Acteoside-containing caffeic acid is bioactive functional group of antifibrotic effect by suppressing inflammation via inhibiting AHR nuclear translocation in chronic kidney disease

Abstract

Chronic kidney disease (CKD) is a common disorder with increasing prevalence and morbidity worldwide. However, the present agents do not effectively inhibit pathological processes. Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediated various diseases. Acteoside (ATS) is a commercial ATP-competitive inhibitor of protein kinase C. Clinical study showed ATS mitigated Th22 cell disorder and proteinuria in patients with immunoglobulin A nephropathy. This study analyzed AHR and nuclear factor kappa B (NF-κB) p65 expression in CKD patients. We compared the effects of ATS and its isomer isoacteoside (IAT) on renal function to identify their active functional group of antifibrosis in adenine-induced CKD rats. We further determined the effects of their active functional group on AHR signalling and inflammation pathway. The results showed increasing intrarenal AHR and NF-κB p65 expression in CKD patients. ATS improved renal function and fibrosis while IAT did not significantly improve fibrosis in CKD rats. Both ATS and IAT inhibited intrarenal mRNA expression of AHR and its downstream genes while ATS not IAT significantly inhibited nuclear AHR protein expression. Structure-activity analysis indicated that ATS-containing caffeic acid group by ester bond binding is transformed from C-11 to C-15 becoming IAT leads to a weakened inhibition of fibrosis and AHR nuclear translocation, indicating that caffeic acid group is bioactive functional group of ATS. Furthermore, ATS not IAT significantly regulated protein expression of NF-κB p65 and nuclear factor erythroid 2-related factor 2 (Nrf2) as well as their downstream gene products. Similar results were observed in indole-3-acetic acid (IAA)-induced NRK-52E cells. However, IAT did not show a significant effect. The inhibitory effects of ATS on NF-κB and Nrf2 pathways were partially abolished in IAA-stimulated NRK-52E cells treated with CH223191. However, ATS did not affect AHR expression in IAA-induced NRK-52E cells treated with BAY 11-7082. Therefore, ATS was identified as an AHR antagonist that ameliorated CKD by improving NF-κB/Nrf2 signalling axis. Conclusively, ATS holds promise as a chemical scaffold for the development of new antifibrotic agents.

Keywords: Nrf2; acteoside; aryl hydrocarbon receptor; caffeic acid; chronic kidney disease; nuclear factor kappa B.