Mild hyperuricemia and salt-sensitive hypertension

Increased plasma uric acid (hyperuricemia) has been associated with worse outcomes for chronic kidney disease (CKD). But some attempts to control uric acid (UA) in large-cohort clinical trials did not produce clinically meaningful benefits for CKD. Some studies suggest that only hyperuricemia with crystals, but not asymptomatic hyperuricemia promotes the progression of CKD. Salt-sensitivity (SS) in blood pressure is a prevalent trait that is sexually dimorphic and results in kidney damage. But the connection between hyperuricemia and SS hypertension (HTN) is still unclear. Here we tested the connection between the two using both male and female Dahl SS rats, a well-establish model of SS HTN. We hypothesized that mild asymptomatic hyperuricemia is beneficial in controlling the progression of SS HTN. A uricase inhibitor, oxonic acid (2%) (Oxo) was used to induce hyperuricemia and high-salt (HS) (4% NaCl) diet was used to induce SS HTN. 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 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). 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. Furthermore, the HS/Oxo treated males had less oxidative damage in their tubules than the HS-only males. Bulk-RNA seq done on the male kidneys revealed that 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 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 and highlight that this is an oversimplified view of UA’s role in disease.血浆尿酸水平升高（高尿酸血症，hyperuricemia）与慢性肾脏病（CKD，chronic kidney disease）的不良预后密切相关。然而，多项大队列临床试验显示，针对尿酸（UA，uric acid）的控酸干预并未为慢性肾脏病患者带来具有临床意义的获益。已有研究提示，仅伴结晶的高尿酸血症而非无症状高尿酸血症，会促进慢性肾脏病的病情进展。血压盐敏感性（SS，salt-sensitivity）是一种普遍存在的性别二态性表型，可引发肾脏损伤。但高尿酸血症与盐敏感性高血压（HTN，hypertension）之间的关联仍未明确。 本研究以雌雄两性Dahl盐敏感性高血压大鼠——一种已被广泛验证的盐敏感性高血压成熟模型——为研究对象，探究二者之间的潜在关联。我们提出假说：轻度无症状高尿酸血症可延缓盐敏感性高血压的病情进展。本研究采用尿酸酶抑制剂氧嗪酸（2%浓度）诱导高尿酸血症，辅以4%氯化钠的高盐（HS）饮食构建盐敏感性高血压模型。 干预3周后，与仅接受高盐饮食的对照组相比，雌雄大鼠经氧嗪酸处理后血浆尿酸水平均显著升高（雄性：0.63±0.07 vs 2.17±0.34；雌性：0.78±0.15 vs 2.04±0.35 mg/dl，高盐组 vs 高盐+氧嗪酸组）。值得注意的是，仅雄性高盐+氧嗪酸组大鼠出现尿酸尿症显著升高（雄性：0.23±0.03 vs 0.45±0.06；雌性：0.26±0.06 vs 0.26±0.001 UA/Cre，高盐组 vs 高盐+氧嗪酸组）。此外，轻度高尿酸血症可显著延缓雄性大鼠的平均动脉压升高进程并降低其升高幅度，但对雌性大鼠无此保护作用（雄性：157±3 vs 136±3；雌性：155±6 vs 154±5 mmHg，高盐组 vs 高盐+氧嗪酸组）。 黄嘌呤氧化酶（XO，xanthine oxidase）是合成尿酸的关键酶之一，其活性已被证实与高血压发生发展相关。因此我们检测了干预后大鼠血浆中的黄嘌呤氧化酶活性。结果显示，同性别内不同饮食组的黄嘌呤氧化酶活性无显著差异，但在两种饮食条件下，雌性大鼠的黄嘌呤氧化酶活性均显著低于雄性大鼠。 为进一步探究雄性大鼠出现的有益表型，我们评估了肾脏病理进展的变化。与仅高盐饮食组相比，高盐+氧嗪酸组大鼠的肾脏重量/体重比值更低，蛋白管型沉积更少，提示肾脏损伤程度更轻。此外，高盐+氧嗪酸处理的雄性大鼠肾小管氧化损伤程度较仅高盐组更轻微。对雄性大鼠肾脏进行批量RNA测序（bulk-RNA seq）结果显示，血压改善表型与Mas1（MAS受体）、Klk-1（激肽释放酶-1）及Pcsk6（PCSK6酶）的表达上调相关，上述分子均可激活不同的血管舒张通路。 本研究表明，在雄性而非雌性Dahl盐敏感性高血压大鼠中，伴尿酸尿症升高的轻度无症状高尿酸血症可延缓盐敏感性高血压的进展，并保护肾脏免受进一步损伤。我们的发现挑战了"高尿酸血症天生有害健康"的固有观点，提示尿酸在疾病中的作用被过度简化了。