Sodium–glucose cotransporter 2 inhibition normalizes glucose metabolism and suppresses oxidative stress in the kidneys of diabetic mice
2018
It is unclear whether long-term sodium–glucose
cotransporter2 (SGLT2) inhibition such as that during the treatment of diabetes has deleterious effects on the kidney. Therefore, we first sought to determine whether abnormal glucose metabolism occurs in the kidneys of 22-week-old BTBR ob/ob diabetic mice. Second, the cumulative effect of chronic SGLT2 inhibition by
ipragliflozinand 30%
calorie restriction, either of which lowered blood glucose to a similar extent, on renal glucose metabolism was evaluated. Mass spectrometry–based metabolomics demonstrated that these diabetic mice exhibited an abnormal elevation in the renal pools of
tricarboxylic acidcycle metabolites. This was almost completely nullified by SGLT2 inhibition and
calorie restriction. Moreover, imaging mass spectrometry indicated an increased level of the
tricarboxylic acidcycle intermediate, citrate, in the cortex of the diabetic mice. SGLT2 inhibition as well as
calorie restrictionalmost completely eliminated citrate accumulation in the cortex. Furthermore, imaging mass spectrometry revealed that the accumulation of oxidized glutathione in the cortex of the kidneys, prominent in the glomeruli, was also canceled by SGLT2 inhibition and
calorie restriction. Effects of these beneficial interventions were consistent with improvements in glomerular damage, such as
albuminuria,
glomerular hyperfiltration, and mesangial expansion. Tubulointerstitial macrophage infiltration and fibrosis were ameliorated only by
calorie restriction, which may have been due to autophagy activation, which was observed only with
calorie restriction. Thus, chronic SGLT2 inhibition is efficient in normalizing the levels of accumulated
tricarboxylic acidcycle intermediates and increased oxidative stress in the kidneys of diabetic mice.
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