The sodium–glucose cotransporter 2 inhibitor tofogliflozin prevents diabetic kidney disease progression in type 2 diabetic mice

• Published in: FEBS open bio Vol. 10; no. 12; pp. 2761 - 2770
• Main Authors: Li, Zi, Murakoshi, Maki, Ichikawa, Saki, Koshida, Takeo, Adachi, Eri, Suzuki, Chigure, Ueda, Seiji, Gohda, Tomohito, Suzuki, Yusuke
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2020; John Wiley and Sons Inc
• Subjects: Age; Antibodies; Blood pressure; Body weight; Creatinine; Diabetes; Diabetes mellitus; diabetic kidney disease; Erythropoietin; Food; Food intake; Gene expression; Glucose; Hemoglobin; Hypoxia; Immunoassay; Kidney diseases; KK‐Ay mouse; Metabolism; Microscopy; Monocyte chemoattractant protein; Monocytes; Polymerase chain reaction; RNA-directed DNA polymerase; SGLT2 inhibitor; Sodium; Sodium-glucose cotransporter; Software; Standard deviation; Statistical analysis; tofogliflozin; Tumor necrosis factor receptors; Tumor necrosis factor-TNF; Water intake; United States > US; Japan; Germany; diabetic kidney disease; tofogliflozin; KK-Ay mouse; SGLT2 inhibitor
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.13014

Tofogliflozin may prevent glomerular (enlarged mesangial area, foot process effacement, podocyte loss) and tubulointerstitial damage (increased expression of MCP‐1 and KIM‐1), partly by ameliorating hyperglycemia, renal inflammation, and abnormal mitochondrial morphology. Trials on cardiovascular and renal outcomes in patients with type 2 diabetes have consistently demonstrated that sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of diabetic kidney disease (DKD) progression. However, their renal protective mechanisms have yet to be completely understood and the effect on albuminuria reduction in animal models is controversial. We investigated these issues using KK and KK‐Ay mice as a control (CTRL) and as a model for type 2 diabetes (DKD), respectively. KK‐Ay mice were treated with 0.015% tofogliflozin, which is an SGLT2 inhibitor, starting at seven weeks of age for eight weeks. Compared with the CTRL mice, the DKD mice had higher HbA1c levels and albuminuria. Although tofogliflozin treatment significantly lowered HbA1c levels, it did not reverse albuminuria. Tofogliflozin treatment enhanced damage in both the glomerular (i.e., enlarged mesangial area, increased foot process effacement rate, and decreased number of WT‐1‐positive cells) and tubulointerstitial (increased protein levels of KIM‐1 and MCP‐1, increased number of macrophages, and abnormal mitochondrial morphology) areas. Our results suggest that tofogliflozin may prevent glomerular and tubulointerstitial damage, partly by ameliorating hyperglycemia, renal inflammation, and abnormal mitochondrial morphology.