Liraglutide suppresses production of extracellular matrix proteins and ameliorates renal injury of diabetic nephropathy by enhancing Wnt/β-catenin signaling.
The Wnt/β-catenin signaling pathway is involved in production of the extracellular matrix (ECM) by mesangial cells (MCs). Recent studies by us and others have demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) have protective effects against diabetic nephropathy. The purpose of the present study was to investigate whether the Wnt/β-catenin signaling in MCs contributes to GLP-1RA-induced inhibition of ECM accumulation and mitigation of glomerular injury in diabetic nephropathy. In cultured human mesangial cells, liraglutide (a GLP-1RA) treatment significantly reduced high glucose (HG)-stimulated production of fibronectin, collagen type IV, and α-smooth muscle actin, and the liraglutide effects were significantly attenuated by XAV-939, a selective inhibitor of Wnt/β-catenin signaling. Furthermore, HG treatment significantly decreased protein abundance of Wnt4, Wnt5a, phospho-glycogen synthase kinase-3β, and β-catenin. These HG effects on Wnt/β-catenin signaling proteins were significantly blunted by liraglutide treatment. For in vivo experiments, we administered liraglutide (200 μg·kg-1·12 h-1) by subcutaneous injection to streptozocin-induced type 1 diabetic rats for 8 wk. Administration of liraglutide significantly improved elevated blood urine nitrogen, serum creatinine, and urinary albumin excretion rate and alleviated renal hypertrophy, mesangial expansion, and glomerular fibrosis in type 1 diabetic rats, whereas blood glucose level and body weight did not have significant changes. Consistent with the in vitro experiments, liraglutide treatment significantly reduced the diabetes-induced increases in glomerular fibronectin, collagen type IV, and α-smooth muscle actin and decreases in glomerular Wnt/β-catenin signaling proteins. These results suggest that liraglutide alleviated glomerular ECM accumulation and renal injury in diabetic nephropathy by enhancing Wnt/β-catenin signaling.
['Huang|Linjing|L|', 'Lin|Tingting|T|', 'Shi|Meizhen|M|', 'Chen|Xiuqing|X|', 'Wu|Peiwen|P|']
D000818:Animals D003921:Diabetes Mellitus, Experimental D003928:Diabetic Nephropathies D016326:Extracellular Matrix Proteins D005786:Gene Expression Regulation D005947:Glucose D006801:Humans D007004:Hypoglycemic Agents D000069450:Liraglutide D008297:Male D050527:Mesangial Cells D051381:Rats D017207:Rats, Sprague-Dawley D015398:Signal Transduction D051153:Wnt Proteins D051176:beta Catenin
extracellular matrix diabetic nephropathy Wnt/β-catenin signaling mesangial cells glucagon-like peptide-1 receptor agonist