TY - JOUR
T1 - Regulation of Angiogenic Factors in Angiotensin II Infusion Model in Association With Tubulointerstitial Injuries
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
N1 - Funding Information:
A portion of this study was supported by research grant from a grant-in-aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (YM), Grant-in-Aid from the Tokyo Biochemical Research Foundation (2004, YM) and from the Inamori Foundation (2004, YM). YM is a recipient of the 2002 Research Award from the KANAE Foundation for Life & Socio-Medical Science, the 2002 Young Investigator Award from the Japan Society of Cardiovascular Endocrinology and Metabolism, the 2003 Research Award from the Kobayashi Magobei Memorial Foundation for Medical Science, the 2004 Research Award from the Sanyo Broadcast Academic and Cultural Foundation, and the 2005 Oshima Award (Young Investigator Award) from the Japanese Society of Nephrology.
PY - 2006/7
Y1 - 2006/7
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.
AB - 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.
KW - Angiotensin II
KW - VEGF
KW - angiogenesis
KW - angiopoietin-1
KW - angiopoietin-2
KW - interstitial fibrosis
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U2 - 10.1016/j.amjhyper.2005.09.022
DO - 10.1016/j.amjhyper.2005.09.022
M3 - Article
C2 - 16814127
AN - SCOPUS:33745237683
SN - 0895-7061
VL - 19
SP - 718
EP - 727
JO - American Journal of Hypertension
JF - American Journal of Hypertension
IS - 7
ER -