TY - JOUR A1 - Zebger-Gong, Hong A1 - Mueller, Dominik A1 - Diercke, Michaela A1 - Haffner, Dieter A1 - Hocher, Berthold A1 - Verberckmoes, Steven A1 - Schmidt, Sven A1 - D'Haese, Patrick C. A1 - Querfeld, Uwe T1 - 1,25-Dihydroxyvitamin D-3-induced aortic calcifications in experimental uremia: up-regulation of osteoblast markers, calcium-transporting proteins and osterix JF - Journal of hypertension N2 - Background and objective Whether treatment with vitamin D receptor activators contributes to cardiovascular disease in patients with chronic kidney disease is a matter of debate. We studied mechanisms involved in vitamin D-related vascular calcifications in vivo and in vitro. Methods Aortic calcifications were induced in subtotally nephrectomized (SNX) rats by treatment with a high dose (0.25 mu g/kg per day) of 1,25-dihydroxyvitamin D-3 (calcitriol) given for 6 weeks. Likewise, primary rat vascular smooth muscle cells (VSMCs) were incubated with calcitriol at concentrations ranging from 10(-11) to 10(-7) mol/l. Immunohistochemistry revealed that the aortic expression of osteopontin, osteocalcin and bone sialoprotein was significantly increased in calcitriol-treated SNX rats compared to untreated SNX controls. In addition, aortic expression of the transient receptor potential vanilloid calcium channel 6 (TRPV6) and calbindin D9k was significantly up-regulated by treatment with calcitriol. Furthermore, calcitriol significantly increased expression of the osteogenic transcription factor osterix. In-vitro studies showed similar results, confirming that these effects could be attributed to treatment with calcitriol. Conclusions High-dose calcitriol treatment induces an osteoblastic phenotype in VSMC both in SNX rats and in vitro, associated with up-regulation of proteins regulating mineralization and calcium transport, and of the osteogenic transcription factor osterix. KW - calbindin D9k KW - calcitriol KW - calcium transport KW - osteoblast KW - osterix KW - TRPV5 KW - TRPV6 KW - vascular calcification Y1 - 2011 U6 - https://doi.org/10.1097/HJH.0b013e328340aa30 SN - 0263-6352 VL - 29 IS - 2 SP - 339 EP - 348 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Wengenmayer, Christina A1 - Krikov, Maxim A1 - Mueller, Susanne A1 - Lucht, Kristin A1 - Villringer, Arno A1 - Hocher, Berthold A1 - Unger, Thomas A1 - Thoene-Reineke, Christa T1 - Novel therapy approach in primary stroke prevention simultaneous inhibition of endothelin converting enzyme and neutral endopeptidase in spontaneously hypertensive, stroke-prone rats improves survival JF - Neurological research : a journal of progress in neurosurgery and neurosciences N2 - Objectives: Stroke, frequently a consequence of hypertension, is one of the leading causes of death and neurological disabilities worldwide. In the ischemic brain, levels of endothelin-1, one of the most potent vasoconstrictors, are raised. Anti-inflammatory and neuroprotective effects of endothelin antagonists after stroke have been described in literature. Based on these findings, we investigated the protective effect of the endothelin converting enzyme/neutral endopeptidase blocker, SLV 338, in salt-loaded, stroke-prone, spontaneously hypertensive rats. Methods: Male, 8-week-old spontaneously hypertensive stroke-prone rats were put on a high salt diet and treated with either 30 mg/kg or 100 mg/kg SLV 338 or vehicle for 27 weeks. Blood pressure, neurological outcome, body weight, and mortality were investigated throughout treatment. In weeks 1 and 9, animals were housed in metabolic cages for collection of urinary and blood samples and assessment of salt water and food intake. In weeks 22 and 27, additional blood samples were taken. At the end of the study, all brains were analyzed using magnetic resonance imaging. Results: SLV 338 was well tolerated in all animals. Neurological outcome and infarct size were similar in all groups. Albuminuria was considerably delayed and the incidence of stroke significantly lowered in treated animals. In spontaneously hypertensive stroke-prone rats, treatment with SLV 338 significantly (P=0.01) improved survival in comparison to the vehicle treated group in a blood