The growth factor midkine regulates the renin-angiotensin system in mice

Akinori Hobo, Yukio Yuzawa, Tomoki Kosugi, Noritoshi Kato, Naoto Asai, Waichi Sato, Shoichi Maruyama, Yasuhiko Ito, Hiroyuki Kobori, Shinya Ikematsu, Akira Nishiyama, Seiichi Matsuo, Kenji Kadomatsu

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1616-1625
Number of pages10
JournalJournal of Clinical Investigation
Volume119
Issue number6
DOIs
Publication statusPublished - 01-06-2009

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Renin-Angiotensin System
Intercellular Signaling Peptides and Proteins
Nephrectomy
Lung
Peptidyl-Dipeptidase A
Hypertension
Kidney
Angiotensin II
midkine
Angiotensin Receptor Antagonists
Angiotensin-Converting Enzyme Inhibitors
Proteins
Oxidative Stress
Endothelial Cells
Blood Pressure

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Hobo, A., Yuzawa, Y., Kosugi, T., Kato, N., Asai, N., Sato, W., ... Kadomatsu, K. (2009). The growth factor midkine regulates the renin-angiotensin system in mice. Journal of Clinical Investigation, 119(6), 1616-1625. https://doi.org/10.1172/JCI37249
Hobo, Akinori ; Yuzawa, Yukio ; Kosugi, Tomoki ; Kato, Noritoshi ; Asai, Naoto ; Sato, Waichi ; Maruyama, Shoichi ; Ito, Yasuhiko ; Kobori, Hiroyuki ; Ikematsu, Shinya ; Nishiyama, Akira ; Matsuo, Seiichi ; Kadomatsu, Kenji. / The growth factor midkine regulates the renin-angiotensin system in mice. In: Journal of Clinical Investigation. 2009 ; Vol. 119, No. 6. pp. 1616-1625.
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Hobo, A, Yuzawa, Y, Kosugi, T, Kato, N, Asai, N, Sato, W, Maruyama, S, Ito, Y, Kobori, H, Ikematsu, S, Nishiyama, A, Matsuo, S & Kadomatsu, K 2009, 'The growth factor midkine regulates the renin-angiotensin system in mice', Journal of Clinical Investigation, vol. 119, no. 6, pp. 1616-1625. https://doi.org/10.1172/JCI37249

The growth factor midkine regulates the renin-angiotensin system in mice. / Hobo, Akinori; Yuzawa, Yukio; Kosugi, Tomoki; Kato, Noritoshi; Asai, Naoto; Sato, Waichi; Maruyama, Shoichi; Ito, Yasuhiko; Kobori, Hiroyuki; Ikematsu, Shinya; Nishiyama, Akira; Matsuo, Seiichi; Kadomatsu, Kenji.

In: Journal of Clinical Investigation, Vol. 119, No. 6, 01.06.2009, p. 1616-1625.

Research output: Contribution to journalArticle

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T1 - The growth factor midkine regulates the renin-angiotensin system in mice

AU - Hobo, Akinori

AU - Yuzawa, Yukio

AU - Kosugi, Tomoki

AU - Kato, Noritoshi

AU - Asai, Naoto

AU - Sato, Waichi

AU - Maruyama, Shoichi

AU - Ito, Yasuhiko

AU - Kobori, Hiroyuki

AU - Ikematsu, Shinya

AU - Nishiyama, Akira

AU - Matsuo, Seiichi

AU - Kadomatsu, Kenji

PY - 2009/6/1

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N2 - 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.

AB - 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.

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