Hyperuricemia (HUA) is a metabolic disorder characterized by elevated serum uric acid (UA), primarily attributed to the hepatic overproduction and renal underexcretion of UA. Despite the elucidation of molecular pathways associated with this underexcretion, the etiology of HUA remains largely unknown. In our study, using by knockout rats, HUA mouse, and cell line models, we discovered that the increased WWC1 levels were associated with decreased renal UA excretion. Additionally, using knockdown and overexpression approaches, we found that WWC1 inhibited UA excretion in renal tubular epithelial cells. Mechanistically, WWC1 activated the Hippo pathway, leading to phosphorylation and subsequent degradation of the downstream transcription factor YAP1, thereby impairing the ABCG2 and OAT3 expression through transcriptional regulation. Consequently, this reduction led to a decrease in UA excretion in renal tubular epithelial cells. In conclusion, our study has elucidated the role of upregulated WWC1 in renal tubular epithelial cells inhibiting the excretion of UA in the kidneys and causing HUA.

中文翻译：

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WWC1 上调通过 Hippo 信号通路减少肾脏尿酸排泄，从而加速高尿酸血症


高尿酸血症（HUA）是一种以血清尿酸（UA）升高为特征的代谢性疾病，主要归因于肝脏产生尿酸过多而肾脏排泄不足。尽管与这种排泄不足相关的分子途径已被阐明，但 HUA 的病因仍然很大程度上未知。在我们的研究中，通过基因敲除大鼠、HUA 小鼠和细胞系模型，我们发现 WWC1 水平升高与肾脏 UA 排泄减少相关。此外，通过敲低和过表达方法，我们发现WWC1抑制肾小管上皮细胞中UA的排泄。从机制上讲，WWC1 激活 Hippo 通路，导致下游转录因子 YAP1 磷酸化并随后降解，从而通过转录调控损害 ABCG2 和 OAT3 的表达。因此，这种减少导致肾小管上皮细胞中 UA 排泄减少。总之，我们的研究阐明了肾小管上皮细胞中WWC1上调抑制肾脏UA排泄并引起HUA的作用。