PMID- 26158396
OWN - NLM
STAT- MEDLINE
DCOM- 20161213
LR  - 20181202
IS  - 1439-4286 (Electronic)
IS  - 0018-5043 (Linking)
VI  - 48
IP  - 3
DP  - 2016 Mar
TI  - Tofogliflozin, A Highly Selective Inhibitor of SGLT2 Blocks Proinflammatory and 
      Proapoptotic Effects of Glucose Overload on Proximal Tubular Cells Partly by 
      Suppressing Oxidative Stress Generation.
PG  - 191-5
LID - 10.1055/s-0035-1555791 [doi]
AB  - Ninety percent of glucose filtered by the glomerulus is reabsorbed by a 
      sodium-glucose cotransporter 2 (SGLT2), which is mainly expressed on S1 and S2 
      segment of renal proximal tubules. Since SGLT-2-mediated glucose reabsorption is 
      increased under diabetic conditions, selective inhibition of SGLT2 is a potential 
      therapeutic target for the treatment of diabetes. We have recently shown that an 
      inhibitor of SGLT2 has anti-inflammatory and antifibrotic effects on experimental 
      diabetic nephropathy partly by suppressing advanced glycation end products 
      formation and oxidative stress generation in the kidney. However, the direct 
      effects of SGLT2 inhibitor on tubular cell damage remain unclear. In this study, 
      we investigated the effects of tofogliflozin, a highly selective inhibitor of 
      SGLT2 on oxidative stress generation, inflammatory and proapoptotic reactions in 
      cultured human proximal tubular cells exposed to high glucose. Tofogliflozin 
      dose-dependently suppressed glucose entry into tubular cells. High glucose 
      exposure (30 mM) for 4 and 24 h significantly increased oxidative stress 
      generation in tubular cells, which were suppressed by the treatment of 
      tofogliflozin or an antioxidant N-acetylcysteine (NAC). Monocyte chemoattractant 
      protein-1 (MCP-1) gene expression and apoptotic cell death were induced by 4 h- 
      and 8 day-exposure to high glucose, respectively, both of which were also blocked 
      by tofogliflozin or NAC. The present study suggests that SGLT2-mediated glucose 
      entry into tubular cells could stimulate oxidative stress and evoke inflammatory 
      and proapoptotic reactions in this cell type. Blockade of glucose reabsorption in 
      tubular cells by SGLT2 inhibitor might exert beneficial effects on 
      tubulointerstitial damage in diabetic nephropathy.
CI  - (c) Georg Thieme Verlag KG Stuttgart . New York.
FAU - Ishibashi, Y
AU  - Ishibashi Y
AD  - Department of Pathophysiology and Therapeutics of Diabetic Vascular 
      Complications, Kurume University School of Medicine, Kurume, Japan.
FAU - Matsui, T
AU  - Matsui T
AD  - Department of Pathophysiology and Therapeutics of Diabetic Vascular 
      Complications, Kurume University School of Medicine, Kurume, Japan.
FAU - Yamagishi, S
AU  - Yamagishi S
AD  - Department of Pathophysiology and Therapeutics of Diabetic Vascular 
      Complications, Kurume University School of Medicine, Kurume, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150709
PL  - Germany
TA  - Horm Metab Res
JT  - Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et 
      metabolisme
JID - 0177722
RN  - 0 (Benzhydryl Compounds)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Glucosides)
RN  - 0 (RNA, Messenger)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Sodium-Glucose Transporter 2)
RN  - 0 (Sodium-Glucose Transporter 2 Inhibitors)
RN  - IY9XDZ35W2 (Glucose)
RN  - P8DD8KX4O4 
      (6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol)
SB  - IM
MH  - Apoptosis/*drug effects/genetics
MH  - Benzhydryl Compounds/pharmacology/*therapeutic use
MH  - Cell Line
MH  - Chemokine CCL2/genetics/metabolism
MH  - Gene Expression Regulation/drug effects
MH  - Glucose/*pharmacology
MH  - Glucosides/pharmacology/*therapeutic use
MH  - Humans
MH  - Inflammation/*drug therapy/pathology
MH  - Kidney Tubules, Proximal/drug effects/*pathology
MH  - Oxidative Stress/*drug effects/genetics
MH  - RNA, Messenger/genetics/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Sodium-Glucose Transporter 2/metabolism
MH  - *Sodium-Glucose Transporter 2 Inhibitors
EDAT- 2015/07/15 06:00
MHDA- 2016/12/15 06:00
CRDT- 2015/07/10 06:00
PHST- 2015/07/10 06:00 [entrez]
PHST- 2015/07/15 06:00 [pubmed]
PHST- 2016/12/15 06:00 [medline]
AID - 10.1055/s-0035-1555791 [doi]
PST - ppublish
SO  - Horm Metab Res. 2016 Mar;48(3):191-5. doi: 10.1055/s-0035-1555791. Epub 2015 Jul 
      9.