Regulation of Angiogenic Factors in Angiotensin II Infusion Model in Association With Tubulointerstitial Injuries

Hiroyuki Kitayama, Yohei Maeshima, Yuki Takazawa, Yoshihiko Yamamoto, Yan Wu, Kunihiro Ichinose, Kumiko Hirokoshi, Hitoshi Sugiyama, Yasushi Yamasaki, Hirofumi Makino

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Background: Among various angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang1), and angiopoietin-2 (Ang2) play crucial roles in regulating angiogenesis and vascular integrity. Infusion of angiotensin-II (ang II) induces hypertension and focal renal tubulointerstitial injuries. In the present study we investigated the renal expression of VEGF, Ang1, Ang2, and corresponding receptors in association with tubulointerstitial lesions in a rat ang II infusion model. Methods: Male Sprague-Dawley (SD) rats received an infusion of ang II or norepinephrine (NE) through osmotic minipumps for 14 days. Angiotensin II type 1 (AT1) or type 2 (AT2) receptor antagonist (losartan or PD123319, respectively) or hydralazine was co-administered. Results: Interstitial fibrosis, infiltration of monocyte/macrophage, and peritubular capillary rarefaction induced by ang II was significantly attenuated in the losartan- or PD123319-treated groups. Immunoreactivity of VEGF and Ang1 in cortical tubules was increased by ang II and was attenuated by losartan or PD123319. The increase of VEGF induced by ang II was suppressed by losartan, and the increase of Ang1 induced by ang II was inhibited by PD123319 as detected by immunoblot. The increase of flk-1 and flt-1 (VEGF receptors) and tie-2 (Ang1 receptor) induced by ang II was significantly suppressed by PD123319. These alterations were not observed in hydralazine plus ang II or NE-infused animals. Conclusions: These results demonstrate that an infusion of ang II induced the expression of VEGF mainly through AT1 receptors, and increased the expression of VEGF receptors, tie-2, and Ang1/Ang2 ratio mainly through AT2 receptors. The increase of VEGF/flk-1/flt-1 may be associated with vascular permeability, monocyte/macrophage infiltration, and rarefaction of peritubular capillaries, and the increase of the Ang1/Ang2 ratio may be a compensatory mechanism counteracting the permeability inducing effect of VEGF after ang II infusion.

Original languageEnglish
Pages (from-to)718-727
Number of pages10
JournalAmerican Journal of Hypertension
Volume19
Issue number7
DOIs
Publication statusPublished - Jul 2006

Fingerprint

Angiogenesis Inducing Agents
Angiotensin II
Angiopoietin-1
Vascular Endothelial Growth Factor A
Wounds and Injuries
Angiopoietin-2
Losartan
Hydralazine
Vascular Endothelial Growth Factor Receptor-2
Monocytes
Norepinephrine
Macrophages
Angiotensin Type 1 Receptor
Angiotensin Receptors
Renal Hypertension
Capillary Permeability
Blood Vessels
Sprague Dawley Rats
Permeability
Fibrosis

Keywords

  • angiogenesis
  • angiopoietin-1
  • angiopoietin-2
  • Angiotensin II
  • interstitial fibrosis
  • VEGF

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Regulation of Angiogenic Factors in Angiotensin II Infusion Model in Association With Tubulointerstitial Injuries. / Kitayama, Hiroyuki; Maeshima, Yohei; Takazawa, Yuki; Yamamoto, Yoshihiko; Wu, Yan; Ichinose, Kunihiro; Hirokoshi, Kumiko; Sugiyama, Hitoshi; Yamasaki, Yasushi; Makino, Hirofumi.

In: American Journal of Hypertension, Vol. 19, No. 7, 07.2006, p. 718-727.

Research output: Contribution to journalArticle

Kitayama, Hiroyuki ; Maeshima, Yohei ; Takazawa, Yuki ; Yamamoto, Yoshihiko ; Wu, Yan ; Ichinose, Kunihiro ; Hirokoshi, Kumiko ; Sugiyama, Hitoshi ; Yamasaki, Yasushi ; Makino, Hirofumi. / Regulation of Angiogenic Factors in Angiotensin II Infusion Model in Association With Tubulointerstitial Injuries. In: American Journal of Hypertension. 2006 ; Vol. 19, No. 7. pp. 718-727.
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AU - Kitayama, Hiroyuki

AU - Maeshima, Yohei

AU - Takazawa, Yuki

AU - Yamamoto, Yoshihiko

AU - Wu, Yan

AU - Ichinose, Kunihiro

AU - Hirokoshi, Kumiko

AU - Sugiyama, Hitoshi

AU - Yamasaki, Yasushi

AU - Makino, Hirofumi

PY - 2006/7

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N2 - Background: Among various angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang1), and angiopoietin-2 (Ang2) play crucial roles in regulating angiogenesis and vascular integrity. Infusion of angiotensin-II (ang II) induces hypertension and focal renal tubulointerstitial injuries. In the present study we investigated the renal expression of VEGF, Ang1, Ang2, and corresponding receptors in association with tubulointerstitial lesions in a rat ang II infusion model. Methods: Male Sprague-Dawley (SD) rats received an infusion of ang II or norepinephrine (NE) through osmotic minipumps for 14 days. Angiotensin II type 1 (AT1) or type 2 (AT2) receptor antagonist (losartan or PD123319, respectively) or hydralazine was co-administered. Results: Interstitial fibrosis, infiltration of monocyte/macrophage, and peritubular capillary rarefaction induced by ang II was significantly attenuated in the losartan- or PD123319-treated groups. Immunoreactivity of VEGF and Ang1 in cortical tubules was increased by ang II and was attenuated by losartan or PD123319. The increase of VEGF induced by ang II was suppressed by losartan, and the increase of Ang1 induced by ang II was inhibited by PD123319 as detected by immunoblot. The increase of flk-1 and flt-1 (VEGF receptors) and tie-2 (Ang1 receptor) induced by ang II was significantly suppressed by PD123319. These alterations were not observed in hydralazine plus ang II or NE-infused animals. Conclusions: These results demonstrate that an infusion of ang II induced the expression of VEGF mainly through AT1 receptors, and increased the expression of VEGF receptors, tie-2, and Ang1/Ang2 ratio mainly through AT2 receptors. The increase of VEGF/flk-1/flt-1 may be associated with vascular permeability, monocyte/macrophage infiltration, and rarefaction of peritubular capillaries, and the increase of the Ang1/Ang2 ratio may be a compensatory mechanism counteracting the permeability inducing effect of VEGF after ang II infusion.

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KW - angiogenesis

KW - angiopoietin-1

KW - angiopoietin-2

KW - Angiotensin II

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KW - VEGF

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