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(American Journal of Pathology. 2002;161:1679-1693.)
© 2002 American Society for Investigative Pathology

Immunosuppressive Treatment Protects Against Angiotensin II-Induced Renal Damage

Dominik N. Muller^*, Erdenechimeg Shagdarsuren^*, Joon-Keun Park, Ralf Dechend^*, Eero Mervaala, Franziska Hampich^*, Anette Fiebeler, Xinsheng Ju, Piet Finckenberg, Jürgen Theuer^*, Christiane Viedt^¶, Joerg Kreuzer^¶, Harald Heidecke^||, Hermann Haller, Martin Zenke and Friedrich C. Luft^*

From the HELIOS Klinikum-Berlin,^* Franz Volhard Clinic and Medical Faculty of the Charité, Humboldt University of Berlin, Berlin, Germany; the Max Delbrück Center for Molecular Medicine, Berlin-Buch, Berlin, Germany; the Department of Medicine-Nephrology, Hannover Medical School, Hannover, Germany; the Department of Cardiology,^¶ University of Heidelberg, Heidelberg, Germany; CellTrend,|| Luckenwalde, Germany; and the Department of Pharmacology, University of Helsinki Medical School, Helsinki, Finland

Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining co-localized with macrophages and partially with T cells. dTGR dendritic cells expressed major histocompatibility complex II and CD86, indicating maturation. DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T-cell infiltration. In additional experiments, we treated dTGRs with mycophenolate mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of mycophenolate mofetil and its effect on dendritic and T cells were similar to those obtained with DEXA. We next investigated whether or not Ang II directly promotes dendritic cell maturation in vitro. Ang II did not alter CD80, CD83, and MHC II expression, but increased CCR7 expression and cell migration. To explore the role of tumor necrosis factor (TNF)- on dendritic cell maturation in vivo, we treated dTGRs with the soluble TNF- receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-B activation, and infiltration of all immunocompetent cells. These data suggest that immunosuppression prevents dendritic cell maturation and T-cell infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces dendritic migration directly, whereas in vivo TNF- is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response.

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