Glucagon-like peptide-1 receptor pathway inhibits extracellular matrix production by mesangial cells through store-operated Ca2+ channel
Glucagon-like peptide-1 receptor pathway inhibits extracellular matrix production by mesangial cells through store-operated Ca2+ channel
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胰高血糖素样肽-1 受体途径通过钙池操纵的 Ca2 通道抑制系膜细胞产生细胞外基质
DOI：
10.1177/1535370219876531
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发表时间：
2019-09
影响因子：
3.2
通讯作者：
Wu Peiwen
中科院分区：
文献类型：
--
作者：
Huang Linjing;Ma Rong;Lin Tingting;Chaudhari Sarika;Shotorbani Parisa Y.;Yang Liyong;Wu Peiwen
肾小球系膜细胞是系膜基质的主要来源。我们之前的研究表明，储存操作的Ca2+通道信号抑制系膜细胞的细胞外基质蛋白的产生。近年来研究表明胰高血糖素样肽-1受体（GLP-1R）途径具有保护肾的作用。然而，其潜在机制尚不清楚。本研究旨在确定GLP-1R的激活是否通过上调储存操作的Ca2+功能来减少系膜细胞的细胞外基质蛋白产生。实验在培养的人系膜细胞中进行。利拉鲁肽和exendin 9-39分别激活和抑制GLP-1R。通过评估soc介导的Ca2+进入（SOCE）来估计存储操作的Ca2+功能。我们发现利拉鲁肽治疗降低了高糖刺激的纤维连接蛋白和胶原蛋白IV的产生。在exendin 9-39存在的情况下，利拉鲁肽没有观察到抑制作用。另一种GLP-1R激动剂Exendin-4也能抑制高糖刺激的纤维连接蛋白和IV型胶原的产生。利拉鲁肽处理人肾小球系膜细胞24小时可显著减弱高糖诱导的Orai1蛋白的降低。一致地，Ca2+成像实验表明，利拉鲁肽显著减弱了高糖对SOCE的抑制作用。然而，在exendin 9-39存在的情况下，利拉鲁肽未能逆转高糖效应。此外，利拉鲁肽对纤维连接蛋白和胶原IV蛋白丰度的影响被GSK-7975A显著减弱，GSK-7975A是一种选择性储存Ca2+阻滞剂。综上所述，我们的研究结果表明，GLP-1R信号通过恢复储存操作的Ca2+功能来抑制高糖诱导的系膜细胞细胞外基质蛋白的产生。糖尿病肾病仍然是世界卫生保健系统面临的主要挑战。目前还没有已知的治疗方法可以治愈这种疾病。本研究提供了令人信服的证据，证明GLP-1R的激活抑制肾小球系膜细胞产生细胞外基质蛋白。我们进一步表明，GLP-1R的有益作用归因于上调储存操作的Ca2+通道功能。因此，我们确定了GLP-1R通路对肾脏保护作用的新机制。MCs中GLP-1R通路和/或储存操作的Ca2+通道信号的激活可能是糖尿病肾病患者的一种选择。
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.
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影响因子：
16.1
作者：
Scindia, Yogesh M.;Deshmukh, Umesh S.;Bagavant, Harini
通讯作者：
Bagavant, Harini
DOI：
10.1152/ajprenal.00437.2011
发表时间：
2012-07-01
影响因子：
4.2
作者：
Blaes, Nelly;Pecher, Christiane;Girolami, Jean-Pierre
通讯作者：
Girolami, Jean-Pierre
影响因子：
6.7
作者：
B. Walker-Allgaier;M. Schaub;I. Alesutan;J. Voelkl;S. Geue;P. Münzer;José M Rodríguez;Dietmar Kuhl;F. Lang;M. Gawaz;O. Borst
通讯作者：
B. Walker-Allgaier;M. Schaub;I. Alesutan;J. Voelkl;S. Geue;P. Münzer;José M Rodríguez;Dietmar Kuhl;F. Lang;M. Gawaz;O. Borst
系膜细胞中钙池操纵的 Ca2 通道抑制基质蛋白表达
影响因子：
13.6
作者：
Wu, Peiwen;Wang, Yanxia;Ma, Rong
通讯作者：
Ma, Rong
影响因子：
4
作者：
J. Zuckerman;A. Gale;Peiwen Wu;R. Ma;Mark E. Davis
通讯作者：
J. Zuckerman;A. Gale;Peiwen Wu;R. Ma;Mark E. Davis