Imeglimin protects against acute kidney injury caused by transient ischemia

Abstract

Imeglimin is a first-in-class oral antidiabetic that enhances glucose-induced insulin secretion and improves insulin resistance. Although imeglimin has been shown to exert protective effects on β-cells and hepatocytes partly by reducing the production of reactive oxygen species, its renoprotective effects remain largely unknown. In this study, we evaluated the effects of imeglimin on the kidneys using a mouse model of acute kidney injury induced by ischemia-reperfusion injury. Imeglimin significantly attenuated the increase in serum creatinine and blood urea nitrogen levels, as well as histological kidney injury. Gene ontology analysis of differentially expressed genes identified by RNA-sequencing of kidney tissues revealed that pathways related to inflammation were enriched in genes downregulated by imeglimin, whereas lipid metabolism and regulation of sodium ion transport were among the top enriched categories for genes upregulated by imeglimin. Moreover, ischemia-induced increase in the number of γH2AX-positive nuclei in proximal tubules was significantly suppressed by imeglimin. In addition, imeglimin inhibited increase in reactive oxygen species levels in human proximal tubule cells induced by transient hypoxia. These results indicate that imeglimin protects the kidney from ischemia-reperfusion injury by attenuating inflammatory responses and DNA damage, thereby maintaining gene expression associated with renal function. This protective effect may be partly mediated by a reduction in reactive oxygen species production. The potential of imeglimin to provide clinically meaningful protection against kidney complications warrants further investigation, considering the protective effects observed in ischemia-reperfusion injury.