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.

Psoriatic Arthritis Is an Indicator of Significant Renal Damage in Patients with Psoriasis: An Observational and Epidemiological Study

“…This finding is in sharp contrast to our observation of a positive association between the risk of renal involvement and age of the patients. However, our finding of positive association between increasing age and the risk of renal disease in patients with psoriasis is supported by other relevant studies [22]. It has been argued that aging leads to a higher activity of inflammation-associated transcription factors, namely, NF κ B, STAT1, and STAT3.…”

GEN3VA: aggregation and analysis of gene expression signatures from related studies

“…The enrichment vector analysis with ENCODE also points to STAT1 and STAT2 as being significant. This pair of transcription factors has previously been identified to be involved in aging kidneys [37], and our analysis confirms a global pro-inflammatory mechanism. Finally, drugs that can potentially accelerate or attenuate aging include celastrol, which was reported to indirectly inhibit NFKB signaling [38, 39], and radicicol, which is potentially a HSP90 and topoisomerase inhibitor [40].…”

The Aging Epigenome

“…Inflammatory pathways and genes are upregulated in older animals, including humans (Tilstra et al, 2011). 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). Consistent with a causative role in aging, 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).…”

“…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). Consistent with a causative role in aging, 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). NF-κB is regulated by many upstream factors and regulators including cytokines, growth factors, the deacetylases SIRT1 and SIRT6, and the transcription factor FOXO (Kawahara et al, 2009; Salminen et al, 2008).…”