Beneficial Effects of Mild Hyperuricemia in Salt-Sensitive Hypertension

Abstract

Hyperuricemia (HrU) or increased plasma uric acid (UA) is associated with worsening hypertension (HTN) and kidney damage. Paradoxically, UA is also known to be an endogenous antioxidant. Some studies suggest that only HrU with crystals, but not asymptomatic HrU promotes the progression of these diseases. We hypothesized that mild asymptomatic HrU is beneficial in controlling the progression of salt-sensitive (SS) HTN. Due to sex differences in urate handling and SS HTN, we used both male and female Dahl SS rats in this study. Radiotelemetry was used to measure blood pressure and various approaches, including RNA-Seq, were employed to assess kidney injury and identify potential molecular mechanisms. Mild HrU was induced using 2% oxonic acid in the diet, a uricase inhibitor that prevents the breakdown of UA further into more soluble allantoin. Groups: 1-2) male and female 4% NaCl high salt (HS) diet; 3-4) male and female HS + 2% oxonic acid (HS/oxo) diet. After 3 weeks, in response to oxonic acid 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; Femaels: 0.26 ±0.06 vs. 0.26 ±0.001 UA/Cre, HS vs. HS/oxo). Moreover, the mild HrU 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). Xanthine oxidase (XO) is one of the enzymes that produce UA, and its activity has been shown to affect HTN as well. Therefore, we examined the level of XO activity in the plasma after the treatment. While there was no difference in the activity based on the diet within each sex, females had significantly lower levels of XO activity compared to males in each of the diets. To further investigate the beneficial phenotype seen in male rats, we evaluate changes in the progression of renal pathology. The HS/oxo group compared to the HS group had a lower kidney weight/body weight ratio and lower protein cast accumulation, indicating lower kidney damage. RNA-Seq analysis showed that the attenuated HTN phenotype was associated with an 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. Our study showed that in male but not female Dahl SS rats, asymptomatic mild HrU accompanied by hyperuricosuria ameliorates the progression of SS HTN and protects kidneys from further damage. This work is supported by the American Society of Nephrology Ben J. Lipps Research Fellowship Program (Dimitrios G. Oreopoulos Research Fellowship Award to L.V.D.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.