The Inflammatory Transcription Factors NFκB, STAT1 and STAT3 Drive Age-Associated Transcriptional Changes in the Human Kidney
Open accessAbstract
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.
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Antigen processing and inflammatory pathways were significantly up-regulated with age.
“Antigen processing and inflammatory pathways were significantly up-regulated with age, a result that has also been observed across tissues in previous reports (Rodwell et al. 2004; O'Brown et al. 2015; Ori et al. 2015; Benayoun et al. 2019).”
From Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging (2019) · cites this paper as O'Brown et al. 2015
NF-κB, STAT1, and STAT3 mediate many age-related inflammatory changes.
“The pro-inflammatory transcription factors NF-κB, STAT1, and STAT3 are mediating many of these changes (O’Brown et al., 2015; Tilstra et al., 2011).”
From The Aging Epigenome (2016) · cites this paper as O’Brown et al., 2015
Activity of these transcription factors increases with age in humans, and reducing NF-κB activity ameliorates mouse progeria models and reverses age-associated pathology.
“the activity of these transcription factors increases with age in humans, and reducing NF-κB activity ameliorates mouse models of progeria and reverses age-associated pathology (O’Brown et al., 2015; Tilstra et al., 2011).”
From The Aging Epigenome (2016) · cites this paper as O’Brown et al., 2015
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- [58]Westra H-J, Peters MJ, Esko T, Yaghootkar H, Schurmann C, et al (2013) Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet 45: 1238– 1243. 10.1038/ng.2756 24013639 PMC3991562 · DOI · Paper page
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- Authors
- O’Brown, Z. K., Van Nostrand, E. L., Higgins, J. P., & Kim, S. K.
- Affiliations
- Stanford University (US)
- Stanford Medicine (US)
- Corresponding author
- O’Brown, Zach K.
- Venue
- PLOS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-12-17
- Volume
- 11
- Issue
- 12
- Pages
- e1005734
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC4682820
- OpenAlex
- W2215361131
- Cited by
- 90
- References
- 64
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 6 · 2023: 9 · 2022: 10 · 2021: 10 · 2020: 11 · 2019: 12 · 2018: 10 · 2017: 6 · 2016: 3 · 2015: 1
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institute on Aging (R01AG025941, R01 AG0250941)
- National Cancer Institute (CA09302, T32CA009302)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Keywords
- kidney aging, NF-κB, STAT1, STAT3, transcription factors, chronic kidney disease, renal tubular epithelial cells, inflammation, gene expression changes, RelA, NFKB1, genetic variants, renal function, interleukin-6, interferon-gamma, TNF-α, transcription factor occupancy
- MeSH terms
- Aging, Humans, Inflammation, Interferon-gamma, Transcription, Genetic, Tumor Necrosis Factor-alpha, Interleukin-6, NF-kappa B, STAT1 Transcription Factor, STAT3 Transcription Factor, Renal Insufficiency, Chronic, Transcription Factor RelA, NF-kappa B p50 Subunit, Genetic Association Studies
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