TY  - JOUR
AB  - Kidney fibrosis is the common pathophysiological mechanism in end-stage renal disease characterized by excessive accumulation of myofibroblast-derived extracellular matrix. Natriuretic peptides have been demonstrated to have cyclic guanosine monophosphate (cGMP)-dependent anti-fibrotic properties likely due to interference with pro-fibrotic tissue growth factor β (TGF-β) signaling. However, in vivo, natriuretic peptides are rapidly degraded by neutral endopeptidases (NEP). In a unilateral ureteral obstruction (UUO) mouse model for kidney fibrosis we assessed the anti-fibrotic effects of SOL1, an orally active compound that inhibits NEP and endothelin-converting enzyme (ECE). Mice (n=10 per group) subjected to UUO were treated for 1 week with either solvent, NEP-/ECE-inhibitor SOL1 (two doses), reference NEP-inhibitor candoxatril or the angiotensin II receptor type 1 (AT1)-antagonist losartan. While NEP-inhibitors had no significant effect on blood pressure, they did increase urinary cGMP levels as well as endothelin-1 (ET-1) levels. Immunohistochemical staining revealed a marked decrease in renal collagen (∼55% reduction, P<0.05) and α-smooth muscle actin (α-SMA; ∼40% reduction, P<0.05). Moreover, the number of α-SMA positive cells in the kidneys of SOL1-treated groups inversely correlated with cGMP levels consistent with a NEP-dependent anti-fibrotic effect. To dissect the molecular mechanisms associated with the anti-fibrotic effects of NEP inhibition, we performed a 'deep serial analysis of gene expression (Deep SAGE)' transcriptome and targeted metabolomics analysis of total kidneys of all treatment groups. Pathway analyses linked increased cGMP and ET-1 levels with decreased nuclear receptor signaling (peroxisome proliferator-activated receptor [PPAR] and liver X receptor/retinoid X receptor [LXR/RXR] signaling) and actin cytoskeleton organization. Taken together, although our transcriptome and metabolome data indicate metabolic dysregulation, our data support the therapeutic potential of NEP inhibition in the treatment of kidney fibrosis via cGMP elevation and reduced myofibroblast formation.
AU  - Bijkerk, R.*
AU  - Aleksinskaya, M.A.*
AU  - Duijs, J.M.*
AU  - Veth, J.*
AU  - Husen, B.*
AU  - Reiche, D.*
AU  - Prehn, C.
AU  - Adamski, J.
AU  - Rabelink, T.J.*
AU  - De Mey, J.G.R.*
AU  - van Zonneveld, A.J.*
C1  - 55096
C2  - 46292
SP  - 239-252
TI  - Neutral endopeptidase inhibitors blunt kidney fibrosis by reducing myofibroblast formation.
JO  - Clin. Sci.
VL  - 133
IS  - 2
PY  - 2019
SN  - 0143-5221
ER  - 

TY  - JOUR
AB  - Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, small airway remodeling and emphysema. Emphysema is the destruction of alveolar structures, leading to enlarged airspaces and reduced surface area impairing the ability for gaseous exchange. To further understand the pathological mechanisms underlying progressive emphysema we used mass spectrometry-based approaches to quantitate the lung, bronchoalveolar-lavage fluid (BALF) and serum metabolome during emphysema progression in the established murine porcine pancreatic elastase (PPE) model on days 28, 56 and 161, compared to PBS controls. Partial Least Square analysis revealed greater changes in the metabolome of lung followed by BALF rather than serum during emphysema progression. Furthermore, we demonstrate for the first time that emphysema progression is associated with a reduction in lung specific L-carnitine, a metabolite critical for transporting long chain fatty acids into the mitochondria for their subsequent β-oxidation. In vitro , stimulation of the ATII-like LA4 cell line with L-carnitine diminished apoptosis induced by both PPE and H2O2. Moreover, PPE-treated mice demonstrated impaired lung function compared to PBS treated controls (lung compliance; 0.067±0.008ml/cmH20 vs 0.035±0.005ml/cmH20, p<0.0001), which improved following supplementation with L-carnitine (0.051±0.006, p<0.01) and was associated with a reduction in apoptosis. In summary, our results provide a new insight into the role of L-carnitine and, importantly, suggest therapeutic avenues for COPD.
AU  - Conlon, T.M.
AU  - Bartel, J.
AU  - Ballweg, K.
AU  - Günter, S.
AU  - Prehn, C.
AU  - Krumsiek, J.
AU  - Meiners, S.
AU  - Theis, F.J.
AU  - Adamski, J.
AU  - Eickelberg, O.
AU  - Yildirim, A.Ö.
C1  - 47302
C2  - 39272
CY  - London
SP  - 273-287
TI  - Metabolomics screening identifies reduced L-carnitine to be associated with progressive emphysema.
JO  - Clin. Sci.
VL  - 130
IS  - 4
PB  - Portland Press Ltd
PY  - 2016
SN  - 0143-5221
ER  - 

