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Background and purposeIncreasing 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 approachBased 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 resultsSix 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 implicationsWe 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: Membranous nephropathy (MN) is an immune‐mediated glomerular disease in adults. Antibody‐ and antigen‐bonding mechanisms have been largely clarified, but the subepithelium immune complex deposition‐mediated downstream molecular mechanisms are currently unresolved. Increasing evidence has suggested that gut microbiota contribute to MN pathogenesis. Experimental Approach: In this study, we identified alterations in faecal gut microbiota and serum metabolites that mediate an aryl hydrocarbon receptor (AhR) mechanism in cationic bovine serum albumin (CBSA)‐induced MN rats and in patients with idiopathic MN (IMN). Key Results: Impaired renal function correlated with the relative abundance of reduced faecal probiotics, Lactobacillus and Bifidobacterium, and altered serum levels of tryptophan‐produced indole derivatives (TPIDs) in MN rats. Further results showed that reduced relative abundance of five probiotics, namely Lactobacillus johnsonii, Lactobacillus murinus, Lactobacillus vaginalis, Lactobacillus reuteri and Bifidobacterium animalis, positively correlated with decreased levels of indole‐3‐pyruvic acid, indole‐3‐aldehyde and tryptamine and negatively correlated with increased levels of indole‐3‐lactic acid and indole‐3‐acetic acid in serum of MN rats. Altered five probiotics and five TPIDs also were observed in patients with IMN. Further studies showed that MN rats exhibited a significant increase in intrarenal mRNA expression of AhR and its target genes CYP1A1, CYP1A2 and CYP1B1, which were accompanied by protein expression of down‐regulated cytoplasmic AhR, but up‐regulated nuclear AhR, in MN rats and IMN patients. Conclusion and Implications: Activation of the intrarenal AhR signalling pathway may involve five TPIDs. These data suggest that gut microbiota could influence MN through TPIDs that engage host receptors. [ABSTRACT FROM AUTHOR]

Background and Purpose: In chronic kidney disease (CKD), patients inevitably reach end‐stage renal disease and require renal transplant. Evidence suggests that CKD is associated with metabolite disorders. However, the molecular pathways targeted by metabolites remain enigmatic. Here, we describe roles of 1‐hydroxypyrene in mediating renal fibrosis. Experimental Approach We analysed 5406 urine and serum samples from patients with Stage 1–5 CKD using metabolomics, and 1‐hydroxypyrene was identified and validated using longitudinal and drug intervention cohorts as well as 5/6 nephrectomised and adenine‐induced rats. Key Results: We identified correlations between the urine and serum levels of 1‐hydroxypyrene and the estimated GFR in patients with CKD onset and progression. Moreover, increased 1‐hydroxypyrene levels in serum and kidney tissues correlated with decreased renal function in two rat models. Up‐regulated mRNA expression of aryl hydrocarbon receptor and its target genes, including CYP1A1, CYP1A2 and CYP1B1, were observed in patients and rats with progressive CKD. Further we showed up‐regulated mRNA expression of aryl hydrocarbon receptor and its three target genes, plus up‐regulated nuclear aryl hydrocarbon receptor protein levels in mice and HK‐2 cells treated with 1‐hydroxypyrene, which caused accumulation of extracellular matrix components. Treatment with aryl hydrocarbon receptor short hairpin RNA or flavonoids inhibited mRNA expression of aryl hydrocarbon receptor and its target genes in 1‐hydroxypyrene‐induced HK‐2 cells and mice. Conclusion and Implications: Metabolite 1‐hydroxypyrene was demonstrated to mediate renal fibrosis through activation of the aryl hydrocarbon receptor signalling pathway. Targeting aryl hydrocarbon receptor may be an alternative therapeutic strategy for CKD progression. [ABSTRACT FROM AUTHOR]