Die Bedeutung des Sphingolipidstoffwechsels für die Generierung von inflammatorischen und fibrotischen Mediatoren in renalen Mesangiumzellen

Sphingolipide wie Ceramid, Sphingosin und Sphingosin-1-Phosphat (S1P) werden in jüngster Zeit neben ihrer Funktion als reine Membranbestandteile zunehmend als bioaktive Signalmoleküle verstanden. Im Fokus der derzeitigen Forschung steht S1P, da es vielfältige physiologische und pathophysiologische Prozesse wie die Organisation des Zytoskelettes, die Regulation des Ca2+-Haushaltes sowie Proliferation, Migration und Apoptose reguliert (Meyer zu Heringdorf et al., 2007; Rivera et al., 2008). Zudem wird eine Beeinflussung der Sphingolipid-metabolisierenden Enzyme sowie eine daraus resultierende Verschiebung des S1P-Metabolismus mit einer Vielzahl verschiedener Erkrankungen in Verbindung gebracht, darunter Krebs, Arteriosklerose, Asthma oder Diabetes (Takabe et al., 2008; Pyne et al., 2010). Im Rahmen dieser Arbeit sollten daher verschiedene intra- und extrazelluläre Wirkmechanismen von S1P auf den Sphingolipid- und Eicosanoidmetabolismus in Mesangiumzellen untersucht werden um wertvolle und neue Erkenntnisse für die zukünftige Behandlung von fibrotischen und entzündlichen Nierenerkrankungen zu erhalten. Ein Schlüsselfaktor von Fibroseprozessen ist der Wachstumsfaktor transforming growth factor-β (TGF-β), der die Expression des pro-fibrotischen Bindegewebswachstumsfaktors connective tissue growth factor (CTGF) induzieren kann (Ren et al., 2009). Aus diesem Grund zählen CTGF und TGF-β zu attraktiven therapeutischen Ansatzpunkten bei der Behandlung von fibrotischen Erkrankungen (Boor et al., 2007). Allerdings können Thiazolidindione (TZDs) wie Troglitazon (TRO) oder Rosiglitazon (RSG) seit einiger Zeit neben ihrem Einsatz als antidiabetische Medikamente auch als potentielle Therapeutika zur Behandlung von chronischen, sowohl diabetisch als auch nicht-diabetisch induzierten Nierenerkrankungen und fibrotischen Prozessen zunehmend in Betracht gezogen werden (Lefebvre et al., 2006). Aus diesem Grund wurde in einem ersten Teilprojekt dieser Arbeit der Einfluss von TZDs als Agonisten von Peroxisome proliferator activated receptor (PPARγ) auf den intrazellulären Sphingolipidstoffwechsel und die Rolle von intrazellulär generiertem S1P für die Synthese von pro-fibrotischem CTGF untersucht um weitere Erklärungsansätze für die bekannten reno-protektiven Effekte von TZDs zu erhalten. Zudem wurde im Hinblick auf die Entstehung von Nierenerkrankungen der durch die PPARγ-Agonisten TRO und RSG aktivierte S1P-Rezeptorsubtyp in Rattenmesangiumzellen analysiert. Im zweiten Teil der Arbeit wurde die funktionelle Rolle von extra- und intrazellulärem S1P auf die Expression und Aktivität der pro-inflammatorischen Cyclooxygenase-2 (COX-2) und die daran beteiligten Signalwege in renalen Mesangiumzellen untersucht

Downregulation of sphingosine 1-phosphate (S1P) receptor 1 by dexamethasone inhibits S1P-induced mesangial cell migration

Sphingosine 1-phosphate (S1P) is generated by sphingosine kinase (SK)-1 and -2 and acts mainly as an extracellular ligand at five specific receptors, denoted S1P1-5. After activation, S1P receptors regulate important processes in the progression of renal diseases, such as mesangial cell migration and survival. Previously, we showed that dexamethasone enhances SK-1 activity and S1P formation, which protected mesangial cells from stress-induced apoptosis. Here we demonstrate that dexamethasone treatment lowered S1P1 mRNA and protein expression levels in rat mesangial cells. This effect was abolished in the presence of the glucocorticoid receptor antagonist RU-486. In addition, in vivo studies showed that dexamethasone downregulated S1P1 expression in glomeruli isolated from mice treated with dexamethasone (10 mg/kg body weight). Functionally, we identified S1P1 as a key player mediating S1P-induced mesangial cell migration. We show that dexamethasone treatment significantly lowered S1P-induced migration of mesangial cells, which was again reversed in the presence of RU-486. In summary, we suggest that dexamethasone inhibits S1P-induced mesangial cell migration via downregulation of S1P1. Overall, these results demonstrate that dexamethasone has functional important effects on sphingolipid metabolism and action in renal mesangial cells

