Midkine regulates BP through cytochrome P450derived eicosanoids

Yuka Sato, Waichi Sato, Shoichi Maruyama, Christopher S. Wilcox, J R Falck, Tomohiro Masuda, Tomoki Kosugi, Hiroshi Kojima, Kayaho Maeda, Kazuhiro Furuhashi, Masahiko Ando, Enyu Imai, Seiichi Matsuo, Kenji Kadomatsu

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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-typemice afterNOS 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.

Original languageEnglish (US)
Pages (from-to)1806-1815
Number of pages10
JournalJournal of the American Society of Nephrology
Volume26
Issue number8
DOIs
Publication statusPublished - Aug 1 2015

    Fingerprint

ASJC Scopus subject areas

  • Nephrology

Cite this

Sato, Y., Sato, W., Maruyama, S., Wilcox, C. S., Falck, J. R., Masuda, T., ... Kadomatsu, K. (2015). Midkine regulates BP through cytochrome P450derived eicosanoids. Journal of the American Society of Nephrology, 26(8), 1806-1815. https://doi.org/10.1681/ASN.2013121259