Glucagon-like peptide-1 receptor pathway inhibits extracellular matrix production by mesangial cells through store-operated Ca2+ channel

Glomerular mesangial cell is the major source of mesangial matrix. Our previous study demonstrated that store-operated CA²⁺ channel signaling suppressed extracellular matrix protein production by mesangial cells. Recent studies demonstrated that glucagon-like peptide-1 receptor (GLP-1R) pathway had renoprotective effects. However, the underlying mechanism(s) remains unclear. The present study was aimed to determine if activation of GLP-1R decreased extracellular matrix protein production by mesangial cells through upregulation of store-operated CA²⁺ function. Experiments were conducted in cultured human mesangial cells. Liraglutide and exendin 9–39 were used to activate and inhibit GLP-1R, respectively. Store-operated CA²⁺ function was estimated by evaluating the SOC-mediated CA²⁺ entry (SOCE). We found that liraglutide treatment reduced high glucose-stimulated production of fibronectin and collagen IV. The inhibitory effects of liraglutide were not observed in the presence of exendin 9–39. Exendin-4, another GLP-1R agonist also blunted high glucose-stimulated fibronectin and collagen IV production. Treatment of human mesangial cells with liraglutide for 24 h significantly attenuated the high glucose-induced reduction of Orai1 protein. Consistently, CA²⁺ imaging experiments showed that the inhibition of high glucose on SOCE was significantly attenuated by liraglutide. However, in the presence of exendin 9–39, liraglutide failed to reverse the high glucose effect. Furthermore, liraglutide effects on fibronectin and collagen IV protein abundance were significantly attenuated by GSK-7975A, a selective blocker of store-operated CA²⁺. Taken together, our findings suggest that GLP-1R signaling inhibited high glucose-induced extracellular matrix protein production in mesangial cells by restoring store-operated CA²⁺ function.

Impact statement: Diabetic kidney disease continues to be a major challenge to health care system in the world. There are no known therapies currently available that can cure the disease. The present study provided compelling evidence that activation of GLP-1R inhibited extracellular matrix protein production by glomerular mesangial cells. We further showed that the beneficial effect of GLP-1R was attributed to upregulation of store-operated CA²⁺ channel function. Therefore, we identified a novel mechanism contributing to the renal protective effects of GLP-1R pathway. Activation of GLP-1R pathway and/or store-operated CA²⁺ channel signaling in MCs could be an option for patients with diabetic kidney disease.