title: The growth factor midkine regulates the renin-angiotensin system in mice.
abstract: The renin-angiotensin system plays a pivotal role in regulating blood pressure and is involved in the pathogenesis of kidney disorders and other diseases. Here, we report that the growth factor midkine is what we believe to be a novel regulator of the renin-angiotensin system. The hypertension induced in mice by 5/6 nephrectomy was accompanied by renal damage and elevated plasma angiotensin II levels and was ameliorated by an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin receptor blocker. Notably, ACE activity in the lung, midkine expression in the lung, and midkine levels in the plasma were all increased after 5/6 nephrectomy. Exposure to midkine protein enhanced ACE expression in primary cultured human lung microvascular endothelial cells. Furthermore, hypertension was not induced and renal damage was less severe in midkine-deficient mice. Supplemental administration of midkine protein to midkine-deficient mice restored ACE expression in the lung and hypertension after 5/6 nephrectomy. Oxidative stress might be involved in midkine expression, since expression of NADH/NADPH oxidase-1, -2, and -4 was induced in the lung after 5/6 nephrectomy. Indeed, the antioxidative reagent tempol reduced midkine expression and plasma angiotensin II levels and consequently ameliorated hypertension. These results suggest that midkine regulates the renin-angiotensin system and mediates the kidney-lung interaction after 5/6 nephrectomy.
authors.affiliation: Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Hobo
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yuzawa
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kosugi
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Kato
authors.forename: Naoto
authors.initials: N
authors.lastname: Asai
authors.forename: Waichi
authors.initials: W
authors.lastname: Sato
authors.forename: Shoichi
authors.initials: S
authors.lastname: Maruyama
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Ito
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
authors.forename: Shinya
authors.initials: S
authors.lastname: Ikematsu
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Seiichi
authors.initials: S
authors.lastname: Matsuo
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
mesh_terms: D000818:Animals; D001835:Body Weight; D016207:Cytokines / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000078792:Midkine; D009392:Nephrectomy; D009414:Nerve Growth Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D018384:Oxidative Stress; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D012084:Renin-Angiotensin System
chemical_list: D016207:Cytokines; D009414:Nerve Growth Factors; D000078792:Midkine; D007703:Peptidyl-Dipeptidase A