TY  - JOUR
AB  - COPD (chronic obstructive pulmonary disease) is caused by exposure to toxic gases and particles, most often CS (cigarette smoke), leading to emphysema, chronic bronchitis, mucus production and a subsequent decline in lung function. The disease pathogenesis is related to an abnormal CS-induced inflammatory response of the lungs. Similar to active (mainstream) smoking, second hand (sidestream) smoke exposure severely affects respiratory health. These processes can be studied in vivo in models of CS exposure of mice. We compared the acute inflammatory response of female C57BL/6 mice exposed to two concentrations [250 and 500 mg/m3 TPM (total particulate matter)] of sidestream and mainstream CS for 3 days and interpreted the biological effects based on physico-chemical differences in the gas and particulate phase composition of CS. BAL (bronchoalveolar lavage fluid) was obtained to perform differential cell counts and to measure cytokine release. Lung tissue was used to determine mRNA and protein expression of proinflammatory genes and to assess tissue inflammation. A strong acute inflammatory response characterized by neutrophilic influx, increased cytokine secretion [KC (keratinocyte chemoattractant), TNF-α (tumour necrosis factor α), MIP-2 (macrophage inflammatory protein 2), MIP-1α and MCP-1 (monocyte chemoattractant protein-1)], pro-inflammatory gene expression [KC, MIP-2 and MMP12 (matrix metalloproteinase 12)] and up-regulated GM-CSF (granulocyte macrophage colony-stimulating factor) production was observed in the mainstream model. After sidestream exposure there was a dampened inflammatory reaction consisting only of macrophages and diminished GM-CSF levels, most likely caused by elevated CO concentrations. These results demonstrate that the composition of CS determines the dynamics of inflammatory cell recruitment in COPD mouse models. Different initial inflammatory processes might contribute to COPD pathogenesis in significantly varying ways, thereby determining the outcome of the studies.
AU  - John, G.
AU  - Kohse, K.
AU  - Orasche, J.
AU  - Reda, A.
AU  - Schnelle-Kreis, J.
AU  - Zimmermann, R.
AU  - Schmid, O.
AU  - Eickelberg, O.
AU  - Yildirim, A.Ö.
C1  - 28089
C2  - 32923
CY  - London
SP  - 207-221
TI  - The composition of cigarette smoke determines inflammatory cell recruitment to the lung in COPD mouse models.
JO  - Clin. Sci.
VL  - 126
IS  - 3
PB  - Portland Press
PY  - 2014
SN  - 0143-5221
ER  - 

