Amelioration of diabetic nephropathy by SGLT2 inhibitors independent of its glucose-lowering effect: A possible role of SGLT2 in mesangial cells

Toshinobu Maki, Sayaka Maeno, Yasutaka Maeda, Mayumi Yamato, Noriyuki Sonoda, Yoshihiro Ogawa, Masanori Wakisaka, Toyoshi Inoguchi

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Several clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on diabetic nephropathy. The underlying mechanisms are not fully understood. We found that administration of canagliflozin at a low dose (0.01 mg/kg/day) did not affect either blood glucose levels or glycosuria, but it improved albuminuria and mesangial expansion in db/db mice to a similar extent as at a high dose (3.0 mg/kg/day) that lowered blood glucose levels. This indicated the existence of a tubular SGLT2-independent reno-protective mechanism. Here we focused on the potential role of SGLT2 in mesangial cells (MCs). Western blot analysis revealed the expression of SGLT2 in cultured mouse MCs. Exposure of MCs to high glucose levels for 72 h significantly increased the expression of SGLT2. Canagliflozin or ipragliflozin (both 100 nM) treatment inhibited glucose consumption in the medium under high-glucose conditions but not under normal-glucose conditions. Furthermore, canagliflozin inhibited high-glucose-induced activation of the protein kinase C (PKC)-NAD(P)H oxidase pathway and increases in reactive oxygen species (ROS) production. Thus, the inhibition of mesangial SGLT2 may cause an inhibition of PKC activation and ROS overproduction in diabetic nephropathy, and this may at least in part account for the reno-protective effect of SGLT2 inhibitors.

Original languageEnglish
Article number4703
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

Fingerprint

Sodium-Glucose Transport Proteins
Mesangial Cells
Diabetic Nephropathies
Glucose
Protein Kinase C
Blood Glucose
Reactive Oxygen Species
Glycosuria
Albuminuria
NADPH Oxidase
Western Blotting

All Science Journal Classification (ASJC) codes

  • General

Cite this

Amelioration of diabetic nephropathy by SGLT2 inhibitors independent of its glucose-lowering effect : A possible role of SGLT2 in mesangial cells. / Maki, Toshinobu; Maeno, Sayaka; Maeda, Yasutaka; Yamato, Mayumi; Sonoda, Noriyuki; Ogawa, Yoshihiro; Wakisaka, Masanori; Inoguchi, Toyoshi.

In: Scientific reports, Vol. 9, No. 1, 4703, 01.12.2019.

Research output: Contribution to journalArticle

Maki, Toshinobu ; Maeno, Sayaka ; Maeda, Yasutaka ; Yamato, Mayumi ; Sonoda, Noriyuki ; Ogawa, Yoshihiro ; Wakisaka, Masanori ; Inoguchi, Toyoshi. / Amelioration of diabetic nephropathy by SGLT2 inhibitors independent of its glucose-lowering effect : A possible role of SGLT2 in mesangial cells. In: Scientific reports. 2019 ; Vol. 9, No. 1.
@article{6ba46b26f65e42f5a3f368044fe7b97f,
title = "Amelioration of diabetic nephropathy by SGLT2 inhibitors independent of its glucose-lowering effect: A possible role of SGLT2 in mesangial cells",
abstract = "Several clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on diabetic nephropathy. The underlying mechanisms are not fully understood. We found that administration of canagliflozin at a low dose (0.01 mg/kg/day) did not affect either blood glucose levels or glycosuria, but it improved albuminuria and mesangial expansion in db/db mice to a similar extent as at a high dose (3.0 mg/kg/day) that lowered blood glucose levels. This indicated the existence of a tubular SGLT2-independent reno-protective mechanism. Here we focused on the potential role of SGLT2 in mesangial cells (MCs). Western blot analysis revealed the expression of SGLT2 in cultured mouse MCs. Exposure of MCs to high glucose levels for 72 h significantly increased the expression of SGLT2. Canagliflozin or ipragliflozin (both 100 nM) treatment inhibited glucose consumption in the medium under high-glucose conditions but not under normal-glucose conditions. Furthermore, canagliflozin inhibited high-glucose-induced activation of the protein kinase C (PKC)-NAD(P)H oxidase pathway and increases in reactive oxygen species (ROS) production. Thus, the inhibition of mesangial SGLT2 may cause an inhibition of PKC activation and ROS overproduction in diabetic nephropathy, and this may at least in part account for the reno-protective effect of SGLT2 inhibitors.",
author = "Toshinobu Maki and Sayaka Maeno and Yasutaka Maeda and Mayumi Yamato and Noriyuki Sonoda and Yoshihiro Ogawa and Masanori Wakisaka and Toyoshi Inoguchi",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41598-019-41253-7",
language = "English",
volume = "9",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Amelioration of diabetic nephropathy by SGLT2 inhibitors independent of its glucose-lowering effect

