Diabetes & Metabolism Journal

Brief Report

Drug/Regimen
Evogliptin, a Dipeptidyl Peptidase-4 Inhibitor, Attenuates Renal Fibrosis Caused by Unilateral Ureteral Obstruction in Mice: Mi-Jin Kim, Na-young Kim, Yun-A Jung, Seunghyeong Lee, Gwon-Soo Jung, Jung-Guk Kim, In-Kyu Lee, Sungwoo Lee, Yeon-Kyung Choi, Keun-Gyu Park; Diabetes Metab J. 2020;44(1):186-192. Published online October 31, 2019; DOI: https://doi.org/10.4093/dmj.2018.0271

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Renal fibrosis is considered to be the final common outcome of chronic kidney disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors have demonstrated protective effects against diabetic kidney disease. However, the anti-fibrotic effect of evogliptin, a DPP-4 inhibitor, has not been studied. Here, we report the beneficial effects of evogliptin on unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Evogliptin attenuated UUO-induced renal atrophy and tubulointerstitial fibrosis. Immunohistochemistry and Western blotting demonstrated that evogliptin treatment inhibits pro-fibrotic gene expressions and extracellular matrix production. In vitro findings showed that the beneficial effects of evogliptin on renal fibrosis are mediated by inhibition of the transforming growth factor-β/Smad3 signaling pathway. The present study demonstrates that evogliptin is protective against UUO-induced renal fibrosis, suggesting that its clinical applications could extend to the treatment of kidney disease of non-diabetic origin.

Citations

Citations to this article as recorded by

Targeting cluster of differentiation 26 / dipeptidyl peptidase 4 (CD26/DPP4) in organ fibrosis
Birte Ohm, Isabelle Moneke, Wolfgang Jungraithmayr
British Journal of Pharmacology.2023; 180(22): 2846. CrossRef
Linagliptin ameliorates pulmonary fibrosis in systemic sclerosis mouse model via inhibition of endothelial-to-mesenchymal transition
Biwei Pei, Na Zhang, Tingting Pang, Gengyun Sun
Molecular and Cellular Biochemistry.2022; 477(4): 995. CrossRef
Association Between DPP4 Inhibitor Use and the Incidence of Cirrhosis, ESRD, and Some Cancers in Patients With Diabetes
Yewon Na, Soo Wan Kim, Ie Byung Park, Soo Jung Choi, Seungyoon Nam, Jaehun Jung, Dae Ho Lee
The Journal of Clinical Endocrinology & Metabolism.2022; 107(11): 3022. CrossRef
Evogliptin Directly Inhibits Inflammatory and Fibrotic Signaling in Isolated Liver Cells
Hye-Young Seo, So-Hee Lee, Eugene Han, Jae Seok Hwang, Sol Han, Mi Kyung Kim, Byoung Kuk Jang
International Journal of Molecular Sciences.2022; 23(19): 11636. CrossRef
Optimization and validation of a fluorogenic dipeptidyl peptidase 4 enzymatic assay in human plasma
Hyunyee Yoon, Su Hee Cho, Yu Rim Seo, Kyung-Sang Yu, Sung Sup Park, Moon Jung Song
Analytical Biochemistry.2021; 612: 113952. CrossRef
Use of Anti-Diabetic Agents in Non-Diabetic Kidney Disease: From Bench to Bedside
Sungjin Chung, Gheun-Ho Kim
Life.2021; 11(5): 389. CrossRef
Targeting Dermal Fibroblast Subtypes in Antifibrotic Therapy: Surface Marker as a Cellular Identity or a Functional Entity?
Xin Huang, Yimin Khoong, Chengyao Han, Dai Su, Hao Ma, Shuchen Gu, Qingfeng Li, Tao Zan
Frontiers in Physiology.2021;[Epub] CrossRef
Efficacy and safety of evogliptin treatment in patients with type 2 diabetes: A multicentre, active‐controlled, randomized, double‐blind study with open‐label extension (the EVERGREEN study)
Gyuri Kim, Soo Lim, Hyuk‐Sang Kwon, Ie B. Park, Kyu J. Ahn, Cheol‐Young Park, Su K. Kwon, Hye S. Kim, Seok W. Park, Sin G. Kim, Min K. Moon, Eun S. Kim, Choon H. Chung, Kang S. Park, Mikyung Kim, Dong J. Chung, Chang B. Lee, Tae H. Kim, Moon‐Kyu Lee
Diabetes, Obesity and Metabolism.2020; 22(9): 1527. CrossRef
Effect of Switching from Linagliptin to Teneligliptin Dipeptidyl Peptidase-4 Inhibitors in Older Patients with Type 2 Diabetes Mellitus

