FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity

Wang, Xiaoxin X.; Wang, Dong; Luo, Yuhuan; Myakala, Komuraiah; Dobrinskikh, Evgenia; Rosenberg, Avi Z.; Levi, Jonathan; Kopp, Jeffrey B.; Field, Amanda; Hill, Andrea A.; Lucia, Scott; Qiu, Liru; Jiang, Tao; Peng, Yingqiong; Orlicky, David J.; García, Gabriel; Herman‐Edelstein, Michal; D’Agati, Vivette D.; Henriksen, Kammi J.; Adorini, Luciano; Pruzanski, Mark; Xie, Cen; Krausz, Kristopher W.; Gonzalez, Frank J.; Ranjit, Suman; Dvornikov, Alexander; Gratton, Enrico; Levi, Moshe

doi:10.1681/asn.2017020222

Cited by 161 publications

(115 citation statements)

References 78 publications

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“…Our results shown that Farnesiferol B effectively inhibited the expression of inflammatory cytokines, such as MCP-1, LTB4, and TNFα. Farnesiferol B inhibited LPS-induced NF-κB activation and decreased p65 translocation in J774 macrophages, possessing similar effects as other TGR5 agonists [40]. Moreover, the anti-inflammatory effect of Farnesiferol B was blocked in RAW264.7 cells, which do not express TGR5 [21,30].…”

Section: Discussionmentioning

confidence: 74%

“…Recently, Nrf2/HO-1 has also been shown to be protective in AKI and diabetic nephropathy [37][38][39]. It has been reported that treatment with either FXR/TGR5 dual agonist INT-767 or TGR5 specific agonist INT-777 could prevent diabetic nephropathy through inducing Nrf2-mediated antioxidant generation, and reducing renal expression of oxidative stress [23,40]. We have seen similar effects in the I/R-induced mouse AKI model with treatment with FXR/TGR5 dual agonist [25].…”

Section: Discussionmentioning

confidence: 99%

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Effects of Farnesiferol B on Ischemia-Reperfusion-Induced Renal Damage, Inflammation, and NF-κB Signaling

Zhang

Gui

et al. 2019

IJMS

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Background: G-protein-coupled bile acid receptor (TGR5), a membrane bile acid receptor, regulates macrophage reactivity, and attenuates inflammation in different disease models. However, the regulatory effects of TGR5 in ischemia/reperfusion (I/R)-induced kidney injury and inflammation have not yet been extensively studied. Therefore, we hypothesize that Farnesiferol B, a natural TGR5 agonist, could alleviate renal I/R injury by reducing inflammation and macrophage migration through activating TGR5. Methods: Mice were treated with Farnesiferol B before I/R or sham procedures. Renal function, pathological analysis, and inflammatory mediators were examined. In vitro, the regulatory effects of Farnesiferol B on the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in macrophages were investigated. Results: After I/R, Farnesiferol B-treated mice displayed better renal function and less tubular damage. Farnesiferol B reduced renal oxidative stress and inflammation significantly. In vitro, Farnesiferol B treatment alleviated lipopolysaccharide (LPS)-induced macrophage migration and activation, as well as LPS-induced NF-κB activation through TGR5. Conclusions: Farnesiferol B could protect kidney function from I/R-induced damage by attenuating inflammation though activating TGR5 in macrophages. Farnesiferol B might be a potent TGR5 ligand for the treatment of I/R-induced renal inflammation.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Effects of Farnesiferol B on Ischemia-Reperfusion-Induced Renal Damage, Inflammation, and NF-κB Signaling

Zhang

Gui

et al. 2019

IJMS

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“…Lipid levels are dependent on multiple mechanisms of regulation including dietary intake and de-novo synthesis, and also on the exchange and recycling systems. Among those regulatory mechanisms, reverse cholesterol transport and its regulation by specific receptors, namely the farnesoid X receptor (FXR) and the liver X receptor (LXR), has been receiving increasing attention in relation to inflammation, especially in the pathogenesis of diabetic kidney disease [103,104] and diabetic retinopathy [105]. LXR activation was also shown to improve peripheral nerve function in rodents with obesity and diabetes-induced neuropathy, specifically by reducing endoplasmic reticulum stress or restoring myelin lipid composition; however, little is known about the anti-inflammatory effects of LXR in the setting of neuropathy [106,107].…”

