TY - JOUR
T1 - Sodium–glucose cotransporter 2 inhibition normalizes glucose metabolism and suppresses oxidative stress in the kidneys of diabetic mice
AU - Tanaka, Shinji
AU - Sugiura, Yuki
AU - Saito, Hisako
AU - Sugahara, Mai
AU - Higashijima, Yoshiki
AU - Yamaguchi, Junna
AU - Inagi, Reiko
AU - Suematsu, Makoto
AU - Nangaku, Masaomi
AU - Tanaka, Tetsuhiro
N1 - Funding Information:
The work of the authors is supported by a Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan 26111003 (MN) and 26111006 (YS), a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science 24390213 (MN), 26461215 (TT), and 16H06145 (YS). This research is also partially supported by the “Development of a novel therapeutic strategy for diabetic kidney disease by using information and communication technology (ICT)” from Japan Agency for Medical Research and Development (AMED). MN has received consulting fees from Astellas Pharma Inc.
Funding Information:
Because IMS allows us to analyze metabolic molecules within microtissue regions, we employed this technology to identify the tissue regions responsible for alterations of GSSG and GSH. GSSG accumulated in the cortex of ob/ob mice, and this accumulation was ameliorated by ipragliflozin treatment and calorie restriction, whereas GSSG accumulation in the inner medulla was not different among the groups (Figure 4b). These distribution patterns are in accordance with those of citrate, which may support a connection between the TCA cycle and oxidative stress, possibly via OxPhos. Interestingly, many “hot spots” of GSSG accumulation were observed in the cortex of the ob/ob vehicle group. By merging the IMS images with periodic acid–Schiff–stained images obtained from the same section, we found that many of the GSSG “hot spots” were colocalized in the glomeruli (Figure 4b). Here ipragliflozin treatment and calorie restriction successfully reduced the intensity of GSSG signals as well as the number of GSSG-accumulated glomeruli. Additionally, GSH was mainly distributed in the glomeruli within the kidney cortex (Figure 4c). The GSH signal in the glomeruli was not evident in the ob/ob vehicle group; however, ipragliflozin treatment and calorie restriction restored the signal. Malondialdehyde, another marker of oxidative stress, was significantly increased in the cortex of ob/ob mice, which was almost completely eliminated by ipragliflozin treatment and calorie restriction (Figure 4d). Taken together, the cortex of diabetic kidneys was exposed to accelerated oxidative stress, and the glomerulus was among the most sensitive components. These results indicate that ipragliflozin treatment and calorie restriction may exhibit renal protection by ameliorating oxidative stress.
Publisher Copyright:
© 2018 International Society of Nephrology
PY - 2018/11
Y1 - 2018/11
N2 - It is unclear whether long-term sodium–glucose cotransporter 2 (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 ipragliflozin and 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 acid cycle metabolites. This was almost completely nullified by SGLT2 inhibition and calorie restriction. Moreover, imaging mass spectrometry indicated an increased level of the tricarboxylic acid cycle intermediate, citrate, in the cortex of the diabetic mice. SGLT2 inhibition as well as calorie restriction almost 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 acid cycle intermediates and increased oxidative stress in the kidneys of diabetic mice.
AB - It is unclear whether long-term sodium–glucose cotransporter 2 (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 ipragliflozin and 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 acid cycle metabolites. This was almost completely nullified by SGLT2 inhibition and calorie restriction. Moreover, imaging mass spectrometry indicated an increased level of the tricarboxylic acid cycle intermediate, citrate, in the cortex of the diabetic mice. SGLT2 inhibition as well as calorie restriction almost 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 acid cycle intermediates and increased oxidative stress in the kidneys of diabetic mice.
KW - albuminuria
KW - diabetes
KW - diabetic nephropathy
KW - oxidative stress
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U2 - 10.1016/j.kint.2018.04.025
DO - 10.1016/j.kint.2018.04.025
M3 - Article
C2 - 30021702
AN - SCOPUS:85051342323
VL - 94
SP - 912
EP - 925
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 5
ER -