Midkine Regulates BP through Cytochrome P450-Derived Eicosanoids.
The effects of endothelium-derived hyperpolarizing factors have been attributed to cytochrome P450-derived epoxyeicosatrienoic acids (EETs), but the regulation and role of EETs in endothelial dysfunction remain largely unexplored. Hypertension is a primary risk factor for renal dysfunction, which is frequently accompanied by various systemic diseases induced by endothelial dysfunction in the microcirculation. We previously reported that the endothelial growth factor midkine (MK) enhances hypertension in a model of CKD. Here, we investigated the hypothesis that MK regulates EET activity and thereby BP. MK gene-deleted mice were resistant to hypertension and developed less glomerulosclerosis and proteinuria after administration of a nitric oxide synthase (NOS) inhibitor in the setting of uninephrectomy. The hypertension observed in uninephrectomized wild-type mice after NOS inhibition was ameliorated by anti-MK antibody. MK-deficient mice produced higher amounts of EETs, and EETs dominantly regulated BP in these mice. Furthermore, MK administration to MK-deficient mice recapitulated the BP control observed in wild-type mice. EETs also dominantly regulated renal blood flow, which may influence renal function, in MK-deficient mice. Taken together, these results suggest that the MK/EET pathway is physiologically engaged in BP control and could be a target for the treatment of hypertension complicated by endothelial dysfunction.
Departments of Biochemistry and Nephrology.
Yuka
Y
Sato
Nephrology.
Waichi
W
Sato
Nephrology.
Shoichi
S
Maruyama
Hypertension, Kidney and Vascular Research Center, Georgetown University, Washington, DC; and.
Christopher S
CS
Wilcox
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas.
John R
JR
Falck
Nephrology.
Tomohiro
T
Masuda
Nephrology.
Tomoki
T
Kosugi
Nephrology.
Hiroshi
H
Kojima
Nephrology.
Kayaho
K
Maeda
Nephrology.
Kazuhiro
K
Furuhashi
Center for Advanced Medicine and Clinical Research, Nagoya University Graduate School of Medicine, Nagoya, Japan;
Masahiko
M
Ando
Nephrology.
Enyu
E
Imai
Nephrology.
Seiichi
S
Matsuo
Departments of Biochemistry and kkadoma@med.nagoya-u.ac.jp.
Kenji
K
Kadomatsu
D000818:Animals; D001685:Biological Factors / Q000378:metabolism; D001794:Blood Pressure; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism*; D006973:Hypertension / Q000209:etiology; D008297:Male; D051379:Mice; D000078792:Midkine; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011897:Random Allocation; D012079:Renal Circulation; D051437:Renal Insufficiency / Q000209:etiology; D012084:Renin-Angiotensin System; D013564:Sympathetic Nervous System / Q000378:metabolism
D001685:Biological Factors; D016207:Cytokines; D015777:Eicosanoids; D004852:Epoxy Compounds; C067410:endothelium-dependent hyperpolarization factor; D000078792:Midkine; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase
CKD; endothelial cell; endothelium-derived hyperpolarizing factor; hypertension