T2 - A possible role of SGLT2 in mesangial cells

AU - Maki, Toshinobu

AU - Maeno, Sayaka

AU - Maeda, Yasutaka

AU - Yamato, Mayumi

AU - Sonoda, Noriyuki

AU - Ogawa, Yoshihiro

AU - Wakisaka, Masanori

AU - Inoguchi, Toyoshi

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Several clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on diabetic nephropathy. The underlying mechanisms are not fully understood. We found that administration of canagliflozin at a low dose (0.01 mg/kg/day) did not affect either blood glucose levels or glycosuria, but it improved albuminuria and mesangial expansion in db/db mice to a similar extent as at a high dose (3.0 mg/kg/day) that lowered blood glucose levels. This indicated the existence of a tubular SGLT2-independent reno-protective mechanism. Here we focused on the potential role of SGLT2 in mesangial cells (MCs). Western blot analysis revealed the expression of SGLT2 in cultured mouse MCs. Exposure of MCs to high glucose levels for 72 h significantly increased the expression of SGLT2. Canagliflozin or ipragliflozin (both 100 nM) treatment inhibited glucose consumption in the medium under high-glucose conditions but not under normal-glucose conditions. Furthermore, canagliflozin inhibited high-glucose-induced activation of the protein kinase C (PKC)-NAD(P)H oxidase pathway and increases in reactive oxygen species (ROS) production. Thus, the inhibition of mesangial SGLT2 may cause an inhibition of PKC activation and ROS overproduction in diabetic nephropathy, and this may at least in part account for the reno-protective effect of SGLT2 inhibitors.

AB - Several clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on diabetic nephropathy. The underlying mechanisms are not fully understood. We found that administration of canagliflozin at a low dose (0.01 mg/kg/day) did not affect either blood glucose levels or glycosuria, but it improved albuminuria and mesangial expansion in db/db mice to a similar extent as at a high dose (3.0 mg/kg/day) that lowered blood glucose levels. This indicated the existence of a tubular SGLT2-independent reno-protective mechanism. Here we focused on the potential role of SGLT2 in mesangial cells (MCs). Western blot analysis revealed the expression of SGLT2 in cultured mouse MCs. Exposure of MCs to high glucose levels for 72 h significantly increased the expression of SGLT2. Canagliflozin or ipragliflozin (both 100 nM) treatment inhibited glucose consumption in the medium under high-glucose conditions but not under normal-glucose conditions. Furthermore, canagliflozin inhibited high-glucose-induced activation of the protein kinase C (PKC)-NAD(P)H oxidase pathway and increases in reactive oxygen species (ROS) production. Thus, the inhibition of mesangial SGLT2 may cause an inhibition of PKC activation and ROS overproduction in diabetic nephropathy, and this may at least in part account for the reno-protective effect of SGLT2 inhibitors.

UR - http://www.scopus.com/inward/record.url?scp=85063059548&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063059548&partnerID=8YFLogxK

U2 - 10.1038/s41598-019-41253-7

DO - 10.1038/s41598-019-41253-7

M3 - Article

C2 - 30886225

AN - SCOPUS:85063059548

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 4703

ER -