Investigating the molecular and genetic basis of human kidney aging and age-associated renal diseases
Abstract/Contents
- 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 age-associated gene expression changes, 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 candidate regulators were the inflammation-associated transcription factors NFκB, STAT1 and STAT3. The activities of these transcription factors increase with age in epithelial compartments of the renal cortex, and stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a STAT3 activator), IFN-γ (a STAT1 activator), or TNFα (an NFκB activator) was sufficient to recapitulate age-associated gene expression changes. We found that macrophage abundance increases with age and is tightly correlated with the activities of NFκB, STAT1 and STAT3 in individual kidneys, independent of chronological age. Thus, we hypothesized that a coordinated mode of regulation links macrophage infiltration to the activation of inflammatory transcription factors in the renal epithelium. We found that the general transcriptional response of human cells to macrophage-conditioned media recapitulates kidney age-associated gene expression changes and mirrors the transcriptional response to inflammatory cytokines, suggesting that macrophages may contribute locally to activation of NFκB, STAT1 and STAT3 via paracrine production of inflammatory cytokines. We next sought to determine whether common genetic variation in the genes encoding NFκB, STAT1 and STAT3 are associated with variation in renal function or chronic kidney disease risk in humans. We performed a candidate gene association study using public genotype data from gene association studies to ask whether polymorphisms in STAT1, STAT3 or the NFκB genes (RELA and NFKB1) show an association with renal function or chronic kidney disease. We found 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, providing the first genetic evidence that NFκB contributes to renal aging-related phenotypes in the human population. Our results suggest that NFκB, STAT1 and STAT3 are major regulators of transcriptional changes, chronic inflammation and functional decline in the aging human kidney.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2015 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | O'Brown, Zach Klapholz | |
|---|---|---|
| Associated with | Stanford University, Cancer Biology Program. | |
| Primary advisor | Kim, Stuart | |
| Thesis advisor | Kim, Stuart | |
| Thesis advisor | Brunet, Anne, 1972- | |
| Thesis advisor | Rando, Thomas A | |
| Thesis advisor | West, Robert | |
| Advisor | Brunet, Anne, 1972- | |
| Advisor | Rando, Thomas A | |
| Advisor | West, Robert |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Zach Klapholz O'Brown. |
|---|---|
| Note | Submitted to the Cancer Biology Program. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2015. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2015 by Zach Klapholz O'Brown
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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