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The glucagon-like peptide-1 (GLP-1) analog liraglutide attenuates renal fibrosis.
Pharmacol Res. 2018 05; 131:102-111.PR

Abstract

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-β1). The results indicated that UUO increased collagen deposition and the mRNA expression of fibronectin (FN) and collagen type I alpha 1 (Col1α1) in the obstructed kidney tissues. The effects were blunted in liraglutide-treated UUO mice compared with control mice. The upregulation of Snail1 and alpha smooth muscle actin (α-SMA), and downregulation of E-cadherin revealed that EMT occurred in the UUO kidneys, and these effects were ameliorated following liraglutide treatment. Additionally, liraglutide treatment decreased the expression of TGF-β1 and its receptor (TGF-β1R) 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-β1. In addition, the Smad3 and ERK1/2 signaling pathways were highly activated in cells cultured with TGF-β1. 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-β1 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-β1/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.

Authors+Show Affiliations

Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, and Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, and Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China; Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, and Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong, University of Science and Technology, Wuhan, China.Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, and Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.Institute of organ transplantation, Changhai Hospital, Second Military Medical University, Shanghai, China.Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, and Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong, University of Science and Technology, Wuhan, China. Electronic address: shuyanwen@yahoo.com.Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, and Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China. Electronic address: jy@tjh.tjmu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29530599

Citation

Li, Ya-Kun, et al. "The Glucagon-like Peptide-1 (GLP-1) Analog Liraglutide Attenuates Renal Fibrosis." Pharmacological Research, vol. 131, 2018, pp. 102-111.
Li YK, Ma DX, Wang ZM, et al. The glucagon-like peptide-1 (GLP-1) analog liraglutide attenuates renal fibrosis. Pharmacol Res. 2018;131:102-111.
Li, Y. K., Ma, D. X., Wang, Z. M., Hu, X. F., Li, S. L., Tian, H. Z., Wang, M. J., Shu, Y. W., & Yang, J. (2018). The glucagon-like peptide-1 (GLP-1) analog liraglutide attenuates renal fibrosis. Pharmacological Research, 131, 102-111. https://doi.org/10.1016/j.phrs.2018.03.004
Li YK, et al. The Glucagon-like Peptide-1 (GLP-1) Analog Liraglutide Attenuates Renal Fibrosis. Pharmacol Res. 2018;131:102-111. PubMed PMID: 29530599.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The glucagon-like peptide-1 (GLP-1) analog liraglutide attenuates renal fibrosis. AU - Li,Ya-Kun, AU - Ma,Dong-Xia, AU - Wang,Zhi-Min, AU - Hu,Xiao-Fan, AU - Li,Shang-Lin, AU - Tian,Hong-Zhe, AU - Wang,Meng-Jun, AU - Shu,Yan-Wen, AU - Yang,Jun, Y1 - 2018/03/09/ PY - 2017/09/13/received PY - 2018/02/07/revised PY - 2018/03/07/accepted PY - 2018/3/14/pubmed PY - 2019/2/1/medline PY - 2018/3/14/entrez KW - Chronic kidney disease KW - Epithelial-mesenchymal transition KW - Exendin-3 (9-39) (PubChem CID: 16198321) KW - GLP-1 KW - Liraglutide KW - Liraglutide (PubChem CID: 16134956) KW - Renal fibrosis SP - 102 EP - 111 JF - Pharmacological research JO - Pharmacol. Res. VL - 131 N2 - 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-β1). The results indicated that UUO increased collagen deposition and the mRNA expression of fibronectin (FN) and collagen type I alpha 1 (Col1α1) in the obstructed kidney tissues. The effects were blunted in liraglutide-treated UUO mice compared with control mice. The upregulation of Snail1 and alpha smooth muscle actin (α-SMA), and downregulation of E-cadherin revealed that EMT occurred in the UUO kidneys, and these effects were ameliorated following liraglutide treatment. Additionally, liraglutide treatment decreased the expression of TGF-β1 and its receptor (TGF-β1R) 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-β1. In addition, the Smad3 and ERK1/2 signaling pathways were highly activated in cells cultured with TGF-β1. 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-β1 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-β1/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. SN - 1096-1186 UR - https://www.unboundmedicine.com/medline/citation/29530599/The_glucagon_like_peptide_1__GLP_1__analog_liraglutide_attenuates_renal_fibrosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1043-6618(17)31160-X DB - PRIME DP - Unbound Medicine ER -