Fuchs, Michaela Alexandra Anna.
Cellular localization and characterization of Cyclooxygenase-2 in interstitial cells of the kidney.
Degree: PhD, Biologie und Vorklinische Medizin, 2019, Universität Regensburg
Cyclooxygenase 2 is a key enzyme in the production of prostaglandins. The widespread application of Cox-2 selective inhibitors to treat pain and inflammation has shown severe renal side effects for these drugs. But the exact expression sites for Cox-2 and its normal function in the kidney is not yet clear.
Utilizing a novel in-situ hybridization technique Cox-2 could be distinctly located in two developmentally different cell populations of the murine kidney. In the cortex only specialized macula densa cells of the cTAL express Cox-2. In the renal medulla, interstitial fibroblast-like cells, characterized by the expression of PDGFR-β and TNC, produce Cox-2 mRNA.
Stimulating Cox-2 expression in the kidneys of mice, through a high dietary sodium intake, Cox-2 expression was induced only in the inner medulla and the inner stripe of the outer medulla. This recruitment of Cox-2 expressing cells only took place in interstitial PDGFR-β+/TNC+ cells. In mice deprived of water for 24h the recruitment pattern and cell type was the same, but the total number of Cox-2 expressing cells was on average lower than in high salt treated mice. The model of genetic stabilization of the HIF pathway in PDGFR-β+/iCre Vhlfl/fl mice not only showed that Cox-2 is a hypoxia inducible gene, but that an overlap between Cox-2 and EPO expression in the same cell is possible. The locally very restricted inducible expression of medullary interstitial Cox-2 led me to classify these cells as a functional subpopulation of the large pool of PDGFR-β+ interstitial cells. No Cox-2 expression could be detected in non-interstitial cells or in interstitial cells of the cortex in the conditions investigated in the scope of this work.
The medullary Cox-2+ cells, as well as most cells involved in the severe phenotype of global Cox-2 deficient mice, namely mesangial cells and vascular smooth muscle cells derive from the FoxD1+ stromal progenitor compartment. The role of Cox-2 during nephrogenesis was evaluated with a selective deletion in this compartment with FoxD1+/Cre Cox2fl/fl mice. The mice with a targeted Cox-2 deletion in the stromal compartment, but intact Cox-2 function in the cells of the macula densa, showed no developmental or functional defects. In FoxD1+/Cre Cox2fl/fl mice the recruitment of renin on a low salt stimulus was normal unlike in the mice with a total deletion of Cox-2.
In adult mice, the strong medullary induction of Cox-2 with a high dietary sodium intake implicates a functional connection between Cox-2 and the salt handling capability of the kidney. The lack of an adequate model made the distinction between the functions of the different Cox-2 expression sites difficult. With the use of PDGFR-β+/iCre Cox2fl/fl mice, it was possible to study the functional consequences of the isolated deletion of Cox-2 only in medullary interstitial cells under different conditions. This model showed that missing Cox-2 expression in the renal medulla led to reduced concentrating ability for sodium with a compensatory rise in urine volume and…
Advisors/Committee Members: Kurtz, Armin (advisor).
to Zotero / EndNote / Reference
APA (6th Edition):
Fuchs, M. A. A. (2019). Cellular localization and characterization of Cyclooxygenase-2 in interstitial cells of the kidney. (Doctoral Dissertation). Universität Regensburg. Retrieved from https://epub.uni-regensburg.de/41001
Chicago Manual of Style (16th Edition):
Fuchs, Michaela Alexandra Anna. “Cellular localization and characterization of Cyclooxygenase-2 in interstitial cells of the kidney.” 2019. Doctoral Dissertation, Universität Regensburg. Accessed December 08, 2019.
MLA Handbook (7th Edition):
Fuchs, Michaela Alexandra Anna. “Cellular localization and characterization of Cyclooxygenase-2 in interstitial cells of the kidney.” 2019. Web. 08 Dec 2019.
Fuchs MAA. Cellular localization and characterization of Cyclooxygenase-2 in interstitial cells of the kidney. [Internet] [Doctoral dissertation]. Universität Regensburg; 2019. [cited 2019 Dec 08].
Available from: https://epub.uni-regensburg.de/41001.
Council of Science Editors:
Fuchs MAA. Cellular localization and characterization of Cyclooxygenase-2 in interstitial cells of the kidney. [Doctoral Dissertation]. Universität Regensburg; 2019. Available from: https://epub.uni-regensburg.de/41001