Obesity-induced kidney injury is attenuated by amelioration of aberrant PHD2 activation in proximal tubules

Koji Futatsugi, Hirobumi Tokuyama, Shinsuke Shibata, Makiko Naitoh, Takeshi Kanda, Hitoshi Minakuchi, Shintaro Yamaguchi, Koichi Hayashi, Yoji Andrew Minamishima, Motoko Yanagita, Shu Wakino, Hiroshi Itoh

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The involvement of tissue ischemia in obesity-induced kidney injury remains to be elucidated. Compared with low fat diet (LFD)-mice, high fat diet (HFD)-fed mice became obese with tubular enlargement, glomerulomegaly and peritubular capillary rarefaction, and exhibited both tubular and glomerular damages. In HFD-fed mice, despite the increase in renal pimonidazole-positive areas, the expressions of the hypoxia-responsive genes such as Prolyl-hydroxylase PHD2, a dominant oxygen sensor, and VEGFA were unchanged indicating impaired hypoxic response. Tamoxifen inducible proximal tubules (PT)-specific Phd2 knockout (Phd2-cKO) mice and their littermate control mice (Control) were created and fed HFD or LFD. Control mice on HFD (Control HFD) exhibited renal damages and renal ischemia with impaired hypoxic response compared with those on LFD. After tamoxifen treatment, HFD-fed knockout mice (Phd2-cKO HFD) had increased peritubular capillaries and the increased expressions of hypoxia responsive genes compared to Control HFD mice. Phd2-cKO HFD also exhibited the mitigation of tubular damages, albuminuria and glomerulomegaly. In human PT cells, the increased expressions of hypoxia-inducible genes in hypoxic condition were attenuated by free fatty acids. Thus, aberrant hypoxic responses due to dysfunction of PHD2 caused both glomerular and tubular damages in HFD-induced obese mice. Phd2-inactivation provides a novel strategy against obesity-induced kidney injury.

Original languageEnglish
Article number36533
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 2016 Nov 9

Fingerprint

High Fat Diet
Obesity
Kidney
Wounds and Injuries
Fat-Restricted Diet
Obese Mice
Tamoxifen
Ischemia
Genes
Prolyl Hydroxylases
Albuminuria
Nonesterified Fatty Acids
Knockout Mice
Oxygen
Hypoxia

ASJC Scopus subject areas

  • General

Cite this

Obesity-induced kidney injury is attenuated by amelioration of aberrant PHD2 activation in proximal tubules. / Futatsugi, Koji; Tokuyama, Hirobumi; Shibata, Shinsuke; Naitoh, Makiko; Kanda, Takeshi; Minakuchi, Hitoshi; Yamaguchi, Shintaro; Hayashi, Koichi; Minamishima, Yoji Andrew; Yanagita, Motoko; Wakino, Shu; Itoh, Hiroshi.

In: Scientific Reports, Vol. 6, 36533, 09.11.2016.

Research output: Contribution to journalArticle

@article{d31552c5ab5a4c719de53ba832b709e8,
title = "Obesity-induced kidney injury is attenuated by amelioration of aberrant PHD2 activation in proximal tubules",
abstract = "The involvement of tissue ischemia in obesity-induced kidney injury remains to be elucidated. Compared with low fat diet (LFD)-mice, high fat diet (HFD)-fed mice became obese with tubular enlargement, glomerulomegaly and peritubular capillary rarefaction, and exhibited both tubular and glomerular damages. In HFD-fed mice, despite the increase in renal pimonidazole-positive areas, the expressions of the hypoxia-responsive genes such as Prolyl-hydroxylase PHD2, a dominant oxygen sensor, and VEGFA were unchanged indicating impaired hypoxic response. Tamoxifen inducible proximal tubules (PT)-specific Phd2 knockout (Phd2-cKO) mice and their littermate control mice (Control) were created and fed HFD or LFD. Control mice on HFD (Control HFD) exhibited renal damages and renal ischemia with impaired hypoxic response compared with those on LFD. After tamoxifen treatment, HFD-fed knockout mice (Phd2-cKO HFD) had increased peritubular capillaries and the increased expressions of hypoxia responsive genes compared to Control HFD mice. Phd2-cKO HFD also exhibited the mitigation of tubular damages, albuminuria and glomerulomegaly. In human PT cells, the increased expressions of hypoxia-inducible genes in hypoxic condition were attenuated by free fatty acids. Thus, aberrant hypoxic responses due to dysfunction of PHD2 caused both glomerular and tubular damages in HFD-induced obese mice. Phd2-inactivation provides a novel strategy against obesity-induced kidney injury.",
author = "Koji Futatsugi and Hirobumi Tokuyama and Shinsuke Shibata and Makiko Naitoh and Takeshi Kanda and Hitoshi Minakuchi and Shintaro Yamaguchi and Koichi Hayashi and Minamishima, {Yoji Andrew} and Motoko Yanagita and Shu Wakino and Hiroshi Itoh",
year = "2016",
month = "11",
day = "9",
doi = "10.1038/srep36533",
language = "English",
volume = "6",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Obesity-induced kidney injury is attenuated by amelioration of aberrant PHD2 activation in proximal tubules