Section: Rise Of the Role Of Lipid Metabolism In Diabetic Complicationsmentioning

confidence: 99%

New insights into the mechanisms of diabetic complications: role of lipids and lipid metabolism

et al. 2019

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Diabetes adversely affects multiple organs, including the kidney, eye and nerve, leading to diabetic kidney disease, diabetic retinopathy and diabetic neuropathy, respectively. In both type 1 and type 2 diabetes, tissue damage is organ specific and is secondary to a combination of multiple metabolic insults. Hyperglycaemia, dyslipidaemia and hypertension combine with the duration and type of diabetes to define the distinct pathophysiology underlying diabetic kidney disease, diabetic retinopathy and diabetic neuropathy. Only recently have the commonalities and differences in the metabolic basis of these tissue-specific complications, particularly those involving local and systemic lipids, been systematically examined. This review focuses on recent progress made using preclinical models and human-based approaches towards understanding how bioenergetics and metabolomic profiles contribute to diabetic kidney disease, diabetic retinopathy and diabetic neuropathy. This new understanding of the biology of complication-prone tissues highlights the need for organ-specific interventions in the treatment of diabetic complications.

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“…In the last several years, research on BAs and their receptors has been extended to their possible roles on the regulation of endothelium functions. 13 Moreover, they have also been studied in the field of ophthalmology. It was found that intermittent fasting increases generation of tauroursodeoxycholate (TUDCA), a metabolite belonging to the BAs family, and thus prevents the development of DR. 12 TGR5 activation is thought to contribute to retinal protection, but the underlying mechanisms are still incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

TGR5 receptor activation attenuates diabetic retinopathy through suppression of RhoA/ROCK signaling

et al. 2020

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Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus. Abnormal energy metabolism in microvascular endothelium is involved in the progression of diabetic retinopathy. Bile Acid G‐Protein‐Coupled Membrane Receptor (TGR5) has emerged as a novel regulator of metabolic disorders. However, the role of TGR5 in diabetes mellitus‐induced microvascular dysfunction in retinas is largely unknown. Herein, enzyme‐linked immunosorbent assay was used for analyzing bile acid (BA) profiles in diabetic rat retinas and retinal microvascular endothelial cells (RMECs) cultured in high glucose medium. The effects of TGR5 agonist on streptozotocin (STZ)‐induced diabetic retinopathy were evaluated by HE staining, TUNEL staining, retinal trypsin digestion, and vascular permeability assay. A pharmacological inhibitor of RhoA was used to study the role of TGR5 on the regulation of Rho/Rho‐associated coiled‐coil containing protein kinase (ROCK) and western blot, immunofluorescence and siRNA silencing were performed to study the related signaling pathways. Here we show that bile acids were downregulated during DR progression in the diabetic rat retinas and RMECs cultured in high glucose medium. The TGR5 agonist obviously ameliorated diabetes‐induced retinal microvascular dysfunction in vivo, and inhibited the effect of TNF‐α on endothelial cell proliferation, migration, and permeability in vitro. In contrast, knockdown of TGR5 by siRNA aggravated TNF‐α‐induced actin polymerization and endothelial permeability. Mechanistically, the effects of TGR5 on the improvement of endothelial function was due to its regulatory role on the ROCK signaling pathway. An inhibitor of RhoA significantly reversed the loss of tight junction protein under TNF‐α stimulation. Taken together, our findings suggest that insufficient BA signaling plays an important pathogenic role in the development of DR. Upregulation or activation of TGR5 may inhibit RhoA/ROCK‐dependent actin remodeling and represent an important therapeutic intervention for DR.

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FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity

Cited by 161 publications

References 78 publications

Effects of Farnesiferol B on Ischemia-Reperfusion-Induced Renal Damage, Inflammation, and NF-κB Signaling

Effects of Farnesiferol B on Ischemia-Reperfusion-Induced Renal Damage, Inflammation, and NF-κB Signaling

New insights into the mechanisms of diabetic complications: role of lipids and lipid metabolism

TGR5 receptor activation attenuates diabetic retinopathy through suppression of RhoA/ROCK signaling

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