Abstract：
Humans are predisposed to gout because they lack uricase that converts uric acid to allantoin. Rodents have uricase, resulting in low basal serum uric acid. A uricase inhibitor raises serum uric acid in rodents. There were two aims of the study in polycystic kidney disease (PKD): 1) to determine whether increasing serum uric acid with the uricase inhibitor, oxonic acid, resulted in faster cyst growth and 2) to determine whether treatment with the xanthine oxidase inhibitor, oxypurinol, reduced the cyst growth caused by oxonic acid. Orthologous models of human PKD were used: PCK rats, a polycystic kidney and hepatic disease 1 (Pkhd1) gene model of autosomal recessive PKD (ARPKD) and Pkd1RC/RC mice, a hypomorphic Pkd1 gene model. In PCK rats and Pkd1RC/RC mice, oxonic acid resulted in a significant increase in serum uric acid, kidney weight, and cyst index. Mechanisms of increased cyst growth that were investigated were proinflammatory cytokines, the inflammasome, and crystal deposition in the kidney. Oxonic acid resulted in an increase in proinflammatory cytokines in the serum and kidney in Pkd1RC/RC mice. Oxonic acid did not cause activation of the inflammasome or uric acid crystal deposition in the kidney. In Pkd1RC/RC male and female mice analyzed together, oxypurinol decreased the oxonic acid-induced increase in cyst index. In summary, increasing serum uric acid by inhibiting uricase with oxonic acid results in an increase in kidney weight and cyst index in PCK rats and Pkd1RC/RC mice. The effect is independent of inflammasome activation or crystal deposition in the kidney.NEW & NOTEWORTHY This is the first reported study of uric acid measurements and xanthine oxidase inhibition in polycystic kidney disease (PKD) rodents. Raising serum uric acid with a uricase inhibitor resulted in increased kidney weight and cyst index in Pkd1RC/RC mice and PCK rats, elevated levels of proinflammatory cytokines in the serum and kidney in Pkd1RC/RC mice, and no uric acid crystal deposition or activation of the caspase-1 inflammasome in the kidney.
摘要：
人类容易患痛风，因为他们缺乏将尿酸转化为尿囊素的尿酸酶。啮齿动物有尿酸酶,导致低基础血清尿酸。尿酸酶抑制剂提高啮齿动物的血清尿酸。多囊肾病（PKD）的研究有两个目的：1）确定尿酸酶抑制剂是否增加血清尿酸，含氧酸,导致更快的囊肿生长和2）确定是否用黄嘌呤氧化酶抑制剂治疗，氧普尿酸,减少了由含氧酸引起的囊肿生长。使用人PKD的直系同源模型：PCK大鼠，常染色体隐性遗传PKD（ARPKD）和Pkd1RC/RC小鼠的多囊肾和肝病1（Pkhd1）基因模型，Pkd1基因模型。在PCK大鼠和Pkd1RC/RC小鼠中，含氧酸导致血清尿酸显着增加，肾脏重量和囊肿指数。研究的囊肿生长增加的机制是促炎细胞因子，肾脏中的炎性体和晶体沉积。草酸导致Pkd1RC/RC小鼠血清和肾脏中促炎细胞因子的增加。草酸不会引起炎症小体或尿酸晶体在肾脏中沉积的活化。在一起分析的Pkd1RC/RC雄性和雌性小鼠中，氧吡喃醇降低了草酸引起的囊肿指数的增加。总之,在PCK大鼠和Pkd1RC/RC小鼠中，通过用含氧酸抑制尿酸酶来增加血清尿酸会导致肾脏重量和囊肿指数增加。该作用独立于肾中的炎性体活化或晶体沉积。
