Hua Miao1, Gang Cao2, Xia-Qing Wu1, Yuan-Yuan Chen1, Dan-Qian Chen1, Lin Chen1, Nosratola D Vaziri3, Ya-Long Feng1, Wei Su4, Yi Gao5, Shougang Zhuang6, Xiao-Yong Yu7, Li Zhang8, Yan Guo9, Ying-Yong Zhao1. 1. Faculty of Life Science & Medicine, Northwest University, Xi'an, Shaanxi, China. 2. School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China. 3. Division of Nephrology and Hypertension, School of Medicine, University of California Irvine, Irvine, California, USA. 4. Department of Nephrology, Baoji Central Hospital, Baoji, Shaanxi, China. 5. Department of Nephrology, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China. 6. Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island, USA. 7. Department of Nephrology, Shaanxi Traditional Chinese Medicine Hospital, Xi'an, Shaanxi, China. 8. Department of Nephrology, Xi'an No. 4 Hospital, Xi'an, Shaanxi, China. 9. Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA.
Abstract
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSION AND IMPLICATIONS: 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.
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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 CKDpatients. KEY RESULTS: 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. CONCLUSION AND IMPLICATIONS: 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.
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