Dysfunctional glucose metabolism triggers oxidative stress to induce kidney injury in diabetes

Abstract

In this editorial, we discussed the article published in the recent issue of the World Journal of Diabetes. To understand the effect of mizagliflozin on kidney injury induced by diabetes, we focused on the mechanisms by which high glucose triggers oxidative stress and contributes to kidney injury in diabetes. The high level of unmetabolized glucose reaching the kidney triggers glucose reabsorption by renal tubules, which elevates the cellular glucose level of renal cells. High glucose induces lactate dehydrogenase overexpression and thus shifts glucose metabolism, which causes mitochondrial dysfunction. Mitochondria generate approximately 90% of the reactive oxygen species in cells, whose dysfunction further alters glucose metabolism and enhances reactive oxygen species generation. Oxidative stress stimulates proinflammatory factor production and kidney inflammatory injury. Mizagliflozin decreases glucose reabsorption and thus ameliorates diabetes-induced kidney injury.

Keywords: Glucose metabolism; Glucose reabsorption; Inflammation; Mitochondrial dysfunction; Reactive oxygen species; Sodium-D-glucose cotransporter 1.

Figure 1

Common complications of diabetes mellitus. Chronic hyperglycemia stimulates tissues and organs, which causes multiple problems and pathological changes including retinopathy, neuropathy, nephropathy, cardiovascular diseases, and chronic healing.

Figure 2

High glucose induces kidney cell injury and the protective effect of mizagliflozin. High glucose is absorbed into the cytosol and induces lactate dehydrogenase overexpression and thus shifts metabolism (glycolysis and fatty acid oxidation), which causes mitochondrial dysfunction. Dysfunctional mitochondria generate excessive reactive oxygen species, causing oxidative stress. Low-density lipoprotein oxidation leads to nuclear factor kappa B activation, which further triggers the expression of inflammatory factors. Oxidative stress and inflammation contribute to kidney cell injury. Mizagliflozin inhibits sodium-D-glucose cotransporter 1 and changes these processes, thus protecting cells. LDH: Lactate dehydrogenase; LDL: Low-density lipoproteins; NF-κB: Nuclear factor kappa B; ROS: reactive oxygen species; SGLT1: Sodium-D-glucose cotransporter 1.