AU - Futatsugi, Koji

AU - Tokuyama, Hirobumi

AU - Shibata, Shinsuke

AU - Naitoh, Makiko

AU - Kanda, Takeshi

AU - Minakuchi, Hitoshi

AU - Yamaguchi, Shintaro

AU - Hayashi, Koichi

AU - Minamishima, Yoji Andrew

AU - Yanagita, Motoko

AU - Wakino, Shu

AU - Itoh, Hiroshi

PY - 2016/11/9

Y1 - 2016/11/9

N2 - The involvement of tissue ischemia in obesity-induced kidney injury remains to be elucidated. Compared with low fat diet (LFD)-mice, high fat diet (HFD)-fed mice became obese with tubular enlargement, glomerulomegaly and peritubular capillary rarefaction, and exhibited both tubular and glomerular damages. In HFD-fed mice, despite the increase in renal pimonidazole-positive areas, the expressions of the hypoxia-responsive genes such as Prolyl-hydroxylase PHD2, a dominant oxygen sensor, and VEGFA were unchanged indicating impaired hypoxic response. Tamoxifen inducible proximal tubules (PT)-specific Phd2 knockout (Phd2-cKO) mice and their littermate control mice (Control) were created and fed HFD or LFD. Control mice on HFD (Control HFD) exhibited renal damages and renal ischemia with impaired hypoxic response compared with those on LFD. After tamoxifen treatment, HFD-fed knockout mice (Phd2-cKO HFD) had increased peritubular capillaries and the increased expressions of hypoxia responsive genes compared to Control HFD mice. Phd2-cKO HFD also exhibited the mitigation of tubular damages, albuminuria and glomerulomegaly. In human PT cells, the increased expressions of hypoxia-inducible genes in hypoxic condition were attenuated by free fatty acids. Thus, aberrant hypoxic responses due to dysfunction of PHD2 caused both glomerular and tubular damages in HFD-induced obese mice. Phd2-inactivation provides a novel strategy against obesity-induced kidney injury.

AB - The involvement of tissue ischemia in obesity-induced kidney injury remains to be elucidated. Compared with low fat diet (LFD)-mice, high fat diet (HFD)-fed mice became obese with tubular enlargement, glomerulomegaly and peritubular capillary rarefaction, and exhibited both tubular and glomerular damages. In HFD-fed mice, despite the increase in renal pimonidazole-positive areas, the expressions of the hypoxia-responsive genes such as Prolyl-hydroxylase PHD2, a dominant oxygen sensor, and VEGFA were unchanged indicating impaired hypoxic response. Tamoxifen inducible proximal tubules (PT)-specific Phd2 knockout (Phd2-cKO) mice and their littermate control mice (Control) were created and fed HFD or LFD. Control mice on HFD (Control HFD) exhibited renal damages and renal ischemia with impaired hypoxic response compared with those on LFD. After tamoxifen treatment, HFD-fed knockout mice (Phd2-cKO HFD) had increased peritubular capillaries and the increased expressions of hypoxia responsive genes compared to Control HFD mice. Phd2-cKO HFD also exhibited the mitigation of tubular damages, albuminuria and glomerulomegaly. In human PT cells, the increased expressions of hypoxia-inducible genes in hypoxic condition were attenuated by free fatty acids. Thus, aberrant hypoxic responses due to dysfunction of PHD2 caused both glomerular and tubular damages in HFD-induced obese mice. Phd2-inactivation provides a novel strategy against obesity-induced kidney injury.

UR - http://www.scopus.com/inward/record.url?scp=84994492982&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84994492982&partnerID=8YFLogxK

U2 - 10.1038/srep36533

DO - 10.1038/srep36533

M3 - Article

VL - 6

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 36533

ER -