1-Hydroxypyrene mediates renal fibrosis through aryl hydrocarbon receptor signalling pathway.

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. 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. 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. 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.

Miao H ，Wu XQ ，Wang YN ，Chen DQ ，Chen L ，Vaziri ND ，Zhuang S ，Guo Y ，Su W ，Ma SX ，Zhang HQ ，Shang YQ ，Yu XY ，Zhao YL ，Mao JR ，Gao M ，Zhang JH ，Zhao J ，Zhang Y ，Zhang L ，Zhao YY ，Cao G ... -  《-》

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

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.

Miao H ，Cao G ，Wu XQ ，Chen YY ，Chen DQ ，Chen L ，Vaziri ND ，Feng YL ，Su W ，Gao Y ，Zhuang S ，Yu XY ，Zhang L ，Guo Y ，Zhao YY ... -  《-》

Blockade of aryl hydrocarbon receptor restricts omeprazole-induced chronic kidney disease.

Chronic kidney disease (CKD) is the 16th leading cause of mortality worldwide. Clinical studies have raised that long-term use of omeprazole (OME) is associated with the morbidity of CKD. OME is commonly used in clinical practice to treat peptic ulcers and gastroesophageal reflux disease. However, the mechanism underlying renal failure following OME treatment remains mostly unknown and the rodent model of OME-induced CKD is yet to be established. We described the process of renal injury after exposure to OME in mice; the early renal injury markers were increased in renal tubular epithelial cells (RTECs). And after long-term OME treatment, the OME-induced CKD mice model was established. Herein, aryl hydrocarbon receptor (AHR) translocation appeared after exposure to OME in HK-2 cells. Then for both in vivo and in vitro, we found that Ahr-knockout (KO) and AHR small interfering RNA (siRNA) substantially alleviated the OME-induced renal function impairment and tubular cell damage. Furthermore, our data demonstrate that antagonists of AHR and CYP1A1 could attenuate OME-induced tubular cell impairment in HK-2 cells. Taken together, these data indicate that OME induces CKD through the activation of the AHR-CYP axis in RTECs. Our findings suggest that blocking the AHR-CYP1A1 pathway acts as a potential strategy for the treatment of CKD caused by OME. KEY MESSAGES: We provide an omeprazole-induced chronic kidney disease (CKD) mice model. AHR activation and translocation process was involved in renal tubular damage and promoted the occurrence of CKD. The process of omeprazole nephrotoxicity can be ameliorated by blockade of the AHR-CYP1A1 axis.

Sun N ，Zhang Y ，Ding L ，An X ，Bai F ，Yang Y ，Yu K ，Fan J ，Liu L ，Yang H ，Yang X ... -  《-》

Expression of dioxin-related transactivating factors and target genes in human eutopic endometrial and endometriotic tissues.

Bulun SE ，Zeitoun KM ，Kilic G 《AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY》

Knockout of the aryl hydrocarbon receptor results in distinct hepatic and renal phenotypes in rats and mice.

Harrill JA ，Hukkanen RR ，Lawson M ，Martin G ，Gilger B ，Soldatow V ，Lecluyse EL ，Budinsky RA ，Rowlands JC ，Thomas RS ... -  《-》