pressure-independent manner. Discussion: Our data in spontaneously hypertensive stroke-prone rats demonstrate that combined endothelin converting enzyme/neutral endopeptidase inhibition could offer a new therapeutic approach for primary stroke prevention and improvement of mortality. The mechanism seems to be blood pressure-independent. KW - Endothelin KW - Hypertension KW - Natriuretic peptides KW - Stroke Y1 - 2011 U6 - https://doi.org/10.1179/016164111X12881719352534 SN - 0161-6412 VL - 33 IS - 2 SP - 201 EP - 207 PB - Routledge, Taylor & Francis Group CY - Leeds ER - TY - JOUR A1 - Vignon-Zellweger, Nicolas A1 - Relle, Katharina A1 - Kienlen, Elodie A1 - Alter, Markus L. A1 - Seider, Patrick A1 - Sharkovska, Juliya A1 - Heiden, Susi A1 - Kalk, Philipp A1 - Schwab, Karima A1 - Albrecht-Kuepper, Barbara A1 - Theuring, Franz A1 - Stasch, Johannes-Peter A1 - Hocher, Berthold T1 - Endothelin-1 overexpression restores diastolic function in eNOS knockout mice JF - Journal of hypertension N2 - Background The cardiac nitric oxide and endothelin-1 (ET-1) systems are closely linked and play a critical role in cardiac physiology. The balance between both systems is often disturbed in cardiovascular diseases. To define the cardiac effect of excessive ET-1 in a status of nitric oxide deficiency, we compared left ventricular function and morphology in wild-type mice, ET-1 transgenic (ET+/+) mice, endothelial nitric oxide synthase knockout (eNOS(-/-)) mice, and ET(+/+)eNOS(-/-) mice. Methods and results eNOS(-/-) and ET(+/+)eNOS(-/-) mice developed high blood pressure compared with wild-type and ET+/+ mice. Left ventricular catheterization showed that eNOS(-/-) mice, but not ET(+/+)eNOS(-/-), developed diastolic dysfunction characterized by increased end-diastolic pressure and relaxation constant tau. To elucidate the causal molecular mechanisms driving the rescue of diastolic function in ET(+/+)eNOS(-/-) mice, the cardiac proteome was analyzed. Two-dimensional gel electrophoresis coupled to mass spectrometry offers an appropriate hypothesis-free approach. ET-1 overexpression on an eNOS(-/-) background led to an elevated abundance and change in posttranslational state of antioxidant enzymes (e. g., peroxiredoxin-6, glutathione S-transferase mu 2, and heat shock protein beta 7). In contrast to ET(+/+)eNOS(-/-) mice, eNOS(-/-) mice showed an elevated abundance of proteins responsible for sarcomere disassembly (e. g., cofilin-1 and cofilin-2). In ET(+/+)eNOS(-/-) mice, glycolysis was favored at the expense of fatty acid oxidation. Conclusion eNOS(-/-) mice developed diastolic dysfunction; this was rescued by ET-1 transgenic overexpression. This study furthermore suggests that cardiac ET-1 overexpression in case of eNOS deficiency causes specifically the regulation of proteins playing a role in oxidative stress, myocytes contractility, and energy metabolism. KW - cardiovascular diseases KW - endothelin KW - nitric oxide Y1 - 2011 U6 - https://doi.org/10.1097/HJH.0b013e3283450770 SN - 0263-6352 SN - 1473-5598 VL - 29 IS - 5 SP - 961 EP - 970 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Thawnashom, Kittisak A1 - Tungtrongchitr, Rungsunn A1 - Chanchay, Siriporn A1 - Tungtrongchitr, Anchalee A1 - Raila, Jens A1 - Henze, Andrea A1 - Schweigert, Florian J. T1 - Association between Retinol-Binding protein and renal function among Asian subjects with type 2 diabetes mellitus a cross-sectionaö study JF - The Southeast Asian journal of tropical medicine and public health : official publication of the SEAMEO Regional Tropical Medicine and Public Health Project (TROPMED) N2 - Retinol-binding protein 4 (RBP4) has been suggested as new adipokine, possibly linking obesity to type 2 diabetes mellitus (T2DM). Since the kidneys are the main site of RBP4 degradation and since renal failure is a frequent co-morbid condition with diabetes mellitus, we evaluated the association among RBP4, renal function and T2DM in an Asian population. RBP4 serum levels were analyzed in 110 subjects (50 with T2DM) using an enzyme-linked immunosorbent assay (ELISA). Based on a cut-off estimated glomerular filtration rate (eGFR) of 60 ml/min per 1.73 m(2) (calculated according the