Miao Hua, Cao Gang, Wu Xia-Qing, Chen Yuan-Yuan, Chen Dan-Qian, Chen Lin, Vaziri Nosratola D, Feng Ya-Long, Su Wei, Gao Yi, Zhuang Shougang, Yu Xiao-Yong, Zhang Li, Guo Yan, Zhao Ying-Yong
Faculty of Life Science & Medicine, Northwest University, Xi'an, Shaanxi, China.
School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
Br J Pharmacol. 2020 Aug;177(15):3415-3435. doi: 10.1111/bph.15062. Epub 2020 May 28.
Increasing evidence has indicated that the high risk of cardiovascular disease in chronic kidney disease (CKD) patients cannot be sufficiently explained by classic risk factors.
Based on the least absolute shrinkage and selection operator method, we identified significantly altered renal tissue metabolites during progressive CKD in a 5/6 nephrectomized rat model and in CKD patients.
Six aryl-containing metabolites (ACMs) were significantly increased from Week 1 to Week 20. They were associated with the activation of aryl hydrocarbon receptor (AhR) and its target genes including CYP1A1, CYP1A2 and CYP1B1, which were further validated by molecular docking. Our study further demonstrated that AhR signalling could be activated by ACM in patients with idiopathic membranous nephropathy, diabetic nephropathy and IgA nephropathy. Most importantly, 1-aminopyrene (AP) showed strong positive and negative correlation with serum creatinine and creatinine clearance, respectively. AP significantly up-regulated the mRNA expressions of AhR and its three target genes in both mice and NRK-52E cells, while this effect was partially weakened in AhR small hairpin RNA-treated mice and NRK-52E cells. Furthermore, dietary flavonoid supplementation ameliorated CKD and renal fibrosis through partially inhibiting the AhR activity via lowering the ACM levels. The antagonistic effect of flavonoids on AhR was deeply influenced by the number and location of hydroxyl and glycosyl groups.
We uncovered that endogenous AP is a novel mediator of CKD progression via AhR activation; thus, AhR might serve as a promising target for CKD treatment.
越来越多的证据表明，慢性肾脏病（CKD）患者心血管疾病的高风险不能完全由经典危险因素来解释。
基于最小绝对收缩和选择算子方法，我们在5/6肾切除大鼠模型和CKD患者中，确定了进行性CKD期间肾组织代谢物的显著变化。
从第1周到第20周，六种含芳基代谢物（ACMs）显著增加。它们与芳烃受体（AhR）及其靶基因（包括CYP1A1、CYP1A2和CYP1B1）的激活有关，这通过分子对接进一步得到验证。我们的研究进一步表明，AhR信号通路可在特发性膜性肾病、糖尿病肾病和IgA肾病患者中被ACMs激活。最重要的是，1-氨基芘（AP）分别与血清肌酐和肌酐清除率呈强正相关和负相关。AP显著上调小鼠和NRK-52E细胞中AhR及其三个靶基因的mRNA表达，而在经AhR小发夹RNA处理的小鼠和NRK-52E细胞中，这种作用部分减弱。此外，饮食中补充类黄酮通过降低ACMs水平部分抑制AhR活性，从而改善CKD和肾纤维化。类黄酮对AhR的拮抗作用深受羟基和糖基的数量及位置的影响。
我们发现内源性AP是通过激活AhR促进CKD进展的新型介质；因此，AhR可能是CKD治疗的一个有前景的靶点。
