ReferenceID 1951
Gentiopicroside activates the bile acid receptor Gpbar1 (TGR5) to repress NF-kappaB pathway and ameliorate diabetic nephropathy
Pharmacol Res
Our previous studies indicated that the G-protein-coupled bile acid receptor, Gpbar1 (TGR5), inhibits inflammation by inhibiting the NF-kappaB signalling pathway, eventually attenuating diabetic nephropathy (DN). Gentiop
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Record Fields
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- Reference Id
- 1951
- Evidence Id
- 18541
- Core Evidence Id
- 18541
- Source Reference Id
- 3920
- Herb2 Reference Id
- HBREF004717
- Subject Paper Key
- HBIN027510_31759089
- Pubmed Id
- 31759089
- Doi
- 10.1016/j.phrs.2019.104559
- Paper Title
- Gentiopicroside activates the bile acid receptor Gpbar1 (TGR5) to repress NF-kappaB pathway and ameliorate diabetic nephropathy
- Paper Abstract
- Our previous studies indicated that the G-protein-coupled bile acid receptor, Gpbar1 (TGR5), inhibits inflammation by inhibiting the NF-kappaB signalling pathway, eventually attenuating diabetic nephropathy (DN). Gentiopicroside (GPS), the main active secoiridoid glycoside of Gentiana manshurica Kitagawa, has been demonstrated to inhibit inflammation in various diseases via inhibiting the inflammatory signalling pathways. However, whether GPS inhibits the NF-kappaB signalling pathway by activating TGR5 and regulates the pathological progression of diabetic renal fibrosis requires further investigation. In this study, we found that GPS significantly reversed the downregulation of TGR5 and inhibited the overproduction of fibronectin (FN), transforming growth factor beta1 (TGF-beta1), intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in glomerular mesangial cells (GMCs) exposed to high glucose (HG). Additionally, GPS prevented the phosphorylation and degradation of IkappaBalpha, and subsequently inhibited the activation of the NF-kappaB signalling pathway. Further investigation found that GPS enhanced the stabilization of IkappaBalpha by promoting the interaction of beta-arrestin2 with IkappaBalpha via TGR5 activation, which contributed to the inhibition of NF-kappaB signalling pathway. Importantly, the depletion of TGR5 blocked the inhibition of the NF-kappaB signalling pathway and reversed the downregulation of FN, ICAM-1, VCAM-1 and TGF-beta1 by GPS in HG-induced GMCs. Moreover, GPS increased the TGR5 protein levels and promoted the interaction between IkappaBalpha and beta-arrestin2, thereby inhibiting the reduction of IkappaBalpha and blocked NF-kappaB p65 nuclear translocation in the kidneys of STZ-induced diabetic mice. Collectively, these data suggested that GPS regulates the TGR5-beta-arrestin2-NF-kappaB signalling pathway to prevent inflammation in the kidneys of diabetic mice, and ultimately ameliorates the pathological progression of diabetic renal fibrosis.
- Journal
- Pharmacol Res
- Publish Year
- 2020
- Experiment Subject
- mouse; hg-induced gmcs
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Diabetic Nephropathy; Diabetic Renal Fibrosis; Diabetic
- Paper Title Cn
- Paper Title En
- Gentiopicroside activates the bile acid receptor Gpbar1 (TGR5) to repress NF-kappaB pathway and ameliorate diabetic nephropathy
- Bilingual Status
- semi_complete