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Kidney Int. 2018 Sep;94(3):524-535. doi: 10.1016/j.kint.2018.05.002. Epub 2018 Jul 23.

A sodium-glucose cotransporter 2 inhibitor attenuates renal capillary injury and fibrosis by a vascular endothelial growth factor-dependent pathway after renal injury in mice.

Author information

1
Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan; Department of No. 2 Orthopedics, Shijiazhuang City No. 1 Hospital, Shijiazhuang, Hebei, China.
2
Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan. Electronic address: dnakano@med.kagawa-u.ac.jp.
3
Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan.
4
Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
5
Department of Gastroenterology & Neurology, Kagawa University, Kagawa, Japan.
6
Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan.

Abstract

Multiple large clinical trials have shown that sodium-glucose cotransporter (SGLT) 2 inhibitors reduce the risk of renal events. However, the mechanism responsible for this outcome remains unknown. Here we investigated the effects of the SGLT2 inhibitor luseogliflozin on the development of renal fibrosis after renal ischemia/reperfusion injury in non-diabetic mice. Luseogliflozin significantly suppressed development of renal fibrosis, prevented peritubular capillary congestion/hemorrhage, attenuated CD31-positive cell loss, suppressed hypoxia, and increased vascular endothelial growth factor (VEGF)-A expression in the kidney after ischemia/reperfusion injury. Luseogliflozin failed to induce the above-mentioned protection in animals co-treated with sunitinib, a VEGF receptor inhibitor. Additionally, luseogliflozin reduced glucose uptake and increased VEGF-A expression in the kidneys of glucose transporter 2 (GLUT2)-downregulated mice following ischemia/reperfusion and in GLUT2-knock-down cells compared with those in normal controls. Withdrawal of glucose from cultured medium, to halt glucose uptake, remarkably increased VEGF-A expression and reversed the luseogliflozin-induced increase in VEGF-A expression in the proximal tubular cells. Thus, luseogliflozin prevented endothelial rarefaction and subsequent renal fibrosis after renal ischemia/reperfusion injury through a VEGF-dependent pathway induced by the dysfunction of proximal tubular glucose uptake in tubules with injury-induced GLUT2 downregulation.

KEYWORDS:

glucose uptake; renal fibrosis; sodium glucose co-transporter 2; vascular endothelial growth factor

PMID:
30045814
DOI:
10.1016/j.kint.2018.05.002
[Indexed for MEDLINE]

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