4.7 Article

Omarigliptin ameliorated high glucose-induced nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation through activating adenosine monophosphate-activated protein kinase α (AMPKα) in renal glomerular endothelial cells

期刊

BIOENGINEERED
卷 12, 期 1, 页码 4805-4815

出版社

TAYLOR & FRANCIS INC
DOI: 10.1080/21655979.2021.1957748

关键词

Omarigliptin; AMPK; NLRP3 inflammasome; diabetic nephropathy

资金

  1. National Natural Science Foundation of China [81500589, 81974105]

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Omarigliptin shows significant anti-inflammatory effects in diabetic nephropathy by suppressing NLRP3 inflammasome activation and improving inflammation in renal glomerular endothelial cells induced by high glucose.
Diabetic nephropathy (DN) is a complication of diabetes that induces the development of end-stage renal disease (ESRD). The pathogenesis of DN is reported to be closely related to the activation of the NOD-like receptor 3 (NLRP3) inflammasome in renal glomerular endothelial cells. Omarigliptin is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor developed for the management of type II diabetes, it has been recently reported to possess a significant anti-inflammatory property. This study aims to explore the potential therapeutic effects of Omarigliptin on DN. We established an in vitro injury model in human renal glomerular endothelial cells (HrGECs) using high glucose (HG). The severe cytotoxicity and increased oxidative stress in HrGECs induced by HG were pronouncedly reversed by the introduction of Omarigliptin. Furthermore, the activated NLRP3 inflammasome and the excessive production of interleukin 18 (IL-18) and interleukin 1 beta (IL-1 beta) in HrGECs induced by incubation with HG were pronouncedly reversed by the introduction of Omarigliptin, accompanied by the activation of the AMPK/mTOR signaling pathway. After the co-administration of the adenosine monophosphate-activated protein kinase alpha (AMPK alpha) inhibitor, compound C, the protective effects of Omarigliptin against HG-induced NLRP3 inflammasome activation and production of pro-inflammatory factors were dramatically abolished. Taken together, our data revealed that Omarigliptin ameliorated HG-induced inflammation in renal glomerular endothelial cells through suppressing NLRP3 inflammasome activation mediated by AMPK alpha.

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