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3.
Am J Pathol ; 161(5): 1679-93, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12414515

ABSTRACT

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.


Subject(s)
Angiotensin II/antagonists & inhibitors , Dexamethasone/pharmacology , Immunosuppressive Agents/pharmacology , Kidney Diseases/immunology , Membrane Transport Proteins , Mycophenolic Acid/analogs & derivatives , Angiotensinogen/genetics , Animals , Animals, Genetically Modified , Antigens, CD/metabolism , B7-2 Antigen , Blood Pressure , Dendritic Cells/drug effects , Dendritic Cells/immunology , Etanercept , Histocompatibility Antigens Class II/metabolism , Humans , Immunoglobulin G/pharmacology , Inflammation/prevention & control , Kidney/drug effects , Kidney/immunology , Kidney/pathology , Kidney Diseases/pathology , Kidney Diseases/prevention & control , Kinetics , Macrophage Migration-Inhibitory Factors/metabolism , Male , Membrane Glycoproteins/metabolism , Mycophenolic Acid/pharmacology , NADPH Dehydrogenase/analysis , NADPH Oxidases , NF-kappa B/metabolism , Phosphoproteins/analysis , Protective Agents/pharmacology , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Receptors, Tumor Necrosis Factor , Renin/genetics , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
4.
J Am Soc Nephrol ; 13(9): 2288-98, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12191973

ABSTRACT

Postischemic acute renal failure (ARF) is common and often fatal. Cellular mechanisms include cell adhesion, cell infiltration and generation of oxygen free radicals, and inflammatory cytokine production. Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") directly influence inflammatory mechanisms. The hypothesis that ischemia-induced ARF could be ameliorated with statin treatment was investigated and possible molecular mechanisms were analyzed in a uninephrectomized rat model. Male Sprague-Dawley rats were pretreated with cerivastatin (0.5 mg/kg) or vehicle for 3 d. Ischemic ARF was induced by left renal artery clipping for 45 min, while the right kidney was being removed. After 24 h of ARF, serum creatinine levels were increased 7.5-fold in vehicle-treated control animals with ARF, compared with sham-operated animals (P < 0.005). Statin treatment reduced the creatinine level elevation by 40% (P < 0.005). Simultaneously, ischemia-induced severe decreases in GFR were significantly ameliorated by statin treatment (sham operation, 0.95 +/- 0.09 ml/min, n = 13; ischemia without treatment, 0.06 +/- 0.02 ml/min, n = 9; ischemia with statin pretreatment, 0.21 +/- 0.03 ml/min, n = 11; P < 0.001). Furthermore, statin pretreatment prevented the occurrence of tubular necrosis, with marked loss of the brush border, tubular epithelial cell detachment, and tubular obstruction in the S3 segment of the outer medullary stripe. In addition, monocyte and macrophage infiltration was almost completely prevented, intercellular adhesion molecule-1 upregulation was greatly decreased, and inducible nitric oxide synthase expression was reduced. Fibronectin and collagen IV expression was reduced, approaching levels observed in sham-operated animals. In vehicle-treated rats with ARF, mitogen-activated protein kinase extracellular activated kinase-1/2 activity was increased and the transcription factors nuclear factor-kappaB and activator protein-1 were activated. Statin treatment reduced this activation toward levels observed in sham-operated rats. The data suggest that hydroxy-3-methylglutaryl coenzyme A reductase inhibition protects renal tissue from the effects of ischemia-reperfusion injury and thus reduces the severity of ARF. The chain of events may involve anti-inflammatory effects, with inhibition of mitogen-activated protein kinase activation and the redox-sensitive transcription factors nuclear factor-kappaB and activator protein-1.


Subject(s)
Acute Kidney Injury/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Ischemia/complications , Pyridines/pharmacology , Acute Kidney Injury/etiology , Acute Kidney Injury/pathology , Animals , Disease Models, Animal , Fibronectins/analysis , Intercellular Adhesion Molecule-1/analysis , Ischemia/pathology , Kidney Glomerulus/chemistry , Kidney Glomerulus/enzymology , Kidney Glomerulus/pathology , Male , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3 , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Nitric Oxide Synthase/analysis , Nitric Oxide Synthase Type II , Rats , Rats, Sprague-Dawley
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