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.

Author Summary

The structure and function of human kidneys deteriorate steadily with age, yet little is known about the underlying causes of kidney aging. In this work, we first used a genomics approach to identify candidate regulators of gene expression changes in the aging human kidney and identified inflammation-related transcription factors NFκB, STAT1 and STAT3 as the top candidate regulators. We found that kidney aging is associated with activation of NFκB, STAT1 and STAT3 in the renal parenchyma, and that the gene expression signatures evoked by activation of these transcription factors in human renal epithelial cells mimics age-associated gene expression changes in the kidney. Furthermore, we identified specific genetic variants in the NFκB transcription factor genes RELA and NFKB1 that associate with renal function and chronic kidney disease in humans, implicating NFκB as a potential contributor to the pathogenesis of chronic kidney disease and renal dysfunction in old age. Our findings suggest that activation of the inflammatory transcription factors STAT1, STAT3 and NFκB underlie transcriptional changes and reduced renal function in the elderly.