Geniposidic Acid Attenuates Chronic Tubulointerstitial Nephropathy Through Regulation of the NF‐ƙB/Nrf2 Pathway Via Aryl Hydrocarbon Receptor Signaling

• Published in: Phytotherapy research Vol. 38; no. 11; pp. 5441 - 5457
• Main Authors: Wang, Yan‐Ni, Li, Xiao‐Jun, Wang, Wen‐Feng, Zou, Liang, Miao, Hua, Zhao, Ying‐Yong
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.11.2024; Wiley Subscription Services, Inc
• Subjects: acetates; Acetic acid; Adenine; Animals; apigenin; Aromatic compounds; aryl hydrocarbon receptor; aryl hydrocarbon receptors; blood serum; Butanol; Cell Line; chronic tubulointerstitial nephropathy; Creatinine; etiology; Fibrosis; Fibrosis - drug therapy; genes; geniposidic acid; Hydrocarbons; Inflammation; Kidney - drug effects; Kidney - pathology; Kidney diseases; Male; Molecular modelling; Nephritis, Interstitial - chemically induced; Nephritis, Interstitial - drug therapy; Nephropathy; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; Nrf2; NRF2 protein; nuclear factor kappa B; Oxidative stress; Oxidative Stress - drug effects; phytotherapy; Plant Extracts - pharmacology; Plantaginis semen; Rats; Rats, Sprague-Dawley; Receptors; Receptors, Aryl Hydrocarbon - metabolism; Seeds; semen; Serum levels; Signal Transduction - drug effects; transcription factor NF-kappa B; urea; Plantaginis semen; chronic tubulointerstitial nephropathy; Nrf2; geniposidic acid; nuclear factor kappa B; aryl hydrocarbon receptor
• ISSN: 0951-418X; 1099-1573; 1099-1573
• DOI: 10.1002/ptr.8324

ABSTRACT Renal fibrosis is an outcome of chronic kidney disease, independent of the underlying etiology. Renal fibrosis is caused primarily by oxidative stress and inflammation. We identified the components of Plantaginis semen and elucidated their anti‐fibrotic and anti‐inflammatory mechanisms. The renoprotective components and underlying molecular mechanisms of P. semen were investigated in rats with adenine‐induced chronic tubulointerstitial nephropathy (TIN) and in idole‐3‐acetic acid (IAA)–stimulated NRK‐52E cells. Acetate and n‐butanol extracts were found to be the bioactive fractions of P. semen. A total of 65 compounds including geniposidic acid (GPA), apigenin (APG), and acteoside (ATS) were isolated and identified. Among the seven main extract components, treatment with GPA, APG, and ATS reduced the serum levels of creatinine and urea in TIN rats. Mechanistically, GPA ameliorated renal fibrosis through repressing aryl hydrocarbon receptor (AHR) signaling and regulating redox signaling including inhibiting proinflammatory nuclear factor kappa B (NF‐ƙB) and its target gene products as well as activated antioxidative nuclear factor‐erythroid‐2‐related factor 2 (Nrf2) and its downstream target gene products in both TIN rats and IAA‐stimulated NRK‐52E cells. The inhibitory effect of GPA on AHR, NF‐Ƙb, and Nrf2 signaling were partially abolished in IAA‐stimulated NRK‐52E cells treated with CH223191 compared with untreated IAA‐stimulated NRK‐52E cells. These data demonstrated that GPA alleviates oxidative stress and inflammation partly by suppressing AHR signaling.