Identification of endogenous 1‐aminopyrene as a novel mediator of progressive chronic kidney disease via aryl hydrocarbon receptor activation

Abstract

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.

Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System

“…As mentioned before, AhR plays an important role in CRS, and thus, it must be taken as a possible target for clinical approaches. According to Miao et al (2020), one way to inhibit AhR activation is through treatment with flavonoids. A treatment with 1-aminopyrene was able to mediate the AhR expression in both mice and cells, and also up-regulate its mRNA expression.…”

“…These findings show that AhR could be activated by aryl-containing metabolites, which can be retarded by lowering the aryl-containing metabolite levels using dietary flavonoids. Flavonoids also seem to be able to attenuate renal fibrosis and down-regulate the mRNA expression of AhR target genes (Miao et al, 2020;Mo et al, 2020).…”

How Does Herbal Medicine Treat Idiopathic Membranous Nephropathy?

“…Mounting evidence demonstrated that the intervention mechanisms of herbal medicines on CKD were associated with renin–angiotensin system, inflammation and oxidative stress, aryl hydrocarbon receptor, transforming growth factor β (TGF-β)/Smad signaling, Wnt/β-catenin signaling pathways ( Chen et al., 2019b ; Chen et al., 2019c ; Feng et al., 2020 ; Hu et al., 2020 ). In addition, herb medicine were used for the treatment of CKD by modulating the metabolic disorders such as amino acid metabolism and lipid metabolism ( Zhang et al., 2018 ; Miao et al., 2020 ). A number of studies have demonstrated that herbal medicine could be used for the treatment of IMN ( Xu et al., 2015 ; Shi et al., 2018 ; Wang et al., 2018c ; Jin et al., 2020 ).…”

The Dysregulation of Eicosanoids and Bile Acids Correlates with Impaired Kidney Function and Renal Fibrosis in Chronic Renal Failure

“…The progression of CRF and its complications result in marked abnormal lipid metabolism and changed serum lipid profile [ 14 , 15 ], whereas metabolic disturbances, including dyslipidemia and profound changes in lipid, have been frequently demonstrated that contribute to the pathogenesis and prognosis of CRF and various complications [ 16 ]. Moreover, alteration of metabolomic in kidney diseases may provide clues understanding the pathophysiology of various renal diseases development and progression [ 17 , 18 ]. Therefore, sensitive and specific differential lipid species may yield therapeutic insights for diagnosis and monitoring of disease progression [ 19 ].…”