Eugene Han, Minyoung Lee, Yong-ho Lee, Hye Soon Kim, Byung-wan Lee, Bong-Soo Cha, Eun Seok Kang
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy.2020; Volume 13: 4113. CrossRef
Efficacy and safety of novel dipeptidyl-peptidase-4 inhibitor evogliptin in the management of type 2 diabetes mellitus: A meta-analysis
Deep Dutta, Saptarshi Bhattacharya, Aishwarya Krishnamurthy, LokeshKumar Sharma, Meha Sharma
Indian Journal of Endocrinology and Metabolism.2020; 24(5): 434. CrossRef

Original Articles

Complications
Gemigliptin Attenuates Renal Fibrosis Through Down-Regulation of the NLRP3 Inflammasome: Jung Beom Seo, Yeon-Kyung Choi, Hye-In Woo, Yun-A Jung, Sungwoo Lee, Seunghyeong Lee, Mihyang Park, In-Kyu Lee, Gwon-Soo Jung, Keun-Gyu Park; Diabetes Metab J. 2019;43(6):830-839. Published online March 5, 2019; DOI: https://doi.org/10.4093/dmj.2018.0181

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Abstract PDF PubReader

Background

The hypoglycemic drugs dipeptidyl peptidase-4 (DPP-4) inhibitors have proven protective effects on diabetic kidney disease, including renal fibrosis. Although NOD-like receptor protein 3 (NLRP3) inflammasome activation is known to play an important role in the progression of renal fibrosis, the impact of DPP-4 inhibition on NLRP3-mediated inflammation while ameliorating renal fibrosis has not been fully elucidated. Here, we report that the renoprotective effect of gemigliptin is associated with a reduction in NLRP3-mediated inflammation in a murine model of renal fibrosis.

Methods

We examined the effects of gemigliptin on renal tubulointerstitial fibrosis induced in mice by unilateral ureteral obstruction (UUO). Using immunohistochemical and Western blot analysis, we quantitated components of the NLRP3 inflammasome in kidneys with and without gemigliptin treatment, and in vitro in human kidney tubular epithelial human renal proximal tubule cells (HK-2) cells, we further analyzed the effect of gemigliptin on transforming growth factor-β (TGF-β)-stimulated production of profibrotic proteins.

Results

Immunohistological examination revealed that gemigliptin ameliorated UUO-induced tubular atrophy and renal fibrosis. Gemigliptin-treated kidneys showed a reduction in levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin-1β, which had all been markedly increased by UUO. In line with the in vivo results, TGF-β markedly increased NLRP3 inflammasome markers, which were attenuated by gemigliptin treatment. Furthermore, gemigliptin treatment attenuated phosphorylated nuclear factor-κB levels, which had been increased in the UUO kidney as well as in TGF-β-treated cultured renal cells.

Conclusion

The present study shows that activation of the NLRP3 inflammasome contributes to UUO-induced renal fibrosis and the renoprotective effect of gemigliptin is associated with attenuation of NLRP3 inflammasome activation.

