The growth factor midkine regulates the renin-angiotensin system in mice.
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.
Hobo
Akinori
A
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Yuzawa
Yukio
Y
Kosugi
Tomoki
T
Kato
Noritoshi
N
Asai
Naoto
N
Sato
Waichi
W
Maruyama
Shoichi
S
Ito
Yasuhiko
Y
Kobori
Hiroyuki
H
Ikematsu
Shinya
S
Nishiyama
Akira
A
Matsuo
Seiichi
S
Kadomatsu
Kenji
K
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
D016207:Cytokines; D009414:Nerve Growth Factors; D000078792:Midkine; D007703:Peptidyl-Dipeptidase A