Silva Barbosa, Anne Caroline
(2020)
The Role of Estrogen Sulfotransferase in Ischemic Acute Kidney Injury.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Acute kidney injury (AKI) is a sudden impairment of kidney function. It has been suggested that estrogens may protect mice from AKI. Estrogen sulfotransferase (SULT1E1/EST) plays an important role in estrogen homeostasis by sulfonating and deactivating estrogens, but the role of SULT1E1 in AKI has not been previously reported.
In this dissertation, Wild-type (WT) mice, Sult1e1 knockout (Sult1e1 KO) mice, and Sult1e1 KO mice with hepatic reconstitution of Sult1e1 were subjected to a bilateral kidney ischemia-reperfusion model of AKI, in the absence or presence of gonadectomy. Kidney injury was assessed at biochemical, histological and gene expression levels. WT mice treated with the Sult1e1 inhibitor triclosan were also used to determine the effect of pharmacological inhibition of Sult1e1 on AKI. Results showed that AKI induces the expression of Sult1e1 in a tissue- and sex-specific manner, inducing the hepatic expression of Sult1e1 in both male and female mice, but the kidney induction of Sult1e1 was only observed in male mice. A deeper investigation further demonstrated that (1) genetic knockout or pharmacological inhibition of Sult1e1 protects mice of both sexes from AKI in a sex hormone-independent manner. (2) Moreover, the effect of Sult1e1 on AKI is also tissue- and sex-specific, because transgenic reconstitution of Sult1e1 to the liver of Sult1e1 KO mice abolishes the protection in male mice, but not in female mice.
Finally, it was observed that the protective effect of Sult1e1 ablation is possibly associated with increased vitamin D receptor signaling. Overall, this dissertation elucidates a novel function
v
of Sult1e1 in the pathogenesis of AKI. Sult1e1 inhibitors may have their therapeutic utility in the clinical management of AKI.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
21 August 2020 |
| Date Type: |
Publication |
| Defense Date: |
17 July 2020 |
| Approval Date: |
21 August 2020 |
| Submission Date: |
4 August 2020 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
99 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Acute kidney injury, estrogen sulfotransferase |
| Date Deposited: |
21 Aug 2020 15:30 |
| Last Modified: |
21 Aug 2020 15:30 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/39517 |
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