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

研究成果: Article査読

4 被引用数 (Scopus)

抄録

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.

本文言語English
論文番号36533
ジャーナルScientific reports
6
DOI
出版ステータスPublished - 2016 11 9

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