Angiotensin II type 1 receptor blockade attenuates renal fibrogenesis in an immune-mediated nephritic kidney through counter-activation of angiotensin II type 2 receptor.
The relative roles of angiotensin II (Ang II) type 1 receptor (AT(1)R) and Ang II type 2 receptor (AT(2)R) in immune-mediated nephritis are unknown, and the effect of the blockade of AT(1)R and its indirect counter-activation of AT(2)R relative to the anti-fibrotic action in this disease is unclear. To address this question, we studied the role of AT(1)R and AT(2)R in anti-glomerular basement membrane nephritis in SJL mice. Groups of mice were treated with either an AT(1)R antagonist (CGP-48933; CGP group), an AT(2)R antagonist (PD-123319; PD group), both (CGP/PD group), or a vehicle (PCt group) from Day 29 to 56. At Day 56 post-treatment, fibrosis-related parameters such as interstitial matrix deposition, and the expression of genes of TGF-beta1, plasminogen activator inhibitor-1, and type I collagen were significantly reduced in the kidney in the CGP group. There were no significant effects on these parameters in the PD group. However, this anti-fibrotic action by CGP-48933 was totally abolished by co-treatment with PD-123319 in the CGP/PD group. The gene expression of renin was significantly increased in the kidneys in the CGP and CGP/PD groups, suggesting that CGP-48933 had increased Ang II generation in those groups. In conclusion, counter-activation of AT(2)R by increased Ang II under AT(1)R blockade likely conferred an anti-fibrotic protection in this model.
Okada
Hirokazu
H
Department of Nephrology, Saitama Medical College, Saitama, Japan.
Watanabe
Yusuke
Y
Inoue
Tsutomu
T
Kobayashi
Tatsuya
T
Kikuta
Tomohiro
T
Kanno
Yoshihiko
Y
Ban
Shinichi
S
Suzuki
Hiromichi
H
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D007668:Kidney / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D051379:Mice; D009393:Nephritis; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology*; D012083:Renin / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D017395:Plasminogen Activator Inhibitor 1; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D003094:Collagen; D003404:Creatinine; D012260:Ribonucleases; D012083:Renin