abbreviated MDRD formula which uses serum creatinine level, age and gender) and on the T2DM status, subjects were assigned to four subgroups: Group A - controls with an eGFR > 60 ml/min per 1.73 m(2), Group B - controls with an eGFR < 60 ml/min per 1.73 m(2), Group C- T2DM subjects with an eGFR>60 ml/min per 1.73 m(2), and Group D - T2DM subjects with an eGFR <60 ml/ mm per 1.73 m(2). In both the T2DM and control groups, RBP4 levels were higher in subjects with an eGFR < 60 ml/min per 1.73 m(2) than in subjects with an eGFR >60 ml/min per 1.73 m(2). However, the difference was only significant between the control groups (p <0.05). After adjusting for age, gender, BMI, eGFR and the presence of T2DM, eGFR, not T2DM, was associated with plasma RBP4 levels (p<0.05). These results suggest among Asians the eGFR, but not the presence of T2DM, is a major determinant of RBP4 serum levels. The eGFR should be taken into account when evaluating the role of RBP4 in the pathogenesis of insulin resistance and T2DM. KW - retinol-binding protein 4 KW - renal function KW - type 2 diabetes mellitus KW - Asian subjects Y1 - 2011 SN - 0125-1562 VL - 42 IS - 4 SP - 936 EP - 945 PB - SEAMEO CY - Bangkok ER - TY - JOUR A1 - Sharkovska, Yuliya A1 - Kalk, Philipp A1 - von Websky, Karoline A1 - Relle, Katharina A1 - Pfab, Thiemo A1 - Alter, Markus L. A1 - Fischer, Yvan A1 - Hocher, Berthold T1 - Renoprotective effects of combined endothelin-converting enzyme/neutral endopeptidase inhibitor SLV338 in acute and chronic experimental renal damage JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - Background: Acute kidney injury (AKI) as well as chronic renal failure are associated with a huge mortality/morbidity. However, so far no drugs have been approved for the treatment of acute kidney failure and only a few for the treatment of chronic kidney disease (CKD). We analysed the effect of SLV 338, a neutral endopeptidase (NEP)/endothelin converting enzyme (ECE)-inhibitor in animal models of acute kidney failure as well as chronic renal failure. Methods: Acute renal failure was induced in male Wistar rats by uninephrectomy and clamping of the remaining kidney for 55 minutes. SLV338 (total dose: 4.9 mg/kg) or vehicle was continuously infused for 2 hours (starting 20 minutes prior to clamping). Sham operated animals served as controls. Plasma creatinine was measured at baseline and day 2 and 8 after renal ischemia-reperfusion. Hypertensive renal damage was induced in male Sprague Dawley rats by nitric oxide deficiency using L-NAME (50 mg/kg per day, added to drinking water for 4 weeks). One group was treated over the same time period with SLV338 (30 mg/kg per day, mixed with food). Systolic blood pressure was monitored weekly. At study end, urine and blood samples were collected and kidneys were harvested. Results: Acute renal ischemia-reperfusion caused a 5-fold plasma creatinine elevation (day 2), which was significantly attenuated by more than 50 % in animals treated with SLV338 (p < 0.05). Renal failure was accompanied by a 67 % mortality in vehicle-treated rats, but only 20 % after SLV338 treatment (p = 0.03 compared to sham controls). Chronic L-NAME administration caused hypertension, urinary albumin excretion, glomerulosclerosis, renal arterial remodelling, and renal interstitial fibrosis. Treatment with SLV338 did not significantly affect blood pressure, but abolished renal tissue damage (interstitial fibrosis, glomerulosclerosis, renal arterial remodelling (p < 0.05 versus L-NAME group in each case). Conclusions: The dual ECE/NEP inhibitor SLV338 preserves kidney function and reduces mortality in severe acute ischemic renal failure. Moreover, combined ECE/NEP inhibition prevents hypertensive renal tissue damage in a blood pressure independent manner in L-NAME-treated rats. KW - Renal failure KW - endothelin-converting enzyme KW - neutral endopeptidase Y1 - 2011 SN - 1433-6510 VL - 57 IS - 7-8 SP - 507 EP - 515 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Schildroth, Janice A1 - Rettig-Zimmermann, Juliane A1 - Kalk, Philipp A1 - Steege, Andreas A1 - Faehling, Michael A1 - Sendeski, Mauricio A1 - Paliege, Alexander A1 - Lai, En Yin A1 - Bachmann, Sebastian A1 - Persson, Pontus B. A1 - Hocher, Berthold A1 - Patzak, Andreas T1 - Endothelin type A and B receptors in the control of afferent and efferent arterioles in mice JF - Nephrology, dialysis, transplantation N2 - Background. Endothelin 1 contributes to renal blood flow control and pathogenesis of kidney diseases. The differential effects, however, of endothelin 1 (ET-1) on afferent (AA) and efferent arterioles (EA) remain to be established. Methods. We investigated endothelin type A and B receptor (ETA-R, ETB-R) functions in the control of AA and EA. Arterioles of ETB-R deficient, rescued mice [ETB (-/-)] and wild types [ETB(+/+)] were microperfused. Results. ET-1 constricted AA stronger than EA in ETB (-/-) and ETB(+/+) mice. Results in AA: ET-1 induced similar constrictions in ETB(-/-) and ETB(+/+) mice. BQ-123 (ETA-R antagonist) inhibited this response in both groups. ALA-ET-1 and IRL1620 (ETB-R agonists) had no effect on arteriolar diameter. L-NAME did neither affect basal diameters nor ET-1 responses. Results in EA: ET-1 constricted EA stronger in ETB(+/+) compared to ETB(-/-). BQ-123 inhibited the constriction completely only in ETB(-/-). ALA-ET-1 and IRL1620 constricted only arterioles of ETB(+/+) mice. L-NAME decreased basal diameter in ETB(+/+), but not in ETB(-/-) mice and increased the ET-1 response similarly in both groups. The L-NAME actions indicate a contribution of ETB-R in basal nitric oxide (NO) release in EA and suggest dilatory action of ETA-R in EA. Conclusions. ETA-R mediates vasoconstriction in AA and contributes to vasoconstriction in EA in this mouse model. ETB-R has no effect in AA but mediates basal NO release and constriction in EA. The stronger effect of ET-1 on AA supports observations of decreased glomerular filtration rate to ET-1 and indicates a potential contribution of ET-1 to the pathogenesis of kidney diseases. KW - endothelin KW - ETB receptor-deficient mouse KW - glomerular arterioles KW - renal haemodynamics Y1 - 2011 U6 - https://doi.org/10.1093/ndt/gfq534 SN - 0931-0509 VL - 26 IS - 3 SP - 779 EP - 789 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Rohner, Fabian A1 - Frey, Simone K. A1 - Mothes, Ralf A1 - Hurtienne, Andrea A1 - Hartong, Simone A1 - Bosso, Patrice Emery A1 - Bui, Mai A1 - Schweigert, Florian J. A1 - Northrop-Clewes, Christine T1 - Quantification of vitamin A in palm oil using a fast and simple portable device method validation and comparison to high-performance liquid chromatography JF - International journal for vitamin and nutrition research N2 - Vitamin A deficiency continues to be a global public health problem. Fortification of oil with vitamin A is considered a cost-effective, feasible strategy to prevent this problem but quality control poses a challenge to program implementation. To overcome this, we have validated a newly developed device that quantitatively measures the content of retinyl palmitate in refined palm oil, is simple to use, and yields immediate results. Linearity of analysis rand from 2.5-30 mg retinol equivalents (RE)/kg of palm oil, with 2.5 mg RE/kg being the determination limit; inter- and intra-assay precision ranged from 1.4-7.1 To. Comparison with a high-performance Liquid chromatography method showed high agreement between the methods (R-2 = 0.92; Limits of Agreement: -1.24 mg to 2.53 mg RE/kg), and further comparisons illustrate that the new device is useful in low resource settings. This device offers a field- and user-friendly solution to quantifying the vitamin A content in refined palm oil. KW - Vitamin A KW - retinyl palmitate KW - fortification KW - monitoring KW - rapid test kit KW - palm oil Y1 - 2011 U6 - https://doi.org/10.1024/0300-9831/a000081 SN - 0300-9831 VL - 81 IS - 5 SP - 335 EP - 342 PB - Hogrefe CY - Bern ER - TY - JOUR A1 - Raila, Jens A1 - Schweigert, Florian J. A1 - Kohn, Barbara T1 - C-reactive protein concentrations in serum of dogs with naturally occurring renal disease JF - Journal of veterinary diagnostic investigation N2 - The current study was undertaken to investigate the relation between serum C-reactive protein (CRP) concentrations and parameters of renal function in dogs with naturally