; these distinctions could explain their enhanced susceptibility to failure. Furthermore, these results provide a potential mechanistic explanation for the close relationship between ESRD and atherosclerotic organ failure as two parallel arms of age-associated NFκB-driven processes. Copyright © 2010 by the American Society of Nephrology.