Related Experiment Video

Updated: Mar 19, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
06:54

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

14.7K

TGR5 activation suppressed S1P/S1P2 signaling and resisted high glucose-induced fibrosis in glomerular mesangial

Zhiying Yang1, Fengxiao Xiong2, Yu Wang2

  • 1Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangzhou 510006, China; Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou 510006, China.

Pharmacological Research
|June 19, 2016
PubMed

Insights

Activating the TGR5 receptor reduces kidney fibrosis in diabetic nephropathy by inhibiting sphingosine 1-phosphate/sphingosine 1-phosphate receptor 2 (S1P/S1P2) signaling. This mechanism ameliorates inflammation and pathological markers in kidney cells.

Area of Science:

  • Nephrology
  • Endocrinology
  • Molecular Biology

Background:

  • Diabetic nephropathy (DN) involves glucose/lipid metabolism disorders and kidney inflammation, leading to renal fibrosis.
  • Previous research linked sphingosine 1-phosphate (S1P)/sphingosine 1-phosphate receptor 2 (S1P2) signaling activation to promoting renal fibrosis in diabetes.
  • The G protein-coupled bile acid receptor TGR5 is known for regulating metabolism and possessing anti-inflammatory effects, with high expression in kidney tissues.

Purpose of the Study:

  • To investigate the effects of TGR5 activation on diabetic renal fibrosis.
  • To elucidate the underlying molecular mechanism, specifically whether TGR5 inhibits S1P/S1P2 signaling to attenuate DN.
  • To explore TGR5's role in regulating inflammation and fibrosis markers in kidney cells.

Main Methods:

  • Investigated the impact of TGR5 activation on high glucose-induced expression of intercellular adhesion molecule-1 (ICAM-1), transforming growth factor-beta 1 (TGF-β1), and fibronectin (FN) in glomerular mesangial cells (GMCs).
  • Assessed the effect of TGR5 activation on high glucose-induced S1P2 overexpression and AP-1 activity (including c-Jun/c-Fos phosphorylation).
  • Examined the interaction between S1P2 and TGR5 in GMCs and the effect of INT-777 (a TGR5 activator) on S1P2 expression and internalization.

Main Results:

  • TGR5 activation significantly decreased high glucose-induced ICAM-1, TGF-β1, and fibronectin expression in GMCs.
  • Activation of TGR5 diminished high glucose-induced S1P2 overexpression and attenuated AP-1 activity.
  • S1P2 was found to interact with TGR5 in GMCs, and INT-777 treatment reduced S1P2 expression and promoted its internalization.

Conclusions:

  • TGR5 activation ameliorates diabetic nephropathy by reducing key pathological markers like ICAM-1, TGF-β1, and fibronectin in kidney cells.
  • The mechanism involves the suppression of the S1P/S1P2 signaling pathway.
  • Targeting TGR5 represents a potential therapeutic strategy for managing diabetic nephropathy.
Keywords:
AP-1FibronectinINT-777 (PubChem CID: 45483949)JTE-013 (PubChem CID: 10223146)Renal fibrosisS1P2TGR5

More Related Videos

Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway07:15

Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway

Published on: August 23, 2024

1.0K
Optimizing Isolation and Purification of Murine Glomerular Mesangial Cells04:46

Optimizing Isolation and Purification of Murine Glomerular Mesangial Cells

Published on: March 7, 2025

1.1K

Related Concept Videos

TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
10.9K
GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
8.2K
Glomerular Filtration Rate and its Regulation01:28

Glomerular Filtration Rate and its Regulation

The Glomerular Filtration Rate (GFR) is a measure of kidney function, reflecting the volume of filtrate formed per minute in the kidneys. On average, GFR is approximately 125 mL/min in males and 105 mL/min in females. Maintaining a relatively constant GFR is essential for the kidneys to effectively regulate body fluid homeostasis and maintain extracellular stability.
GFR regulation involves two primary intrinsic controls: the myogenic and tubuloglomerular feedback mechanisms.
The myogenic...
6.2K
GPCR Desensitization01:12

GPCR Desensitization

G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
8.6K
cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
9.1K
Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
12.3K