Infusion of angiotensin II reduces loss of glomerular capillary area in the early phase of anti-Thy-1.1 nephritis possibly via regulating angiogenesis-associated factors.
BACKGROUND
Although angiotensin II (Ang II) is involved in the progression of renal diseases, infusion of Ang II was reported to surprisingly ameliorate the early phase of anti-Thy-1.1 nephritis. Considering the known proangiogenic effect of Ang II and that angiogenic glomerular capillary repair is required for the recovery of damaged glomeruli in rat anti-Thy-1.1 nephritis, we hypothesized that Ang II infusion starting prior to the initiation of nephritis may induce the expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1), resulting in the increased glomerular capillary area in the early phase.


METHODS
Ang II was infused (170 ng/min) in rats, and 5 days later, nephritis was induced by the administration of monoclonal 1-22-3 antibodies. Ang II type 1 or type 2 receptor antagonist (AT(1)R or AT(2)R, respectively) (losartan or PD123319, respectively) was coadministered.


RESULTS
Ang II infusion affected on neither the deposition of Ig nor mesangiolysis in the initial phase, and resulted in the aggravation of creatinine clearance at day 14 and 35 after initiating anti-Thy-1.1 nephritis. Histologic alterations were ameliorated accompanied by reduced loss in rat endothelial cell antigen (RECA)-1(+) endothelial area in Ang II-infused nephritic rats on day 6 and 14 as compared to control nephritic group, and nephritic alterations were mostly resolved on day 35 in both groups. At the early stage (day 6), glomerular expression of VEGF and receptors flk-1 and flt-1 as well as Ang-1, and receptor Tie2 were increased, and glomerular monocyte infiltration and the expression of angiopoietin-2 (Ang-2), a natural antagonist of Ang-1, were reduced. Both Ang II receptors were involved in the regulation of angiogenic factors and receptors.


CONCLUSIONS
These results demonstrate that infusion of exogenous Ang II starting prior to the induction of nephritis activates VEGF and Ang-1 signaling regulated via both Ang II receptors, potentially leading to the accelerated recovery of injured glomerular endothelial cells in the early phase of anti-Thy-1.1 nephritis. Increased expression of VEGF and Ang-1 on podocytes further suggests the crucial association of endothelial cells and podocytes in maintaining proper glomerular capillary structures.
Takazawa
Yuki
Y
Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
Maeshima
Yohei
Y
Kitayama
Hiroyuki
H
Yamamoto
Yoshihiko
Y
Kawachi
Hiroshi
H
Shimizu
Fujio
F
Matsui
Hideki
H
Sugiyama
Hitoshi
H
Yamasaki
Yasushi
Y
Makino
Hirofumi
H
D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D002196:Capillaries / Q000473:pathology / Q000502:physiology; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D006977:Hypertension, Renal / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D007518:Isoantibodies / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology*
D007518:Isoantibodies; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D042461:Vascular Endothelial Growth Factor A; D014662:Vasoconstrictor Agents; C035678:anti-Thy antibody; D000804:Angiotensin II; D000803:Angiotensin I; D042787:Receptor, TIE-2; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2