379-P: Imeglimin May Improve Inflammation and Fibrosis in Diabetic Kidney Disease

Introduction and Objective: Imeglimin is an oral hypoglycemic agent marketed from Japan and has shown glucose-lowering effects in Japanese patients with type 2 diabetes in TIMES trials. However, it is not well known whether imeglimin can affect diabetic kidney disease (DKD). To clarify this, we investigated the protective effects of imeglimin on DKD by using diabetic mice and culture cells (HUVEC). Methods: In vivo study, 8-week-age C57BL/6 mice were fed with control diet or high-fat diet (HFD). For HFD-fed mice, streptozocin (STZ) was single intraperitoneally injected at 12 weeks of age, and STZ-induced diabetic mice were orally administered with vehicle or imeglimin from 16 to 24 weeks of age, resulting in three experimental groups: non-diabetes (NDM), diabetes (DM), and DM+Imeglimin. Urinary albumin excretion was measured at 20 and 24 weeks of age, and mice were sacrificed at 24 weeks of age. In vitro study, the effects of imeglimin on high glucose (HG, 25mM)-induced inflammation were tested. HUVEC were stimulated by HG for 72 hours, and vehicle or imeglimin was co-administered. Total RNA was isolated from mouse renal tissue and HUVEC, and mRNA expression was measured by real-time qPCR. Results: At 24 weeks of age, imeglimin did not affect random glucose level and body weight between DM and DM+Imeglimin. Urinary albumin excretion was increased in DM compared with NDM, which was decreased in DM+Imeglimin. The mRNA expression of Nlrp3, Tlr-4, F4/80, inflammatory cytokines (Il-1b, Icam-1, Tnfa), and fibronectin were increased in DM compared with NDM, which were also decreased in DM+Imeglimin. In vitro study, the mRNA expressions of Nlrp3 and Vcam-1 were upregulated by HG stimulation compared with low glucose (5mM) in HUVEC, which were reduced by imeglimin administration. Conclusion: Imeglimin could improve albuminuria in DKD via anti-inflammation and anti-fibrotic actions and may prevent from the progression of DKD. Disclosure Y. Muta: None. H. Yokomizo: None. T. Kawanami: None. Y. Hamaguchi: None. D. Kawanami: None.