Impacts of Diabetes and an SGLT2 Inhibitor on the Glomerular Number and Volume in db/db Mice, as Estimated by Synchrotron Radiation Micro-CT at SPring-8

Yumi Takiyama, Toshihiro Sera, Masanori Nakamura, Kanaki Ishizeki, Yasuaki Saijo, Tsuyoshi Yanagimachi, Manami Maeda, Ryoichi Bessho, Takao Takiyama, Hiroya Kitsunai, Hidemitsu Sakagami, Daisuke Fujishiro, Yukihiro Fujita, Yuichi Makino, Atsuko Abiko, Masato Hoshino, Kentaro Uesugi, Naoto Yagi, Tsuguhito Ota, Masakazu Haneda

Research output: Contribution to journalArticle

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Abstract

Background: Recent large-scale clinical studies demonstrate that sodium-glucose cotransporter 2 (SGLT2) inhibitors protect the diabetic kidney. However, clinical and animal studies have not shown the changes of the total glomeruli in the whole kidney treated with SGLT2 inhibitors. Methods: We performed computed tomography (CT) imaging on mice using synchrotron radiation to investigate the impact of luseogliflozin, a SGLT2 inhibitor, on the number and volume of glomeruli in the whole kidney. Findings: We did not observe a significant difference in the total glomerular number (N glom ) among mice. Luseogliflozin redistributed the number of glomeruli in different regions, accompanied by the normalization of diabetes-augmented renal volume (V kidney ). Diabetic db/db mice had a larger glomerular volume in the mid-cortex than did control db/m mice, and luseogliflozin increased the glomerular volume in all renal cortical zones of the whole kidney in db/db mice. According to the multivariate regression analysis, hemoglobin A1c level was the most relevant determinant of V kidney , not N glom or mean glomerular volume (V glom ), indicating that hyperglycemia induced renal (tubular) hypertrophy, but not glomerular enlargement. Luseogliflozin increased hypoxia in the juxtamedullary region, sustained upregulated renal renin expression and plasma renin activity, and failed to decrease albuminuria by downregulating megalin in db/db mice. Interpretation: Based on our findings, SGLT2 inhibitors may alter glomerular distribution and size in addition to their glucose-lowering effects, presumably by affecting oxygen metabolism and humoral factors. Fund: Funding for this research was provided by The Japan Society for the Promotion of Science, the Japan Diabetes Foundation, and Asahikawa Medical University.

Original languageEnglish
Pages (from-to)329-346
Number of pages18
JournalEBioMedicine
Volume36
DOIs
Publication statusPublished - Oct 1 2018

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Sodium-Glucose Transport Proteins
Synchrotrons
Medical problems
Synchrotron radiation
Tomography
Radiation
Kidney
Renin
Low Density Lipoprotein Receptor-Related Protein-2
Metabolism
Regression analysis
Hemoglobins
Animals
Oxygen
Japan
Plasmas
Imaging techniques
Glucose
1,5-anhydro-1-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)-1-thioglucitol
Albuminuria

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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Impacts of Diabetes and an SGLT2 Inhibitor on the Glomerular Number and Volume in db/db Mice, as Estimated by Synchrotron Radiation Micro-CT at SPring-8. / Takiyama, Yumi; Sera, Toshihiro; Nakamura, Masanori; Ishizeki, Kanaki; Saijo, Yasuaki; Yanagimachi, Tsuyoshi; Maeda, Manami; Bessho, Ryoichi; Takiyama, Takao; Kitsunai, Hiroya; Sakagami, Hidemitsu; Fujishiro, Daisuke; Fujita, Yukihiro; Makino, Yuichi; Abiko, Atsuko; Hoshino, Masato; Uesugi, Kentaro; Yagi, Naoto; Ota, Tsuguhito; Haneda, Masakazu.

In: EBioMedicine, Vol. 36, 01.10.2018, p. 329-346.

Research output: Contribution to journalArticle

Takiyama, Y, Sera, T, Nakamura, M, Ishizeki, K, Saijo, Y, Yanagimachi, T, Maeda, M, Bessho, R, Takiyama, T, Kitsunai, H, Sakagami, H, Fujishiro, D, Fujita, Y, Makino, Y, Abiko, A, Hoshino, M, Uesugi, K, Yagi, N, Ota, T & Haneda, M 2018, 'Impacts of Diabetes and an SGLT2 Inhibitor on the Glomerular Number and Volume in db/db Mice, as Estimated by Synchrotron Radiation Micro-CT at SPring-8', EBioMedicine, vol. 36, pp. 329-346. https://doi.org/10.1016/j.ebiom.2018.09.048
Takiyama, Yumi ; Sera, Toshihiro ; Nakamura, Masanori ; Ishizeki, Kanaki ; Saijo, Yasuaki ; Yanagimachi, Tsuyoshi ; Maeda, Manami ; Bessho, Ryoichi ; Takiyama, Takao ; Kitsunai, Hiroya ; Sakagami, Hidemitsu ; Fujishiro, Daisuke ; Fujita, Yukihiro ; Makino, Yuichi ; Abiko, Atsuko ; Hoshino, Masato ; Uesugi, Kentaro ; Yagi, Naoto ; Ota, Tsuguhito ; Haneda, Masakazu. / Impacts of Diabetes and an SGLT2 Inhibitor on the Glomerular Number and Volume in db/db Mice, as Estimated by Synchrotron Radiation Micro-CT at SPring-8. In: EBioMedicine. 2018 ; Vol. 36. pp. 329-346.
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AU - Takiyama, Yumi

