Retinoic acid (RA) has been used therapeutically to reduce injury and fibrosis in models of acute kidney injury (AKI), but little is known about whether and how this pathway is normally regulated, and what role it plays in regulating injury and repair after AKI. In these studies we show that RA signaling is activated in mouse and zebrafish models of AKI, and that these responses limit the extent of injury and promote normal repair. These effects are mediated through a novel mechanism by which RA signaling coordinates the dynamic equilibrium of pro-inflammatory M1 spectrum vs. alternatively activated M2 spectrum macrophages. According to this model, direct repression of pro-inflammatory macrophages by locally synthesized RA reduces macrophage-dependent injury post-AKI, while locally synthesized RA activates RA signaling in injured tubular epithelium, which in turn promotes alternatively activated M2 spectrum macrophages. Since RA signaling plays an essential role in kidney development but is repressed in the adult, these findings provide evidence of an embryonic signaling pathway that is reactivated after injury and plays an important role in reducing injury and enhancing repair after AKI.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-05272015-145940 |
| Date | 05 June 2015 |
| Creators | Chiba, Takuto |
| Contributors | David M. Bader, H. Scott Baldwin, Guoqiang Gu, Reymond C. Harris |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-05272015-145940/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.0017 seconds