NFkappaB promotes inflammation, coagulation, and fibrosis in the aging glomerulus.
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-beta activation. We used a nonbiased data-mining approach to identify NFkappaB as the likely transcriptional regulator of these events. We confirmed NFkappaB activation by two independent methods: translocation of NFkappaB p50 to glomerular nuclei and ChIP assays demonstrating NFkappaB p50 binding to the kappaB motif of target genes in old versus young glomeruli. These data suggest that old glomeruli exhibit NFkappaB-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 NFkappaB-driven processes.
Divisions of Geriatrics, University of Michigan, Ann Arbor, Michigan, USA. wiggi@umich.edu
Jocelyn E
JE
Wiggins
Sanjeevkumar R
SR
Patel
Kerby A
KA
Shedden
Meera
M
Goyal
Bryan L
BL
Wharram
Sebastian
S
Martini
Matthias
M
Kretzler
Roger C
RC
Wiggins
D000367:Age Factors; D000818:Animals; D001777:Blood Coagulation; D005355:Fibrosis / Q000209:etiology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000209:etiology*; D007678:Kidney Glomerulus / Q000473:pathology*; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344
D016328:NF-kappa B