Citations

Citations to this article as recorded by

Novel pharmacological interventions for diabetic kidney disease
Seng Kiong Tan, Jairo A. Pinzon-Cortes, Mark E. Cooper
Current Opinion in Nephrology & Hypertension.2024; 33(1): 13. CrossRef
Integrated analysis reveals crosstalk between pyroptosis and immune regulation in renal fibrosis
Fengxia Bai, Longchao Han, Jifeng Yang, Yuxiu Liu, Xiangmeng Li, Yaqin Wang, Ruijian Jiang, Zhaomu Zeng, Yan Gao, Haisong Zhang
Frontiers in Immunology.2024;[Epub] CrossRef
Di (2-ethylhexyl) phthalate and polystyrene microplastics co-exposure caused oxidative stress to activate NF-κB/NLRP3 pathway aggravated pyroptosis and inflammation in mouse kidney
Shanshan Li, Xuedie Gu, Muyue Zhang, Qihang Jiang, Tong Xu
Science of The Total Environment.2024; 926: 171817. CrossRef
Fluorofenidone attenuates renal fibrosis by inhibiting lysosomal cathepsin‑mediated NLRP3 inflammasome activation
Linfeng Zheng, Wenjuan Mei, Jing Zhou, Xin Wei, Zhijuan Huang, Xiaozhen Lin, Li Zhang, Wei Liu, Qian Wu, Jinhong Li, Yan Yan
Experimental and Therapeutic Medicine.2024;[Epub] CrossRef
Gemigliptin mitigates TGF-β-induced renal fibrosis through FGF21-mediated inhibition of the TGF-β/Smad3 signaling pathway
Jun-Kyu Byun, Gwon-Soo Jung
Biochemical and Biophysical Research Communications.2024; 733: 150425. CrossRef
Uncovering the Role of Anoikis-Related Genes in Modulating Immune Infiltration and Pathogenesis of Diabetic Kidney Disease
Jiaqiong Lin, Yan Lin, Xiaoyong Li, Fei He, Qinyuan Gao, Yuanjun Wang, Zena Huang, Fu Xiong
Journal of Inflammation Research.2024; Volume 17: 4975. CrossRef
Activation of NLRP3 inflammasome in patients with renal transplantation: relation to allograft dysfunction, inflammation, and renal fibrosis
Hayam Abdel Meguid El Aggan, Hala Saddik El-Wakil, Sabah Abdel-Hady Mahmoud, Aya Ahmad Saad
Alexandria Journal of Medicine.2024; 60(1): 249. CrossRef
Therapy Targeted to the NLRP3 Inflammasome in Chronic Kidney Disease
Yong Ji, Hu Hua, Zhanjun Jia, Aihua Zhang, Guixia Ding
Kidney Diseases.2024; : 369. CrossRef
HIF1α-BNIP3-mediated mitophagy protects against renal fibrosis by decreasing ROS and inhibiting activation of the NLRP3 inflammasome
Jialin Li, Qisheng Lin, Xinghua Shao, Shu Li, Xuying Zhu, Jingkui Wu, Shan Mou, Leyi Gu, Qin Wang, Minfang Zhang, Kaiqi Zhang, Jiayue Lu, Zhaohui Ni
Cell Death & Disease.2023;[Epub] CrossRef
Pyroptosis in renal inflammation and fibrosis: current knowledge and clinical significance
Ya Liu, Haibo Lei, Wenyou Zhang, Qichang Xing, Renzhu Liu, Shiwei Wu, Zheng Liu, Qingzi Yan, Wencan Li, Xiang Liu, Yixiang Hu
Cell Death & Disease.2023;[Epub] CrossRef
Tubular injury in diabetic kidney disease: molecular mechanisms and potential therapeutic perspectives
Yu Wang, Mingyue Jin, Chak Kwong Cheng, Qiang Li
Frontiers in Endocrinology.2023;[Epub] CrossRef
Hederagenin inhibits high glucose‐induced fibrosis in human renal cells by suppression of NLRP3 inflammasome activation through reducing cathepsin B expression
Guohua Yang, Wang Yang, Hairong Jiang, Qing Yi, Wei Ma
Chemical Biology & Drug Design.2023; 102(6): 1409. CrossRef
Obstructive nephropathy and molecular pathophysiology of renal interstitial fibrosis
Rikke Nørregaard, Henricus A. M. Mutsaers, Jørgen Frøkiær, Tae-Hwan Kwon
Physiological Reviews.2023; 103(4): 2847. CrossRef
Adenine model of chronic renal failure in rats to determine whether MCC950, an NLRP3 inflammasome inhibitor, is a renopreventive
Mahmoud S. Sabra, Fahmy K. Hemida, Essmat A. H. Allam
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Gut microbiota dysbiosis promotes age-related atrial fibrillation by lipopolysaccharide and glucose-induced activation of NLRP3-inflammasome
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Yanqing Liu, Xuezeng Xu, Wangrui Lei, Yuxuan Hou, Yan Zhang, Ran Tang, Zhi Yang, Ye Tian, Yanli Zhu, Changyu Wang, Chao Deng, Shaofei Zhang, Yang Yang
Ageing Research Reviews.2022; 79: 101638. CrossRef
Research progress of endothelial‐mesenchymal transition in diabetic kidney disease
Ying Chen, Hang Zou, Hongwei Lu, Hong Xiang, Shuhua Chen
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Gemigliptin suppresses salivary dysfunction in streptozotocin-induced diabetic rats
Wan Seok Kang, Woo Kwon Jung, Su-Bin Park, Hyung Rae Kim, Junghyun Kim
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Long‐Term Dipeptidyl Peptidase 4 Inhibition Worsens Hypertension and Renal and Cardiac Abnormalities in Obese Spontaneously Hypertensive Heart Failure Rats
Edwin K. Jackson, Zaichuan Mi, Delbert G. Gillespie, Dongmei Cheng, Stevan P. Tofovic
Journal of the American Heart Association.2021;[Epub] CrossRef
Disulfiram inhibits inflammation and fibrosis in a rat unilateral ureteral obstruction model by inhibiting gasdermin D cleavage and pyroptosis
Yu Zhang, Ruicheng Zhang, Xiaohu Han
Inflammation Research.2021; 70(5): 543. CrossRef
Inflammasome as an Effective Platform for Fibrosis Therapy
Ting-Ting Chen, Feng Xiao, Nan Li, Shan Shan, Meng Qi, Zi-Ying Wang, Sheng-Nan Zhang, Wei Wei, Wu-Yi Sun
Journal of Inflammation Research.2021; Volume 14: 1575. CrossRef
Targeting Dermal Fibroblast Subtypes in Antifibrotic Therapy: Surface Marker as a Cellular Identity or a Functional Entity?
Xin Huang, Yimin Khoong, Chengyao Han, Dai Su, Hao Ma, Shuchen Gu, Qingfeng Li, Tao Zan
Frontiers in Physiology.2021;[Epub] CrossRef
Linagliptin Protects against Endotoxin-Induced Acute Kidney Injury in Rats by Decreasing Inflammatory Cytokines and Reactive Oxygen Species
Tsung-Jui Wu, Yi-Jen Hsieh, Chia-Wen Lu, Chung-Jen Lee, Bang-Gee Hsu
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Psidium guajava Flavonoids Prevent NLRP3 Inflammasome Activation and Alleviate the Pancreatic Fibrosis in a Chronic Pancreatitis Mouse Model
Guixian Zhang, Liming Tang, Hongbin Liu, Dawei Liu, Manxue Wang, Jun Cai, Weijun Liu, Wei Nie, Yi Zhang, Xiaomeng Yu
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Effect and Regulation of the NLRP3 Inflammasome During Renal Fibrosis
Hong Zhang, Zhengchao Wang
Frontiers in Cell and Developmental Biology.2020;[Epub] CrossRef
Zhen-Wu-Tang Protects IgA Nephropathy in Rats by Regulating Exosomes to Inhibit NF-κB/NLRP3 Pathway
Honglian Li, Ruirui Lu, Yu Pang, Jicheng Li, Yiwen Cao, Hongxin Fu, Guoxing Fang, Qiuhe Chen, Bihao Liu, Junbiao Wu, Yuan Zhou, Jiuyao Zhou
Frontiers in Pharmacology.2020;[Epub] CrossRef
Protective effect of exogenous hydrogen sulfide on diaphragm muscle fibrosis in streptozotocin-induced diabetic rats
Rui Yang, Qiang Jia, Yan Li, Shomaila Mehmood
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Complications
Serum Levels of PCSK9 Are Associated with Coronary Angiographic Severity in Patients with Acute Coronary Syndrome: Kwi-Hyun Bae, Sung Woo Kim, Yeon-Kyung Choi, Jung Beom Seo, Namkyun Kim, Chang-Yeon Kim, Won Kee Lee, Sungwoo Lee, Jung Guk Kim, In-Kyu Lee, Jang Hoon Lee, Keun-Gyu Park; Diabetes Metab J. 2018;42(3):207-214. Published online May 2, 2018; DOI: https://doi.org/10.4093/dmj.2017.0081

