title: The Inflammatory Transcription Factors NFκB, STAT1 and STAT3 Drive Age-Associated Transcriptional Changes in the Human Kidney.
abstract: Human kidney function declines with age, accompanied by stereotyped changes in gene expression and histopathology, but the mechanisms underlying these changes are largely unknown. To identify potential regulators of kidney aging, we compared age-associated transcriptional changes in the human kidney with genome-wide maps of transcription factor occupancy from ChIP-seq datasets in human cells. The strongest candidates were the inflammation-associated transcription factors NFκB, STAT1 and STAT3, the activities of which increase with age in epithelial compartments of the renal cortex. Stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a STAT3 activator), IFNγ (a STAT1 activator), or TNFα (an NFκB activator) recapitulated age-associated gene expression changes. We show that common DNA variants in RELA and NFKB1, the two genes encoding subunits of the NFκB transcription factor, associate with kidney function and chronic kidney disease in gene association studies, providing the first evidence that genetic variation in NFκB contributes to renal aging phenotypes. Our results suggest that NFκB, STAT1 and STAT3 underlie transcriptional changes and chronic inflammation in the aging human kidney.
authors.affiliation: Department of Developmental Biology, Stanford University, Stanford, California, United States of America.|Department of Genetics, Stanford University, Stanford, California, United States of America.|Cancer Biology Program, Stanford University, Stanford, California, United States of America.
authors.forename: Zach K
authors.initials: ZK
authors.lastname: O'Brown
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Van Nostrand
authors.affiliation: Department of Pathology, Stanford University Medical Center, Stanford, California, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Higgins
authors.affiliation: Department of Developmental Biology, Stanford University, Stanford, California, United States of America.|Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Stuart K
authors.initials: SK
authors.lastname: Kim
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology; D056726:Genetic Association Studies; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6; D016328:NF-kappa B / Q000235:genetics*; D052002:NF-kappa B p50 Subunit / Q000235:genetics*; D051436:Renal Insufficiency, Chronic / Q000235:genetics* / Q000473:pathology; D050794:STAT1 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D051996:Transcription Factor RelA / Q000235:genetics*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C498143:RELA protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma