Abstract: TH-PO895
The GPR120 Agonist TUG-891 Ameliorates Fibrosis in Diabetic Nephropathy
Session Information
- Diabetic Kidney Disease: Basic - I
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Wei, Tiantian, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Ma, Liang, Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan Univeristy, Chengdu, China
- Fu, Ping, West China Hospital, Sichuan University, Chengdu, Sichuan, China
Background
GPR120/FFAR4 is a member of the G protein-coupled receptors that is activated by Omega-3 fatty acids. Recent studies demonstrate that GPR120 inhibits inflammation, regulates lipid and glucose metabolism, which mediates potent insulin sensitizing and anti-diabetic effects. TUG-891 is an a potent and selective agonist for GPR120. In this study, we examined the protective effects of GPR120 agonist TUG-891 in diabetic nephropathy (DN) and investigated the possible mechanisms.
Methods
The expression of GPR120 was detected in human renal biopsy tissue obtained from 18 patients with early or advanced DN and in normal renal tissues from patients with renal-cell carcinoma. Effects of TUG-891 on development of DN was investigated in male C57BLKS/J db/db mice and podocytes. TUG891 was administered by oral gavage at 35 mg/kg body weight once every 24 h in db/db mice for 4 weeks. Murine podocytes (MPC5) were cultured in high glucose (30mmol/L) and with TUG-891 (10umol/L). Collagen type 4, fibronectin, αSMA and TGF-β/smad2/3 were examined in vivo and in vitro. Furthermore, GPR120/β-arrestin2/TAK1 binding protein-1 pathway was measured.
Results
Decrease levels of GPR120 were detected in renal tissues from patients with DN. The intensity of GPR120 staining was negatively correlated with the progression of the disease. In db/db mice, administration of GPR120 agonist, TUG-891, attenuated urinary albumin excretion and delay the extent of glomerulosclerosis and tubulointerstitial fibrosis. Renal fibronectin, collagen type 4 and TGF-β/smad2/3 expressions were reduced by TUG-891. Nevertheless, GPR120 and β-arrestin2 expression were increased after TUG-891 treatment. The coexpression of GPR120 and nephrin were detected in kidney. In high-glucose-treated murine podocytes (MPC5), TUG-891 decreased the subsequent expression of collagen type 4, fibronectin, αSMA and TGF-β/smad2/3. It upregulated expression of GPR120 and β-arrestin2, suppressed the downstream TAK1/IKK/JNK/NF-κB signaling pathway of TAK1 binding protein-1, thus restored podocytes dysfunction.
Conclusion
Our results show that TUG-891 ameliorates kidney fibrosis and podocyte injury by activating the intracellular GPR120/β-arrestin2/TAK1 binding protein-1 pathway, which suggests its efficacy for treating type 2 diabetes associated DN.
Funding
- Government Support - Non-U.S.