Downregulation of sphingosine 1-phosphate (S1P) receptor 1 by dexamethasone inhibits S1P-induced mesangial cell migration

Sphingosine 1-phosphate (S1P) is generated by sphingosine kinase (SK)-1 and -2 and acts mainly as an extracellular ligand at five specific receptors, denoted S1P1-5. After activation, S1P receptors regulate important processes in the progression of renal diseases, such as mesangial cell migration and survival. Previously, we showed that dexamethasone enhances SK-1 activity and S1P formation, which protected mesangial cells from stress-induced apoptosis. Here we demonstrate that dexamethasone treatment lowered S1P1 mRNA and protein expression levels in rat mesangial cells. This effect was abolished in the presence of the glucocorticoid receptor antagonist RU-486. In addition, in vivo studies showed that dexamethasone downregulated S1P1 expression in glomeruli isolated from mice treated with dexamethasone (10 mg/kg body weight). Functionally, we identified S1P1 as a key player mediating S1P-induced mesangial cell migration. We show that dexamethasone treatment significantly lowered S1P-induced migration of mesangial cells, which was again reversed in the presence of RU-486. In summary, we suggest that dexamethasone inhibits S1P-induced mesangial cell migration via downregulation of S1P1. Overall, these results demonstrate that dexamethasone has functional important effects on sphingolipid metabolism and action in renal mesangial cells

which marker is best for prediction? Pooled analysis of four German population-based cohort studies and comparison with a nationwide cohort study

Objective To compare the association between different anthropometric measurements and incident type 2 diabetes mellitus (T2DM) and to assess their predictive ability in different regions of Germany. Methods Data of 10 258 participants from 4 prospective population-based cohorts were pooled to assess the association of body weight, body mass index (BMI), waist circumference (WC), waist-to-hip-ratio (WHR) and waist-to-height-ratio (WHtR) with incident T2DM by calculating HRs of the crude, adjusted and standardised markers, as well as providing receiver operator characteristic (ROC) curves. Differences between HRs and ROCs for the different anthropometric markers were calculated to compare their predictive ability. In addition, data of 3105 participants from the nationwide survey were analysed separately using the same methods to provide a nationally representative comparison. Results Strong associations were found for each anthropometric marker and incidence of T2DM. Among the standardised anthropometric measures, we found the strongest effect on incident T2DM for WC and WHtR in the pooled sample (HR for 1 SD difference in WC 1.97, 95% CI 1.75 to 2.22, HR for WHtR 1.93, 95% CI 1.71 to 2.17 in women) and in female DEGS participants (HR for WC 2.24, 95% CI 1.91 to 2.63, HR for WHtR 2.10, 95% CI 1.81 to 2.44), whereas the strongest association in men was found for WHR among DEGS participants (HR 2.29, 95% CI 1.89 to 2.78). ROC analysis showed WHtR to be the strongest predictor for incident T2DM. Differences in HR and ROCs between the different markers confirmed WC and WHtR to be the best predictors of incident T2DM. Findings were consistent across study regions and age groups (<65 vs ≥65 years). Conclusions We found stronger associations between anthropometric markers that reflect abdominal obesity (ie, WC and WHtR) and incident T2DM than for BMI and weight. The use of these measurements in risk prediction should be encouraged

Anthropometric markers and their association with incident type 2 diabetes mellitus: which marker is best for prediction? Pooled analysis of four German population-based cohort studies and comparison with a nationwide cohort study

Objective: To compare the association between different anthropometric measurements and incident type 2 diabetes mellitus (T2DM) and to assess their predictive ability in different regions of Germany. Methods: Data of 10 258 participants from 4 prospective population-based cohorts were pooled to assess the association of body weight, body mass index (BMI), waist circumference (WC), waist-to-hip-ratio (WHR) and waist-to-height-ratio (WHtR) with incident T2DM by calculating HRs of the crude, adjusted and standardised markers, as well as providing receiver operator characteristic (ROC) curves. Differences between HRs and ROCs for the different anthropometric markers were calculated to compare their predictive ability. In addition, data of 3105 participants from the nationwide survey were analysed separately using the same methods to provide a nationally representative comparison. Results: Strong associations were found for each anthropometric marker and incidence of T2DM. Among the standardised anthropometric measures, we found the strongest effect on incident T2DM for WC and WHtR in the pooled sample (HR for 1 SD difference in WC 1.97, 95% CI 1.75 to 2.22, HR for WHtR 1.93, 95% CI 1.71 to 2.17 in women) and in female DEGS participants (HR for WC 2.24, 95% CI 1.91 to 2.63, HR for WHtR 2.10, 95% CI 1.81 to 2.44), whereas the strongest association in men was found for WHR among DEGS participants (HR 2.29, 95% CI 1.89 to 2.78). ROC analysis showed WHtR to be the strongest predictor for incident T2DM. Differences in HR and ROCs between the different markers confirmed WC and WHtR to be the best predictors of incident T2DM. Findings were consistent across study regions and age groups

