Author ORCID Identifier
Date Available
1-18-2024
Year of Publication
2023
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Medicine
Department/School/Program
Pharmacology and Nutritional Sciences
First Advisor
Dr. Analia Loria
Second Advisor
Dr. Terry Hinds
Abstract
The soluble prorenin receptor (sPRR) is a cleaved form of the full-length prorenin receptor (PRR). It has been demonstrated to activate the renin-angiotensin system (RAS) independent of its full-length receptor and mediate similar physiological and pathophysiological processes, albeit via different mechanisms.
The sPRR hormone, a component of RAS, has been identified as a plasma biomarker for hypertension and cardiovascular diseases in humans. In mice, sPRR infusion has been shown to mediate blood pressure elevation through competitive AT1R binding and activation. However, the biological contribution of renal-derived human sPRR to blood pressure regulation and kidney function remains unknown. Therefore, this study aimed to create a new murine model to investigate the effects of expressing human sPRR (HsPRR) in the renal collecting duct (CD) on cardiovascular and renal hemodynamic mechanisms and intrarenal RAS status. CD-HsPRR mice were generated by breeding human sPRR-Myc-tag transgenic mice with transgenic mice expressing Hoxb7/Cre. HsPRR increased renal sPRR concentration but did not change its circulating levels in both male and female littermates compared to CTL mice. Only female CD-HsPRR littermates displayed increased 24 h blood pressure due to daytime hemodynamic alterations. Both the losartan treatment failed to reduce blood pressure, and the pressor response to a chronic angiotensin II infusion was attenuated only in female CD-HsPRR. During the daytime, the females' CD-HsPRR also showed decreased GFR and increased β-ENaC expression with no change in water intake, urine flow rate, natriuresis, and kaliuresis. Normotensive CD-HsPRR male mice displayed a significant increase in AT1R mRNA expression that was associated with reduced COX2-protein expression in the renal cortex. Conversely, hypertensive CD-HsPRR female mice displayed a significant increase in renin mRNA expression that was associated with increased COX2-protein expression in the renal cortex. These results suggest that renal-derived HsPRR exerts a sex-specific dysregulation in the renal cortex RAS and COX-2 interplay that results in different blood pressure phenotypes between male and female CD-HsPRR mice.
Obesity-related hypertension has been associated with elevated plasma soluble prorenin receptor (sPRR) in men. Additionally, renal PRR and sPRR protein expression is upregulated during obesity and diabetes. However, whether renal-derived HsPRR may influence the intrarenal RAS status to regulate blood pressure and kidney function during obesity has not been investigated. Therefore, we investigated the role of CD-HsPRR on blood pressure and kidney function in male and female mice during obesity. Three months old male and female CD-HsPRR mice were placed on a high-fat diet for 25 weeks. HsPRR increased renal sPRR concentration but did not change its circulating levels in male and female littermates compared to CTL mice. Moreover, after 20 weeks of HFD, blood pressure was higher in all groups except in female HsPRR mice, which normally show higher blood pressure than CTL when fed a regular chow. Male CD-HsPRR had an impaired response to Losartan. Further analysis showed an increase in renin and AT1R mRNA expression in males but not females. These results suggest that losartan resistance could be an HsPRR-specific action mediated by the upregulation of renin.
Overall, this body of work revealed that renal-derived HsPRR induces sex-specific increases in blood pressure associated with elevated renin mRNA expression and b-ENaC protein expression during daytime in female mice fed regular chow, regardless of normal plasma sPRR levels compared to female CTL mice. Thus, renal-derived HsPRR may not contribute to the increased circulating levels of the peptide observed during obesity or other pathophysiological conditions.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2023.348
Funding Information
This work was supported by National Institutes of Health grants (R01-HL-142969 and R01-HL-1647 to ASL); the National Institute of General Medical Sciences (P30 GM127211); and the University of Kentucky, Center for Clinical and Translational Sciences (UL1TR001998).
Recommended Citation
Arthur, Gertrude, "THE ROLE OF RENAL-DERIVED HUMAN SOLUBLE PRORENIN RECEPTOR IN BLOOD PRESSURE REGULATION AND KIDNEY FUNCTION" (2023). Theses and Dissertations--Pharmacology and Nutritional Sciences. 53.
https://uknowledge.uky.edu/pharmacol_etds/53
