The glucagon-like peptide-1 (GLP-1) analog liraglutide attenuates renal fibrosis

被引：65

作者：

Li, Ya-Kun ^{[1
,2
]}

Ma, Dong-Xia ^{[1
,2
,3
]}

Wang, Zhi-Min ^{[1
,2
]}

Hu, Xiao-Fan ^{[4
]}

Li, Shang-Lin ^{[1
,2
]}

Tian, Hong-Zhe ^{[5
]}

Wang, Meng-Jun ^{[1
,2
]}

Shu, Yan-Wen ^{[4
]}

Yang, Jun ^{[1
,2
]}

机构：

[1] Huazhong Univ Sci & Technol, Key Lab Organ Transplantat, Minist Educ, Inst Organ Transplantat,Tongji Hosp,Tongji Med Co, Wuhan 430030, Hubei, Peoples R China

[2] Minist Hlth, Key Lab Organ Transplantat, Wuhan 430030, Hubei, Peoples R China

[3] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Allergy, Wuhan, Hubei, Peoples R China

[4] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Lab Cardiovasc Immunol,Inst Cardiol, Wuhan 430022, Hubei, Peoples R China

[5] Second Mil Med Univ, Changhai Hosp, Inst Organ Transplantat, Shanghai, Peoples R China

来源：

PHARMACOLOGICAL RESEARCH | 2018年 / 131卷

基金：

中国国家自然科学基金;

关键词：

Chronic kidney disease; Renal fibrosis; Epithelial-mesenchymal transition; GLP-1; Liraglutide; TO-MESENCHYMAL TRANSITION; UNILATERAL URETERAL OBSTRUCTION; INTERSTITIAL FIBROSIS; KIDNEY FIBROSIS; MECHANISMS; RECEPTOR; CELLS; MICE; EXPRESSION; EXENDIN-4;

D O I：

10.1016/j.phrs.2018.03.004

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Renal fibrosis is recognized as the common route of all chronic kidney disease (CKD) progressing to end-stage renal disease (ESRD). Additionally, accumulating evidence suggests that epithelial-mesenchymal transition (EMT) plays a significant role in the process of renal fibrogenesis. Liraglutide is a long-acting glucagon-like peptide-1 (GLP-1) analog that has been widely used to treat type 2 diabetes. Recent studies have demonstrated that the GLP-1 analogs could also exert protective effects in cardiac fibrosis models. However, the effects of liraglutide on the progression of CKD remain largely unknown. In the present study, we investigated the effects of liraglutide on the progression to renal fibrosis induced by unilateral ureteral obstruction (UUO) and EMT of rat renal tubular epithelial cells (NRK-52E) induced with recombinant transforming growth factor-beta 1 (TGF-beta 1). The results indicated that UUO increased collagen deposition and the mRNA expression of fibronectin (FN) and collagen type I alpha 1 (Col1 alpha 1) in the obstructed kidney tissues. The effects were blunted in liraglutide-treated UUO mice compared with control mice. The upregulation of Snaill and alpha smooth muscle actin (alpha-SMA), and downregulation of E-calherin revealed that EMT occurred in the UUO kidneys, and these effects were ameliorated following liraglutide treatment. Additionally, liraglutide treatment decreased the expression of TGF-beta 1 and its receptor (TGF-beta 1R) and inhibited the activation of its downstream signaling molecules (pSmad3 and pERK1/2). The in vitro results showed that the EMT and extracellular matrix (ECM) secretion of NRK-52E cells were induced by TGF-beta 1. In addition, the Smad3 and ERK1/2 signaling pathways were highly activated in cells cultured with TGF-beta 1. All these effects were attenuated by liraglutide treatment. However, the protective effects of liraglutide were abolished by co-incubation of the GLP-1 receptor (GLP-1R) antagonist exendin-3 (9-39). These results suggest that liraglutide attenuates the EMT and ECM secretion of NRK-52E cells induced by TGF-beta 1 and EMT and renal fibrosis induced by UUO. The potential mechanism involves liraglutide binding to and activating GLP-1R, which prevents EMT by inhibiting the activation of TGF-beta 1/Smad3 and ERK1/2 signaling pathways, thereby decreasing the ECM secretion and deposition. Therefore, liraglutide is a promising therapeutic agent that may halt the progression of renal fibrosis.

引用

页码：102 / 111

页数：10

共 42 条

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