AU - Sera, Toshihiro

AU - Nakamura, Masanori

AU - Ishizeki, Kanaki

AU - Saijo, Yasuaki

AU - Yanagimachi, Tsuyoshi

AU - Maeda, Manami

AU - Bessho, Ryoichi

AU - Takiyama, Takao

AU - Kitsunai, Hiroya

AU - Sakagami, Hidemitsu

AU - Fujishiro, Daisuke

AU - Fujita, Yukihiro

AU - Makino, Yuichi

AU - Abiko, Atsuko

AU - Hoshino, Masato

AU - Uesugi, Kentaro

AU - Yagi, Naoto

AU - Ota, Tsuguhito

AU - Haneda, Masakazu

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Background: Recent large-scale clinical studies demonstrate that sodium-glucose cotransporter 2 (SGLT2) inhibitors protect the diabetic kidney. However, clinical and animal studies have not shown the changes of the total glomeruli in the whole kidney treated with SGLT2 inhibitors. Methods: We performed computed tomography (CT) imaging on mice using synchrotron radiation to investigate the impact of luseogliflozin, a SGLT2 inhibitor, on the number and volume of glomeruli in the whole kidney. Findings: We did not observe a significant difference in the total glomerular number (N glom ) among mice. Luseogliflozin redistributed the number of glomeruli in different regions, accompanied by the normalization of diabetes-augmented renal volume (V kidney ). Diabetic db/db mice had a larger glomerular volume in the mid-cortex than did control db/m mice, and luseogliflozin increased the glomerular volume in all renal cortical zones of the whole kidney in db/db mice. According to the multivariate regression analysis, hemoglobin A1c level was the most relevant determinant of V kidney , not N glom or mean glomerular volume (V glom ), indicating that hyperglycemia induced renal (tubular) hypertrophy, but not glomerular enlargement. Luseogliflozin increased hypoxia in the juxtamedullary region, sustained upregulated renal renin expression and plasma renin activity, and failed to decrease albuminuria by downregulating megalin in db/db mice. Interpretation: Based on our findings, SGLT2 inhibitors may alter glomerular distribution and size in addition to their glucose-lowering effects, presumably by affecting oxygen metabolism and humoral factors. Fund: Funding for this research was provided by The Japan Society for the Promotion of Science, the Japan Diabetes Foundation, and Asahikawa Medical University.

AB - Background: Recent large-scale clinical studies demonstrate that sodium-glucose cotransporter 2 (SGLT2) inhibitors protect the diabetic kidney. However, clinical and animal studies have not shown the changes of the total glomeruli in the whole kidney treated with SGLT2 inhibitors. Methods: We performed computed tomography (CT) imaging on mice using synchrotron radiation to investigate the impact of luseogliflozin, a SGLT2 inhibitor, on the number and volume of glomeruli in the whole kidney. Findings: We did not observe a significant difference in the total glomerular number (N glom ) among mice. Luseogliflozin redistributed the number of glomeruli in different regions, accompanied by the normalization of diabetes-augmented renal volume (V kidney ). Diabetic db/db mice had a larger glomerular volume in the mid-cortex than did control db/m mice, and luseogliflozin increased the glomerular volume in all renal cortical zones of the whole kidney in db/db mice. According to the multivariate regression analysis, hemoglobin A1c level was the most relevant determinant of V kidney , not N glom or mean glomerular volume (V glom ), indicating that hyperglycemia induced renal (tubular) hypertrophy, but not glomerular enlargement. Luseogliflozin increased hypoxia in the juxtamedullary region, sustained upregulated renal renin expression and plasma renin activity, and failed to decrease albuminuria by downregulating megalin in db/db mice. Interpretation: Based on our findings, SGLT2 inhibitors may alter glomerular distribution and size in addition to their glucose-lowering effects, presumably by affecting oxygen metabolism and humoral factors. Fund: Funding for this research was provided by The Japan Society for the Promotion of Science, the Japan Diabetes Foundation, and Asahikawa Medical University.

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