Chaudhary Anjana, He Zhibin, Atwood Daniel J, Miyazaki Makoto, Oto Ozgur A, Davidoff Allen, Edelstein Charles L
Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States.
XORTX Therapeutics Inc., Calgary, Alberta, Canada.
Am J Physiol Renal Physiol. 2024 Jun 1;326(6):F1004-F1015. doi: 10.1152/ajprenal.00372.2023. Epub 2024 Apr 18.
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): ) to determine whether increasing serum uric acid with the uricase inhibitor, oxonic acid, resulted in faster cyst growth and ) 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 mice, a hypomorphic gene model. In PCK rats and 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 mice. Oxonic acid did not cause activation of the inflammasome or uric acid crystal deposition in the kidney. In 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 mice. The effect is independent of inflammasome activation or crystal deposition in the kidney. 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 mice and PCK rats, elevated levels of proinflammatory cytokines in the serum and kidney in mice, and no uric acid crystal deposition or activation of the caspase-1 inflammasome in the kidney.
人类易患痛风，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，导致基础血清尿酸水平较低。尿酸酶抑制剂会使啮齿动物的血清尿酸升高。该研究针对多囊肾病（PKD）有两个目的：一是确定用尿酸酶抑制剂氧嗪酸增加血清尿酸是否会导致囊肿生长加快；二是确定用黄嘌呤氧化酶抑制剂奥昔嘌醇治疗是否能减少氧嗪酸引起的囊肿生长。使用了人类PKD的直系同源模型：PCK大鼠，一种常染色体隐性PKD（ARPKD）的多囊肾和肝病1（Pkhd1）基因模型，以及 小鼠，一种低表达 基因模型。在PCK大鼠和 小鼠中，氧嗪酸导致血清尿酸、肾脏重量和囊肿指数显著增加。研究的囊肿生长增加机制包括促炎细胞因子、炎性小体和肾脏中的晶体沉积。氧嗪酸导致 小鼠血清和肾脏中的促炎细胞因子增加。氧嗪酸不会引起炎性小体激活或肾脏中的尿酸晶体沉积。在综合分析的雄性和雌性 小鼠中，奥昔嘌醇降低了氧嗪酸诱导的囊肿指数增加。总之，用氧嗪酸抑制尿酸酶增加血清尿酸会导致PCK大鼠和 小鼠的肾脏重量和囊肿指数增加。这种作用与炎性小体激活或肾脏中的晶体沉积无关。这是首次报道的在多囊肾病（PKD）啮齿动物中进行尿酸测量和黄嘌呤氧化酶抑制的研究。用尿酸酶抑制剂提高血清尿酸会导致 小鼠和PCK大鼠的肾脏重量和囊肿指数增加， 小鼠血清和肾脏中的促炎细胞因子水平升高，且肾脏中无尿酸晶体沉积或caspase-1炎性小体激活。
