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

Linjing Huang, Rong Ma, Tingting Lin, Sarika Chaudhari, Parisa Y. Shotorbani, Liyong Yang, Peiwen Wu

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1193-1201
Number of pages9
JournalExperimental Biology and Medicine
Volume244
Issue number14
DOIs
StatePublished - 1 Oct 2019

Fingerprint

Mesangial Cells
Extracellular Matrix
Extracellular Matrix Proteins
Glucose
Fibronectins
Collagen
Chemical activation
Diabetic Nephropathies
Up-Regulation
Glucagon-Like Peptide-1 Receptor
Liraglutide
Health care
Proteins
Experiments
Delivery of Health Care
Kidney
Imaging techniques

Keywords

  • Glucagon-like peptide-1 receptor
  • diabetic kidney disease
  • extracellular matrix
  • liraglutide
  • mesangial cells
  • store-operated calcium entry

Cite this

Huang, Linjing ; Ma, Rong ; Lin, Tingting ; Chaudhari, Sarika ; Shotorbani, Parisa Y. ; Yang, Liyong ; Wu, Peiwen. / Glucagon-like peptide-1 receptor pathway inhibits extracellular matrix production by mesangial cells through store-operated Ca2+ channel. In: Experimental Biology and Medicine. 2019 ; Vol. 244, No. 14. pp. 1193-1201.
@article{5360f638428b4fb9a048fd551f91ff74,
title = "Glucagon-like peptide-1 receptor pathway inhibits extracellular matrix production by mesangial cells through store-operated Ca2+ channel",
abstract = "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.",
keywords = "Glucagon-like peptide-1 receptor, diabetic kidney disease, extracellular matrix, liraglutide, mesangial cells, store-operated calcium entry",
author = "Linjing Huang and Rong Ma and Tingting Lin and Sarika Chaudhari and Shotorbani, {Parisa Y.} and Liyong Yang and Peiwen Wu",
year = "2019",
month = "10",
day = "1",
doi = "10.1177/1535370219876531",
language = "English",
volume = "244",
pages = "1193--1201",
journal = "Experimental Biology and Medicine",
issn = "1535-3702",
publisher = "SAGE Publications Inc.",
number = "14",

}

Glucagon-like peptide-1 receptor pathway inhibits extracellular matrix production by mesangial cells through store-operated Ca2+ channel. / Huang, Linjing; Ma, Rong; Lin, Tingting; Chaudhari, Sarika; Shotorbani, Parisa Y.; Yang, Liyong; Wu, Peiwen.

In: Experimental Biology and Medicine, Vol. 244, No. 14, 01.10.2019, p. 1193-1201.

Research output: Contribution to journalArticle

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

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

VL - 244

SP - 1193

EP - 1201

JO - Experimental Biology and Medicine

JF - Experimental Biology and Medicine

SN - 1535-3702

IS - 14

ER -