Obesity-induced kidney injury is attenuated by amelioration of aberrant PHD2 activation in proximal tubules.
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.
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Koji
K
Futatsugi
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Hirobumi
H
Tokuyama
Department of Physiology, School of Medicine, Keio University, Tokyo, Japan.
Shinsuke
S
Shibata
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Makiko
M
Naitoh
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Takeshi
T
Kanda
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Hitoshi
H
Minakuchi
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Shintaro
S
Yamaguchi
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Koichi
K
Hayashi
Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan.
Yoji Andrew
YA
Minamishima
Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Motoko
M
Yanagita
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Shu
S
Wakino
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Hiroshi
H
Itoh
D000818:Animals; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism*; D007668:Kidney / Q000293:injuries* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications*; D013629:Tamoxifen / Q000008:administration & dosage
D013629:Tamoxifen; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases