A possible anti-inflammatory role of angiotensin II type 2 receptor in immune-mediated glomerulonephritis during type 1 receptor blockade.

Abstract

We previously reported that angiotensin II type 1 receptor (AT1R) blockade attenuates renal inflammation/fibrogenesis in immune-mediated glomerulonephritis via angiotensin II type 2 receptor (AT2R). In the present study, further in vivo experiments revealed that AT2R was expressed in tubular epithelial cells of nephritic kidneys in mice, and feedback activation of the renin-angiotensin system during AT1R blockade significantly reduced p-ERK, but not intranuclear nuclear factor-kappaB, levels via AT2R. This led to reduction in mRNA levels of the proinflammatory mediator monocyte chemoattractant protein-1 and overall interstitial inflammation and subsequent fibrogenesis. Specific blockade of ERK expression in tubular epithelium by anti-sense oligodeoxynucleotides also attenuated interstitial inflammation, mimicking the anti-inflammatory action of AT2R in nephritic kidneys. Alternatively, we succeeded in confirming such an AT(2)R function by demonstrating that AT1R blockade did not confer renoprotection in nephritic, AT2R gene-deficient mice. Additional in vitro experiments revealed that AT2R activation did not affect nuclear factor-kappaB activation by tumor necrosis factor-alpha in cultured tubular epithelial cells, although it inhibited ERK phosphorylation, which reduced monocyte chemoattractant protein-1 mRNA levels. These results suggest that feedback activation of AT2Rs in tubular epithelium of nephritic kidneys plays an important role in attenuating interstitial inflammation.

• Authors: Hirokazu Okada, Tsutomu Inoue, Tomohiro Kikuta, Yusuke Watanabe, Yoshihiko Kanno, Shinichi Ban, Takeshi Sugaya, Masatsugu Horiuchi, Hiromichi Suzuki
• Journal: The American journal of pathology (Am J Pathol) Vol. 169 Issue 5 Pg. 1577-89 (Nov 2006) ISSN: 0002-9440 [Print] United States
• PMID: 17071582 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Ccl2 protein, mouse
• Chemokine CCL2
• NF-kappa B
• RNA, Messenger
• Receptor, Angiotensin, Type 1
• Receptor, Angiotensin, Type 2
• Extracellular Signal-Regulated MAP Kinases

Topics

• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Animals
• Anti-Glomerular Basement Membrane Disease (immunology, pathology)
• Chemokine CCL2 (genetics, metabolism)
• Enzyme Activation (drug effects)
• Epithelial Cells (cytology, drug effects, pathology)
• Epithelium (drug effects, pathology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Expression Regulation (drug effects)
• Inflammation (immunology)
• Kidney Tubules (drug effects)
• Male
• Mice
• NF-kappa B (metabolism)
• RNA, Messenger (genetics, metabolism)
• Receptor, Angiotensin, Type 1 (metabolism)
• Receptor, Angiotensin, Type 2 (deficiency, genetics, metabolism)
• Time Factors