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(American Journal of Pathology. 2006;169:1577-1589.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060178

A Possible Anti-Inflammatory Role of Angiotensin II Type 2 Receptor in Immune-Mediated Glomerulonephritis during Type 1 Receptor Blockade

Hirokazu Okada*, Tsutomu Inoue*, Tomohiro Kikuta*, Yusuke Watanabe*, Yoshihiko Kanno*, Shinichi Ban{dagger}, Takeshi Sugaya{ddagger}, Masatsugu Horiuchi§ and Hiromichi Suzuki*

From the Departments of Nephrology* and Pathology,{dagger} Saitama Medical School, Saitama; the Research Unit for Organ Regeneration,{ddagger} Riken Kobe Institute, Kobe; and the Division of Medical Biochemistry and Cardiovascular Biology,§ Ehime University School of Medicine, Ehime, Japan

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-{kappa}B, 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 AT2R 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-{kappa}B 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.




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