Recovery from acute kidney injury (AKI) requires renal tubule cell regeneration. The population of cells that repair the damaged proximal tubule epithelial cells (PTC) has been proposed to be derived from an external population circulating in the blood stream, an adjacent less-injured renal cell population, or a resident self-renewing PTC population. The identification of renal progenitor cells has been difficult because such a population remains phenotypically indistinguishable from their terminally differentiated counterparts and would require creation and characterization of transgenic reporters.
For my dissertation research, I investigated the role of NFATc1 in PTCs. A single dose of mercuric chloride (HgCl2) was administered to induce AKI. The data presented here show that NFATc1 plays a role in PTC regeneration following AKI and genetic and/or pharmacologic attenuation of NFATc1 results in increased PTC apoptosis, increased serum creatinine, decreased proliferation, and even death.
Using novel NFATc1 transgenic lines that reports activation of an NFATc1 enhancer domain important for autoamplification of NFATc1, we identified a subpopulation of proximal tubule progenitor cells that were resistant to apoptosis following HgCl2 injury. Lineage analysis documented that the NFATc1 labeled PTCs proliferate to repair the damaged proximal tubule segment. The expression profile of this labeled cell population and their labeled progeny was compared to unlabeled PTCs and showed that the labeled population were differentiated proximal tubule cells that had increased transcription of pluripotent stem cell and tubule development markers. To our knowledge, the delayed regeneration after AKI is the first example of a phenotype identified in the Nfatc1+/- mouse and proposes a role for NFATc1 in the regeneration of injured proximal tubule cells by as resident population of progenitor proximal tubules accentuated by NFATc1 expression.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03282008-155041 |
| Date | 14 April 2008 |
| Creators | Langworthy, Melissa Marie |
| Contributors | Raymond Harris, Mark de Caestecker, Chin Chiang, Christopher Wright, H. Scott Baldwin |
| 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-03282008-155041/ |
| 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. |
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