title: Regulation of angiogenic factors in angiotensin II infusion model in association with tubulointerstitial injuries.
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.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kitayama
authors.forename: Yohei
authors.initials: Y
authors.lastname: Maeshima
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takazawa
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Ichinose
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hirokoshi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D042683:Angiopoietin-1 / Q000032:analysis / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000032:analysis / Q000378:metabolism*; D000804:Angiotensin II / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D006977:Hypertension, Renal / Q000139:chemically induced / Q000378:metabolism*; D007263:Infusions, Parenteral; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D009000:Monocytes / Q000276:immunology; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000032:analysis / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000378:metabolism*
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D042787:Receptor, TIE-2