TY - JOUR
T1 - Glucagon-like peptide-1 receptor pathway inhibits extracellular matrix production by mesangial cells through store-operated Ca2+ channel
AU - Huang, Linjing
AU - Ma, Rong
AU - Lin, Tingting
AU - Chaudhari, Sarika
AU - Shotorbani, Parisa Y.
AU - Yang, Liyong
AU - Wu, Peiwen
N1 - Funding Information:
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 Ca 2+ 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 Ca 2+ channel signaling in MCs could be an option for patients with diabetic kidney disease. Glucagon-like peptide-1 receptor store-operated calcium entry mesangial cells extracellular matrix diabetic kidney disease liraglutide National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease 1RO1DK115424-01 National Natural Science Foundation of China http://doi.org/10.13039/501100001809 81870572 Medical Innovation Fund Project of Fujian Province 2018-CX-23 Scientific and Technological Innovation Foundation of Fujian Province 2017Y9091
Publisher Copyright:
© 2019 by the Society for Experimental Biology and Medicine.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
AB - 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.
KW - Glucagon-like peptide-1 receptor
KW - diabetic kidney disease
KW - extracellular matrix
KW - liraglutide
KW - mesangial cells
KW - store-operated calcium entry
UR - http://www.scopus.com/inward/record.url?scp=85073306766&partnerID=8YFLogxK
U2 - 10.1177/1535370219876531
DO - 10.1177/1535370219876531
M3 - Article
C2 - 31510798
AN - SCOPUS:85073306766
SN - 1535-3702
VL - 244
SP - 1193
EP - 1201
JO - Experimental Biology and Medicine
JF - Experimental Biology and Medicine
IS - 14
ER -