Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China.
Health Science Center, East China Normal University, Shanghai, 200241, China.
Acta Pharmacol Sin. 2023 Oct;44(10):2075-2090. doi: 10.1038/s41401-023-01113-7. Epub 2023 Jun 21.
Renal fibrosis is a common pathological feature of chronic kidney disease (CKD) with various etiologies, which seriously affects the structure and function of the kidney. Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily and plays a critical role in regulating the genes related to xenobiotic and endobiotic metabolism in mammals. Previous studies show that PXR is expressed in the kidney and has protective effect against acute kidney injury (AKI). In this study, we investigated the role of PXR in CKD. Adenine diet-induced CKD (AD) model was established in wild-type and PXR humanized (hPXR) mice, respectively, which were treated with pregnenolone-16α-carbonitrile (PCN, 50 mg/kg, twice a week for 4 weeks) or rifampicin (RIF, 10 mg·kg·d, for 4 weeks). We showed that both PCN and RIF, which activated mouse and human PXR, respectively, improved renal function and attenuated renal fibrosis in the two types of AD mice. In addition, PCN treatment also alleviated renal fibrosis in unilateral ureter obstruction (UUO) mice. On the contrary, PXR gene deficiency exacerbated renal dysfunction and fibrosis in both adenine- and UUO-induced CKD mice. We found that PCN treatment suppressed the expression of the profibrotic Wnt7a and β-catenin in AD mice and in cultured mouse renal tubular epithelial cells treated with TGFβ1 in vitro. We demonstrated that PXR was colocalized and interacted with p53 in the nuclei of tubular epithelial cells. Overexpression of p53 increased the expression of Wnt7a, β-catenin and its downstream gene fibronectin. We further revealed that p53 bound to the promoter of Wnt7a gene to increase its transcription and β-catenin activation, leading to increased expression of the downstream profibrotic genes, which was inhibited by PXR. Taken together, PXR activation alleviates renal fibrosis in mice via interacting with p53 and inhibiting the Wnt7a/β-catenin signaling pathway.
肾纤维化是一种常见的慢性肾病（CKD）的病理特征，其病因多种多样，严重影响肾脏的结构和功能。妊娠相关 X 受体（PXR）是核受体超家族的成员，在调节哺乳动物中外源物和内源性代谢物相关基因方面发挥着关键作用。先前的研究表明，PXR 在肾脏中表达，并对急性肾损伤（AKI）具有保护作用。在本研究中，我们研究了 PXR 在 CKD 中的作用。分别在野生型和 PXR 人源化（hPXR）小鼠中建立了腺嘌呤饮食诱导的 CKD（AD）模型，并用孕烯醇酮-16α-腈（PCN，50mg/kg，每周两次，共 4 周）或利福平（RIF，10mg·kg·d，共 4 周）处理。我们发现，分别激活小鼠和人 PXR 的 PCN 和 RIF 改善了两种 AD 小鼠的肾功能并减轻了肾纤维化。此外，PCN 治疗还减轻了单侧输尿管梗阻（UUO）小鼠的肾纤维化。相反，PXR 基因缺失加剧了腺嘌呤和 UUO 诱导的 CKD 小鼠的肾功能障碍和纤维化。我们发现，PCN 治疗抑制了 AD 小鼠和体外用 TGFβ1 处理的培养的小鼠肾小管上皮细胞中致纤维化 Wnt7a 和β-catenin 的表达。我们证明了 PXR 与肾小管上皮细胞核中的 p53 共定位并相互作用。p53 的过表达增加了 Wnt7a、β-catenin 及其下游基因纤连蛋白的表达。我们进一步揭示了 p53 结合到 Wnt7a 基因的启动子上，增加了其转录和β-catenin 的激活，导致下游致纤维化基因的表达增加，这一过程被 PXR 抑制。总之，PXR 的激活通过与 p53 相互作用并抑制 Wnt7a/β-catenin 信号通路，减轻了小鼠的肾纤维化。