TY  - JOUR
AB  - PPAR alpha (peroxisome-proliferator-activated receptor alpha) regulates the expression of genes that are involved in lipid metabolism, tissue homoeostasis and inflammation. Consistent rodent and human studies suggest a link between PPAR alpha function and cardiovascular disease, qualifying PPAR alpha [PPARA in HUGO (Human Genome Organisation) gene nomenclature] as a candidate gene for coronary artery disease. In the present study, we comprehensively evaluated common genetic variations within the PPAR alpha gene and assessed their association with myocardial infarction. First, we characterized the linkage disequilibrium within the PPAR alpha gene in an initial case-control sample of 806 individuals from the Regensburg Myocardial Infarction Family Study using a panel of densely spaced SNPs (single nucleotide polymorphisms) across the gene. Single SNP analysis showed significant association with the disease phenotype [OR (odds ratio) = 0.74, P = 0.012, 95% CI (confidence interval) = 0.61-0.94 for rs135551]. Moreover, we identified a protective three-marker haplotype with an association trend for myocardial infarcition (OR = 0.76, P = 0.067, 95% CI = 0.56-1.02). Subsequently, we were able to confirm the single SNP and haplotype association results in an independent second case-control cohort with 667 cases from the Regensburg Myocardial Infarction Family Study and 862 control individuals from the WHO (World Health Organization) MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) Augsburg project (OR = 0.87, P = 0.046, 95% CI = 0.72-0.99 for rs135551 and OR = 0.80, P = 0.034, 95% CI = 0.65-0.98 for the three-marker haplotype respectively). From these cross-sectional association results, we provide evidence that common variations in the PPAR alpha gene may influence the risk of myocardial infarcition in a European population.
AU  - Reinhard, W.*
AU  - Stark, K.*
AU  - Sedlacek, K.*
AU  - Fischer, M.*
AU  - Baessler, A.*
AU  - Neureuther, K.*
AU  - Weber, S.*
AU  - Kaess, B.*
AU  - Wiedmann, S.*
AU  - Mitsching, S.*
AU  - Lieb, W.*
AU  - Erdmann, J.*
AU  - Meisinger, C.
AU  - Döring, A.
AU  - Tolle, R.*
AU  - Jeron, A.*
AU  - Riegger, G.*
AU  - Hengstenberg, C.*
C1  - 719
C2  - 25997
SP  - 301-308
TI  - Association between PPAR alpha gene polymorphisms and myocardial infarction.
JO  - Clin. Sci.
VL  - 115
IS  - 9-10
PB  - Portland Press Ltd.
PY  - 2008
SN  - 0143-5221
ER  - 

TY  - JOUR
AU  - Lieb, W.*
AU  - Bolbrinker, J.*
AU  - Döring, A.
AU  - Hense, H.-W.*
AU  - Erdmann, J.*
AU  - Schunkert, H.*
AU  - Kreutz, R.*
C1  - 5097
C2  - 24266
SP  - 365-372
TI  - No association of the CYP3A5*/ allele with blood pressure and left ventricular mass and geometry: The KORA/MONICA Augsburg echocardiographic substudy.
JO  - Clin. Sci.
VL  - 111
PY  - 2006
SN  - 0143-5221
ER  - 

TY  - JOUR
AB  - The BK (bradykinin) B2 receptor is the major cellular mediator of the effects of BK. A 9 bp deletion in the promoter of the receptor gene represents an allelic variant that is associated with enhanced mRNA expression levels. We tested whether this polymorphism is associated with the prevalence of MI (myocardial infarction) or with echocardiographically determined left ventricular function in post-MI patients. Patients with documented MI (n=484), matched controls and controls without evidence of coronary heart disease (n=1363) constituted cases and controls. MI patients and controls were carefully matched for age, gender and cardiovascular risk factors. Genotype distributions of the 9 bp insertion/deletion polymorphism were similar across the groups: −9/−9, −9/+9 and +9/+9 were 22.1, 49.5 and 28.5% in MI patients, and 23.0, 44.6 and 32.5% in matched control subjects respectively. The lack of association was also observed in selected subgroups, stratified by age, gender and cardiovascular risk factors. Furthermore, there was no relation between this polymorphism and left ventricular systolic function in post-MI patients. These findings indicate that the 9 bp insertion/deletion polymorphism of the BK B2 receptor gene is neither related to the prevalence of MI nor to left ventricular function after MI.
AU  - Fischer, M.*
AU  - Lieb, W.*
AU  - Marold, D.*
AU  - Berthold, M.*
AU  - Baessler, A.*
AU  - Löwel, H.
AU  - Hense, H.-W.*
AU  - Hengstenberg, C.*
AU  - Holmer, S.*
AU  - Schunkert, H.*
AU  - Erdmann, J.*
C1  - 3429
C2  - 22463
SP  - 505-511
TI  - Lack of association of a 9 bp insertion/deletion polymorphism within the bradykinin 2 receptor gene with myocardial infarction.
JO  - Clin. Sci.
VL  - 107
IS  - 5
PY  - 2004
SN  - 0143-5221
ER  -