Mutchler, Stephanie
(2019)
The Effects of Salt and Aldosterone on Vascular and Renal Function.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Hypertension is a global epidemic that increases risk for stroke, myocardial infarction, vascular disease and chronic kidney disease, making early detection and treatment imperative. Genetic factors and lifestyle choices such as diet can influence an individual’s risk of developing hypertension. The purpose of this study was to identify consequences of two risk factors, high salt diet (HSD) and increased aldosterone levels, on vascular and renal function with an emphasis on the role of the epithelial sodium channel (ENaC).
Previous cell culture studies demonstrate that an increase in extracellular [Na+] coupled with increased aldosterone increases ENaC expression in endothelial cells, leading to decreased nitric oxide production. Therefore, we hypothesized that ENaC contributes to vascular dysfunction with HSD and aldosterone in intact vasculature. Inhibition of ENaC with amiloride in isolated vessels from combination treated animals increased acetylcholine sensitivity, however, the most robust changes we observed in vascular reactivity occurred with HSD alone. We discovered a dynamic response of the vasculature to various HSD treatment lengths, in part mediated by ENaC.
We examined the effects of treatment alone or in combination on renal transporter expression given their importance to ion regulation and BP. Interestingly, HSD and aldosterone led to an increase in transcript and protein expression of all ENaC subunits in the kidney. Furthermore, the combined treatments led to an increase in renal inflammation, oxidative stress, and signs of fibrosis. Our full factorial treatments allowed us to assess the contribution of diet and aldosterone alone as well as in combination.
Finally, we found that chronic HSD surprisingly kept mice from gaining weight with age, despite the fact food intake was comparable to that in control animals. These animals may have shifts in metabolic processes that explain their weight differences, and these changes occur differentially in various organs.
Overall, our results have added to our understanding of how HSD and aldosterone alone and in combination increase risk for hypertension by affecting vascular and renal function. We have shown that ENaC plays a role in mediating the negative effects of this pathological state, and that it may be an attractive pharmacological target beyond the kidney.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Mutchler, Stephanie | | | |
|
| ETD Committee: |
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| Date: |
18 September 2019 |
| Date Type: |
Publication |
| Defense Date: |
3 April 2019 |
| Approval Date: |
18 September 2019 |
| Submission Date: |
1 July 2019 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
176 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Pharmacology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
renal physiology, vascular function, aldosterone, ENaC |
| Date Deposited: |
18 Sep 2019 14:29 |
| Last Modified: |
18 Sep 2019 14:29 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/37020 |
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