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Background

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that promotes degradation of the low density lipoprotein receptor. PCSK9 has emerged as a target for lipid-lowering therapy, but the predictive value of the serum level of PCSK9 for the severity of coronary disease is largely unknown.

Methods

From December 2009 to July 2012, 121 individuals who underwent coronary angiography (CAG) because of clinically suspected acute coronary syndrome were enrolled in this study. Serum levels of PCSK9 and metabolic parameters were measured. SYNTAX (SYNergy between percutaneous coronary intervention with [paclitaxel-eluting] TAXUS stent and cardiac surgery) and GRACE (Global Registry of Acute Coronary Events) scores were calculated.

Results

Individuals with CAG lesions (n=100) had significantly higher levels of PCSK9 than those without lesions (n=21). The study population was stratified into three groups according to serum levels of PCSK9. The odds radio for occurrence of one or more CAG lesions was significantly higher in the group with the highest level of PCSK9 (odds ratio, 7.468; P=0.011) than in the group with the lowest level of PCSK9. Serum PCSK9 was positively associated with the number of involved coronary arteries. Multivariable linear regression indicated that levels of PCSK9 were positively correlated with GRACE risk scores and SYNTAX scores.

Conclusion

Serum PCSK9 concentrations are higher in patients with coronary artery lesions, and are associated with SYNTAX and GRACE scores, suggesting that PCSK9 is a potential biomarker of the severity of coronary artery disease.

Citations

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Letter: Serum Levels of PCSK9 Are Associated with Coronary Angiographic Severity in Patients with Acute Coronary Syndrome (Diabetes Metab J 2018;42:207-14)
Jin Hwa Kim
Diabetes & Metabolism Journal.2018; 42(4): 348. CrossRef
Response: Serum Levels of PCSK9 Are Associated with Coronary Angiographic Severity in Patients with Acute Coronary Syndrome (Diabetes Metab J 2018;42:207-14)
Sung Woo Kim, Keun-Gyu Park
Diabetes & Metabolism Journal.2018; 42(4): 350. CrossRef
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Lipids in Health and Disease.2018;[Epub] CrossRef

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