Mild Hyperuricemia Attenuates Salt-Sensitive Hypertension and Kidney Damage.

BACKGROUND: Asymptomatic hyperuricemia is associated with poor outcomes in kidney and cardiovascular diseases, but its causative role remains controversial. Clinical studies have shown a positive correlation between increased dietary sodium intake and urinary uric acid excretion, suggesting that hyperuricemia may influence salt-sensitive hypertension and associated kidney damage. METHODS: To study the effects of mild hyperuricemia on salt-sensitive hypertension, male and female Dahl SS rats were fed a diet containing a uricase inhibitor (2% oxonic acid) and 4% NaCl (high salt) or a high salt-only diet for 3 weeks. Analyses were conducted using radiotelemetry, immunohistochemistry, and RNA-Sequencing. RESULTS: Uricase inhibition resulted in a ≈3.5-fold increase in plasma uric acid levels in both sexes compared with their respective high salt controls. However, only the male high salt/oxonic acid group exhibited a significant increase in uric acid excretion. The mild hyperuricemia significantly attenuated the progression of hypertension in male but not female rats. The male high salt/oxonic acid group showed reduced kidney hypertrophy and protein cast formation, indicating mitigated kidney damage. Supplementation with oxonic acid reduced oxidative damage in the tubules, as evidenced by the decreased fluorescence intensity of 8-oxodG. RNA-Sequencing analyses of male kidneys revealed that oxonic acid administration was associated with increased expression of genes linked to the activation of various vasodilatory pathways. CONCLUSIONS: Our study demonstrates that in male, but not female, Dahl salt-sensitive rats, mild hyperuricemia accompanied by hyperuricosuria slowed the progression of salt-sensitive hypertension, potentially due to reduced kidney damage.