Hirokazu Okada , Yusuke Watanabe , Tatsuya Kobayashi , Tomohiro Kikuta , Yoshihiko Kanno , Hiromichi Suzuki
06 July 2004
American Journal of Nephrology
Extracellular signal-regulated kinase, Angiotensin II type 1 receptor, Angiotensin II type 2 receptor, Splenic lymphocytes, JE, Transforming growth factor-β1
Angiotensin II (Ang II) type 1 receptor (AT<sub>1</sub>R) has been confirmed to confer renoprotection in the progressive, immune-mediated nephritis in animal models as well as in humans. However, the relative contributions of direct AT<sub>1</sub>R blockade, indirect counteractivation of Ang II type 2 receptor (AT<sub>2</sub>R), or both, to renoprotection through AT<sub>1</sub>R antagonism remains to be clarified. Immunohistochemical studies in the nephritic kidney revealed that tubular epithelial cells and infiltrating immune cells were positive for AT<sub>1</sub>R and AT<sub>2</sub>R. In the present study, we investigated the action of Ang II on both receptors on immune cells. A subpopulation of lipopolysaccharide-activated splenic lymphocytes (mixed lymphocyte populations) was positive for AT<sub>1</sub>R and AT<sub>2</sub>R. Ang II alone could not induce gene expression of a pro-inflammatory chemokine JE or a pro-fibrotic cytokine transforming growth factor-β1 in those cells. However, Ang II could significantly suppress the expression of both genes in those cells under AT<sub>1</sub>R blockade, and this action was mediated through AT<sub>2</sub>R. Conversely, the pro-inflammatory/pro-fibrotic gene expression could be enhanced by AT<sub>2</sub>R blockade, and this was mediated through AT<sub>1</sub>R. AT<sub>1</sub>R and AT<sub>2</sub>R expressed in activated immune cells can modulate pro-inflammatory and pro-fibrotic reactions reciprocally. In advanced immune-mediated nephritic kidneys, AT<sub>1</sub>R antagonism likely confers renoprotection via activation of AT<sub>2</sub>R.
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