Abstract: TH-OR80
Mild Hyperuricemia Is Beneficial for Males with Salt-Sensitive Hypertension and Associated Kidney Damage
Session Information
- Hypertension and CVD: Research Advances
October 24, 2024 | Location: Room 5, Convention Center
Abstract Time: 05:40 PM - 05:50 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Dissanayake, Lashodya Vindana, University of South Florida Morsani College of Medicine, Tampa, Florida, United States
- Zietara, Adrian, University of South Florida Morsani College of Medicine, Tampa, Florida, United States
- Levchenko, Vladislav, University of South Florida Morsani College of Medicine, Tampa, Florida, United States
- Klemens, Christine Anne, University of South Florida Morsani College of Medicine, Tampa, Florida, United States
- Palygin, Oleg, Medical University of South Carolina, Charleston, South Carolina, United States
- Staruschenko, Alexander, University of South Florida Morsani College of Medicine, Tampa, Florida, United States
Background
Hyperuricemia is associated with worse outcomes for chronic kidney disease (CKD). In large-cohort clinical trials, attempts to control uric acid (UA) did not produce clinically meaningful benefits. Humans don’t have the enzyme uricase due to an evolutionary mutation that is hypothesized to have been an adaptation to increase blood pressure under low-salt conditions. We hypothesized that mild asymptomatic hyperuricemia is beneficial in controlling the progression of salt-sensitive (SS) hypertension (HTN), a prevalent trait that occurs in half of HTN patients.
Methods
Both male and female Dahl SS rats were fed a diet with a uricase inhibitor, oxonic acid (2%) (Oxo), and high salt (HS) (4% NaCl). Radiotelemetry, immunohistochemistry, and RNA-Seq were used for analyses.
Results
After 3 wks, in response to Oxo supplementation, both sexes showed a significant increase of UA in plasma compared to their respective HS-only controls (males: 0.63±0.07 vs. 2.17±0.34; females: 0.78±0.15 vs. 2.04±0.35 mg/dl, HS vs. HS/Oxo). Interestingly, only male HS/Oxo rats showed a significant increase in uricosuria (males: 0.23±0.03 vs. 0.45±0.06; females: 0.26±0.06 vs. 0.26±0.01 UA/Cre, HS vs. HS/Oxo). Moreover, mild hyperuricemia was associated with a significant attenuation of the progression and magnitude of the mean arterial pressure in male but not female rats (males: 157±3 vs. 136±3; females: 155±6 vs. 154±5 mmHg, HS vs. HS/Oxo). The male HS/Oxo group had a lower kidney weight/body weight ratio and lower protein cast accumulation, indicating lower kidney damage. Oxo treatment led to less oxidative damage in the tubules compared to HS-only, as evidenced by the lower fluorescence intensity of 8-oxodG. RNA-Seq of male kidneys revealed that HS/Oxo treatment (vs. HS only) increased expression in Mas1 (MAS receptor), Klk-1 (Kallikrein-1), and Pcsk6 (PCSK6 enzyme), which can all lead to the activation of different vasodilatory pathways.
Conclusion
Our study showed that in male but not female Dahl SS rats, asymptomatic mild hyperuricemia accompanied by hyperuricosuria ameliorates the progression of SS HTN and protects kidneys from further damage. Thus, our findings challenge the notion of hyperuricemia being inherently detrimental to health.
Funding
- NIDDK Support