PubMed Health⌕ Search

Biomedical subjects

Ralf Dechend

Publications and source records attributed to Ralf Dechend.

28 records · Page 2Linked to original sources
PubMed2003

Lipoic acid supplementation prevents angiotensin II-induced renal injury.

BACKGROUND: Angiotensin II (Ang II)-induced renal injury is associated with perivascular inflammation, cell proliferation, and increased superoxide production in the vascular wall. We tested whether lipoic acid, an endogenous antioxidant, protects against the Ang II-induced inflammatory response and end-organ damage. METHODS: Light microscopy, immunohistochemistry, electrophoretic mobility shift assay, Northern blots, and high-pressure liquid chromatography (HPLC) were used in kidneys from double transgenic rats (dTGR) harboring human renin and angiotensinogen genes and normotensive Sprague Dawley (SD) rats. The effects of lipoic acid supplementation for three weeks were examined in dTGR and SD rats. RESULTS: Lipoic acid effectively prevented Ang II-induced glomerular and vascular damage in the kidneys and completely prevented the development of albuminuria. Ang II-induced leukocyte infiltration and cell proliferation in the kidney were attenuated. The redox-sensitive transcription factors nuclear factor (kappa) B (NF-kappa B) and activator protein-1 (AP-1) in the kidneys were increased in dTGR compared with SD, and were effectively reduced. Renal glutathione levels were much higher in dTGR than in SD, while the opposite was true for cysteine levels. These results suggested increased renal glutathione oxidation in dTGR, leading to cysteine shortage. Lipoic acid partly prevented renal cysteine depletion and increased hepatic cysteine and glutathione concentrations. This effect was accompanied by increased hepatic gamma-glutamylcysteine synthetase mRNA expression. CONCLUSION: Our in vivo results suggest that lipoic acid protects against Ang II-induced renal injury through anti-inflammatory/antioxidative mechanisms. The effects are associated with decreased NF-kappa B and AP-1 activation, as well as improved thiol homeostasis.

Albuminuria↗
PubMed2002

Angiotensin II induced inflammation in the kidney and in the heart of double transgenic rats.

BACKGROUND: We are investigating a double transgenic rat (dTGR) model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1) are expressed early on the endothelium, while the corresponding ligands are found on circulating leukocytes. Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, iNOS and Tissue Factor expression. Furthermore we show evidence that Ang II causes the upregulation of NF-kB in our model. METHODS: We started PDTC-treatment on four weeks old dTGR (200 mg/kg sc) and age-matched SD rats. Blood-pressure- and albuminuria- measurements were monitored during the treatment period (four weeks). The seven weeks old animals were killed, hearts and kidneys were isolated and used for immunohistochemical-and electromobility shift assay analysis. RESULTS: Chronic treatment with the antioxidant PDTC decreased blood pressure (162 plus minus 8 vs. 190 plus minus 7 mm Hg, p = 0.02). Cardiac hypertrophy index was significantly reduced (4.90 plus minus 0.1 vs. 5.77 plus minus 0.1 mg/g, p < 0.001) compared to dTGR. PDTC reduced 24 h albuminuria by 85 % (2.7 plus minus 0.5 vs. 18.0 plus minus 3.4 mg/d, p < 0.001) and prevented death significantly. Vascular injury was ameliorated in small renal and cardiac vessels. PDTC inhibited NF-kappaB binding activity in heart and kidney. Immunohistochemical analysis shows increased expression of the p65 NF-kappaB subunit in the endothelium, smooth muscles cells of damaged small vessels, infiltrated cells, glomeruli, tubuli and collecting ducts of dTGR. PDTC markedly reduced the immunoreactivity of p65. CONCLUSION: Our data show that inhibition of NF-kappaB by PDTC markedly reduces inflammation, iNOS expression in the dTGR most likely leading to decreased cytotoxicity, and cell proliferation. Thus, NF-kappaB activation plays an important role in ANG II-induced end-organ damage.

Angiotensin II↗
PubMed2002

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.

Angiotensin II↗
PubMed2002

A gene expression analysis in rat kidney following high and low salt intake.

