Immunosuppressive treatment protects against angiotensin II-induced renal damage.
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)-alpha on dendritic cell maturation in vivo, we treated dTGRs with the soluble TNF-alpha receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-kappaB 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-alpha is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response.
Muller
Dominik N
DN
HELIOS Klinikum-Berlin, Franz Volhard Clinic and Medical Faculty of the Charité, Humboldt University of Berlin, Germany.
Shagdarsuren
Erdenechimeg
E
Park
Joon-Keun
JK
Dechend
Ralf
R
Mervaala
Eero
E
Hampich
Franziska
F
Fiebeler
Anette
A
Ju
Xinsheng
X
Finckenberg
Piet
P
Theuer
Jürgen
J
Viedt
Christiane
C
Kreuzer
Joerg
J
Heidecke
Harald
H
Haller
Hermann
H
Zenke
Martin
M
Luft
Friedrich C
FC
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D015703:Antigens, CD / Q000378:metabolism; D051940:B7-2 Antigen; D001794:Blood Pressure; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D003907:Dexamethasone / Q000494:pharmacology*; D000068800:Etanercept; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D007674:Kidney Diseases / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D007700:Kinetics; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D009252:NADPH Dehydrogenase / Q000032:analysis; D019255:NADPH Oxidases; D016328:NF-kappa B / Q000378:metabolism; D010750:Phosphoproteins / Q000032:analysis; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D012083:Renin / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D015703:Antigens, CD; D051940:B7-2 Antigen; C497964:CD86 protein, human; C497966:Cd86 protein, rat; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D008263:Macrophage Migration-Inhibitory Factors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D016328:NF-kappa B; D010750:Phosphoproteins; D020011:Protective Agents; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor; D000808:Angiotensinogen; D000804:Angiotensin II; D003907:Dexamethasone; D019255:NADPH Oxidases; C086986:CYBA protein, human; D009252:NADPH Dehydrogenase; D012083:Renin; D009173:Mycophenolic Acid; D000068800:Etanercept