Farrell, Corinne Elaina
(2024)
The miR-17~92 cluster regulates aldosterone signaling: Contributions to sex differences in
sodium transport in the distal nephron.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Hypertension affects over a billion individuals globally, with aldosterone playing a crucial role in blood pressure regulation through the renin-angiotensin-aldosterone-signaling (RAAS) system. Premenopausal women exhibit a lower risk of hypertension than age-matched men, attributed to both reduced aldosterone levels and estrogen signaling. While our previous work highlighted aldosterone's influence on microRNA (miR) expression in collecting duct epithelial cells, the sex-specific regulation of miRs and their impact on sex differences in blood pressure homeostasis remain unexplored. This study investigates the hypothesis that the miR-17~92 cluster contributes to sex differences in aldosterone signaling within the nephron's collecting duct epithelia. Using in vitro and in vivo models, we examined the response of miR-17~92 to aldosterone and estrogen stimulation. MiR-19, a component of miR-17~92, showed upregulation in response to both aldosterone and estrogen in cultured cells. In vivo, a sex-specific upregulation of the miR-17~92 cluster was evident in female mice on a low-Na+ diet, stimulating aldosterone release. In mCCD cells, estrogen pretreatment attenuated aldosterone stimulation by targeting the serum and glucocorticoid-induced kinase (Sgk1) mRNA. However, neither estrogen receptors (ERs) nor xenobiotic receptors (XRs) were responsible for this effect. Luciferase assays confirmed the binding of miR-19 to the 3’-UTR of Sgk1. Overexpression of miR-19 in cells inhibited aldosterone-induced Na+ transport, while inhibition of miR-19 had the opposite effect. In vivo studies on mice corroborated the sex-specific regulation of Sgk1 by miR-17~92. Female mice exhibited an elevation in relative Sgk1 expression compared to males when placed on low Na+ diets. By examining evolution of the miR-17~92 cluster, phylogenetic sequence analysis indicated that this cluster arose at the same time that other Na+-sparing and salt regulatory proteins, specifically SGK1 first emerged, indicating a conserved role for these miRs in kidney function of salt and water homeostasis. In conclusion, our findings suggest that the miR-17~92 cluster may contribute to sex-specific differences in aldosterone signaling, providing insights into the molecular mechanisms underlying sex disparities in blood pressure regulation.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
16 September 2024 |
| Date Type: |
Publication |
| Defense Date: |
23 January 2024 |
| Approval Date: |
16 September 2024 |
| Submission Date: |
12 February 2024 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
156 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cell Biology and Molecular Physiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
MicroRNA, SGK1, Kidney, Aldosterone, Sex differences, Sodium |
| Date Deposited: |
16 Sep 2024 19:04 |
| Last Modified: |
16 Sep 2024 19:04 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45794 |
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