BACKGROUND: The effects of salt intake on renal regulation have been investigated for decades. To find new pathways and to demonstrate the utility of oligonucleotide expression arrays, we studied whole kidneys. METHODS: Eight Sprague-Dawley rats were divided into two groups. One group received a 6% salt (by weight) diet, while the other group received a 0.3%, otherwise identical, salt diet for 7 days. The rats were sacrificed after 7 days and the left kidney was subjected to RNA extraction. Oligonucleotide expression arrays (Affymetrix) were used to determine downregulation and upregulation, comparing high with low salt intake. Four rats from each group were studied separately. RESULTS: The experiments were reproducible. Thirty genes were downregulated with the high-salt diet, while 35 genes were upregulated. The renin gene, beta-2 glycoprotein-1, retinol binding protein, annexin VI, and the PTP2C protein tyrosine phosphatase were among the downregulated genes. The angiotensin II receptor type 1B receptor, HMG-CoA reductase, B7 antigen, and the rat calcium channel beta subunit III were among the upregulated genes. Differentially regulated were the p55 subunit (upregulated) and the p50 subunit (downregulated) of the phosphatidyl inositol 3-kinase enzyme complex. We verified our results by selecting a high-salt downregulated gene (renin) and an upregulated gene (B7 antigen) and subjecting these genes to real-time polymerase chain reaction. The results were consistent. CONCLUSION: Oligonucleotide expression arrays can detect novel genes encoding for proteins not generally associated with responses to varied salt intake. Experiments of this nature have substantial limitations and require detailed verification. However, overall, the utility is promising.

Animals↗
PubMed2002

Postischemic acute renal failure is reduced by short-term statin treatment in a rat model.

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.

Acute Kidney Injury↗
PubMed2002

Endothelin-converting enzyme inhibition ameliorates angiotensin II-induced cardiac damage.

We tested the hypothesis that endothelin-converting enzyme (ECE) inhibition ameliorates end-organ damage in rats harboring both human renin and human angiotensinogen genes (dTGR). Hypertension develops in the animals, and they die by age 7 weeks of heart and kidney failure. Three groups were studied: dTGR (n=12) receiving vehicle, dTGR receiving ECE inhibitor (RO0687629; 30 mg/kg by gavage; n=10), and Sprague-Dawley control rats (SD; n=10) receiving vehicle, all after week 4, with euthanasia at week 7. Systolic blood pressure was not reduced by ECE inhibitor compared with dTGR (205+/-6 versus 206+/-6 mm Hg at week 7, respectively). In contrast, ECE inhibitor treatment significantly reduced mortality rate to 20% (2 of 10), whereas untreated dTGR had a 52% mortality rate (7 of 12). ECE inhibitor treatment ameliorated cardiac damage and reduced left ventricular ECE activity below SD levels. Echocardiography at week 7 showed reduced cardiac hypertrophy (4.8+/-0.2 versus 5.7+/-0.2 mg/g, P<0.01) and increased left ventricular cavity diameter (5.5+/-0.3 versus 3.1+/-0.1 mm, P<0.001) and filling volume (0.42+/-0.04 versus 0.16+/-0.06 mL, P<0.05) after ECE inhibitor compared with untreated dTGR. ECE inhibitor treatment also reduced cardiac fibrosis, tissue factor expression, left ventricular basic fibroblast growth factor mRNA levels, and immunostaining in the vessel wall, independent of high blood pressure. In contrast, the ECE inhibitor treatment showed no renoprotective effect. These data are the first to show that ECE inhibition reduces angiotensin II-induced cardiac damage.

Angiotensin II↗
PubMed2002

Lacidipine inhibits adhesion molecule and oxidase expression independent of blood pressure reduction in angiotensin-induced vascular injury.

Dihydropyridines can inhibit gene expression in-vitro and may have a protective vascular effect independent of blood pressure reduction. We tested the hypothesis that lacidipine prevents induction of inducible NO synthase (iNOS), influences leukocyte adhesion and infiltration, inhibits nuclear factor (NF)-kappaB transcription factor activity, and ameliorates end-organ damage in a transgenic rat model of angiotensin (Ang) II--dependent organ sclerosis. We treated rats transgenic for human renin and angiotensinogen (dTGR) from week 4 to 7 with lacidipine (0.3 or 3 mg/kg by gavage). Blood pressure was measured by tail cuff. Organ damage was assessed by histology and immunohistochemistry. Adhesion molecules and cytokines were analyzed by immunohistochemistry. Transcription factors were analyzed by mobility shift assays. Untreated dTGR developed moderate hypertension, cardiac hypertrophy, and severe renal damage with albuminuria. Lacidipine decreased blood pressure slightly at the low dose and substantially at the higher dose. However, both treatments reduced albuminuria and plasma creatinine to the same degree (P<0.05). Intercellular adhesion molecule-1 (ICAM-1) was markedly reduced by lacidipine as well as renal neutrophil and monocyte infiltration. Lacidipine reduced mitogen-activated protein (MAP) kinase phosphorylation and iNOS expression in both cortex and medulla. NF-kappaB and AP-1 were activated in dTGR but reduced by lacidipine. Lacidipine ameliorates Ang II-induced end-organ damage independent of blood pressure lowering, perhaps by inhibiting the MAP kinase pathway and NF-kappaB activation.

Angiotensins↗