Relation between awareness of circulatory disorders and smoking in a general population health examination

BACKGROUND: Little is known about proportions of smokers who maintain smoking after they are aware of a circulatory disorder. The goal was to analyze the extent to which the number of circulatory disorders may be related to being a current smoker. METHODS: Cross-sectional survey study with a probability sample of residents in Germany investigated in health examination centers. Questionnaire data of 3,778 ever smoking participants aged 18 – 79 were used, questions included whether the respondent had ever had hypertension, myocardial infarction, other coronary artery disease, heart failure, stroke, other cerebrovascular disease, peripheral vascular disease, and venous thrombosis. Logistic regression was calculated for circulatory disorders and their number with current smoking as the dependent variable, and odds ratios (OR) are presented adjusted for physician contact, inpatient treatment, smoking cessation counseling, heavy smoking, exercise, overweight and obesity, school education, sex and age. RESULTS: Among ever smokers who had 1 circulatory disorder, 52.1 % were current smokers and among those who reported that they had 3 or more circulatory disorders 28.0 % were current smokers at the time of the interview. The adjusted odds of being a current smoker were lower for individuals who had ever smoked in life and had 2 or more central circulatory disorders, such as myocardial infarction, heart failure or stroke, than for ever smokers without central circulatory disorder (2 or more disorders: adjusted OR 0.6, 95 % confidence interval, CI, 0.4 to 0.8). CONCLUSION: Among those with central circulatory disorders, there is a substantial portion of individuals who smoke despite their disease. The data suggest that only a portion of smokers among the general population seems to be discouraged from smoking by circulatory disorders or its accompanying cognitive or emotional processes

Downregulation of sphingosine 1-phosphate (S1P) receptor 1 by dexamethasone inhibits S1P-induced mesangial cell migration

Sphingosine 1-phosphate (S1P) is generated by sphingosine kinase (SK)-1 and -2 and acts mainly as an extracellular ligand at five specific receptors, denoted S1P1-5. After activation, S1P receptors regulate important processes in the progression of renal diseases, such as mesangial cell migration and survival. Previously, we showed that dexamethasone enhances SK-1 activity and S1P formation, which protected mesangial cells from stress-induced apoptosis. Here we demonstrate that dexamethasone treatment lowered S1P1 mRNA and protein expression levels in rat mesangial cells. This effect was abolished in the presence of the glucocorticoid receptor antagonist RU-486. In addition, in vivo studies showed that dexamethasone downregulated S1P1 expression in glomeruli isolated from mice treated with dexamethasone (10 mg/kg body weight). Functionally, we identified S1P1 as a key player mediating S1P-induced mesangial cell migration. We show that dexamethasone treatment significantly lowered S1P-induced migration of mesangial cells, which was again reversed in the presence of RU-486. In summary, we suggest that dexamethasone inhibits S1P-induced mesangial cell migration via downregulation of S1P1. Overall, these results demonstrate that dexamethasone has functional important effects on sphingolipid metabolism and action in renal mesangial cells

Birth Order, Caesarean Section, or Daycare Attendance in Relation to Child- and Adult-Onset Type 1 Diabetes: Results from the German National Cohort

Background: Global incidence of type 1 diabetes (T1D) is rising and nearly half occurred in adults. However, it is unclear if certain early-life childhood T1D risk factors were also associated with adult-onset T1D. This study aimed to assess associations between birth order, delivery mode or daycare attendance and type 1 diabetes (T1D) risk in a population-based cohort and whether these were similar for childhood- and adult-onset T1D (cut-off age 15); (2) Methods: Data were obtained from the German National Cohort (NAKO Gesundheitsstudie) baseline assessment. Self-reported diabetes was classified as T1D if: diagnosis age ≤ 40 years and has been receiving insulin treatment since less than one year after diagnosis. Cox regression was applied for T1D risk analysis; (3) Results: Analyses included 101,411 participants (100 childhood- and 271 adult-onset T1D cases). Compared to “only-children”, HRs for second- or later-born individuals were 0.70 (95% CI = 0.50–0.96) and 0.65 (95% CI = 0.45–0.94), respectively, regardless of parental diabetes, migration background, birth year and perinatal factors. In further analyses, higher birth order reduced T1D risk in children and adults born in recent decades. Caesarean section and daycare attendance showed no clear associations with T1D risk; (4) Conclusions: Birth order should be considered in both children and adults’ T1D risk assessment for early detection

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Reasons for not using smoking cessation aids

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