occurring renal disease. Dogs were assigned to groups according to plasma creatinine concentration, urinary protein-to-creatinine ratio (UP/UC), and exogenous plasma creatinine clearance (P-Cl(Cr)) rates. Group A (healthy control dogs; n = 8): non-azotemic (plasma creatinine <125 mu mol/l) and nonproteinuric (UP/UC <0.2), with P-Cl(Cr) rates >90 ml/min/m(2); group B (n = 11): non-azotemic, nonproteinuric dogs with reduced P-Cl(Cr) rates (50-89 ml/min/m(2)); group C (n = 7): azotemic, borderline proteinuric dogs (P-Cl(Cr) rates: 22-67 ml/min/m(2)); and group D (n = 6): uremic, proteinuric dogs (not tested for P-Cl(Cr)). The serum CRP concentrations were measured via commercial enzyme-linked immunosorbent assay. The CRP concentrations in the clinically healthy dogs (group A) ranged from 2.09 mg/l to 8.60 mg/l (median: 3.21 mg/l). In comparison with dogs of group A, median CRP concentrations were significantly (P < 0.01) elevated in dogs of group B (17.6 mg/l, range: 17.0-19.2 mg/l), group C (24.8 mg/l, range: 18.0-32.5 mg/l), and group D (59.7 mg/l, range: 17.7-123 mg/l). Serum CRP was significantly related to P-Cl(Cr) (r = -0.83; P < 0.001), plasma creatinine (r = 0.81; P < 0.001), UP/UC (r = 0.70; P < 0.001), and leukocytes (r = 0.49; P < 0.01). The significant relations between serum CRP concentrations and biochemical parameters of kidney function in plasma and urine suggest that a stimulation of the acute phase response is implicated in the pathogenesis of canine renal disease. KW - C-reactive protein KW - dogs KW - proteinuria KW - renal disease Y1 - 2011 U6 - https://doi.org/10.1177/1040638711407896 SN - 1040-6387 VL - 23 IS - 4 SP - 710 EP - 715 PB - Sage Publ. CY - Thousand Oaks ER - TY - JOUR A1 - Raila, Jens A1 - Rohn, Sascha A1 - Schweigert, Florian J. A1 - Abraham, Getu T1 - Increased antioxidant capacity in the plasma of dogs after a single oral dosage of tocotrienols JF - The British journal of nutrition : an international journal devoted to the science of human and animal nutrition N2 - The intestinal absorption of tocotrienols (TCT) in dogs is, to our knowledge, so far unknown. Adult Beagle dogs (n 8) were administered a single oral dosage of a TCT-rich fraction (TRF; 40 mg/kg body weight) containing 32% alpha-TCT, 2% beta-TCT, 27% gamma-TCT, 14% delta-TCT and 25% alpha-tocopherol (alpha-TCP). Blood was sampled at baseline (fasted), 1, 2, 3, 4, 5, 6, 8 and 12 h after supplementation. Plasma and chylomicron concentrations of TCT and alpha-TCP were measured at each time point. Plasma TAG were measured enzymatically, and plasma antioxidant capacity was assessed by the Trolox equivalent antioxidant capacity assay. In fasted dogs, levels of TCT were 0.07 (SD 0.03) mu mol/l. Following the administration of the TRF, total plasma TCT peaked at 2 h (7.16 (SD 3.88) mu mol/l; P<0.01) and remained above baseline levels (0.67 (SD 0.44) mu mol/l; P, 0.01) at 12 h. The TCT response in chylomicrons paralleled the increase in TCT in plasma with a maximum peak (3.49 (SD 2.06) mu mol/l; P, 0.01) at 2 h post-dosage. alpha-TCP was the major vitamin E detected in plasma and unaffected by TRF supplementation. The Trolox equivalent values increased from 2 h (776 (SD 51.2) mu mol/l) to a maximum at 12 h (1130 (SD 7.72) mmol/l; P<0.01). The results show that TCT are detected in postprandial plasma of dogs. The increase in antioxidant capacity suggests a potential beneficial role of TCT supplementation in the prevention or treatment of several diseases in dogs. KW - Dogs KW - Tocotrienols KW - Intestinal absorption KW - Antioxidant capacity Y1 - 2011 U6 - https://doi.org/10.1017/S0007114511000511 SN - 0007-1145 VL - 106 IS - 7 SP - S116 EP - S119 PB - Cambridge Univ. Press CY - Cambridge ER - TY - JOUR A1 - Rade-Kukic, Koralja A1 - Schmitt, C. A1 - Rawel, Harshadrai Manilal T1 - Formation of conjugates between beta-lactoglobulin and allyl isothiocyanate effect on protein heat aggregation, foaming and emulsifying properties JF - Food hydrocolloids N2 - Whey proteins are widely used food ingredients due to their nutritional and functional properties (gelling, emulsifying, foaming). Owning to their structure (free thiol group, lysine residues, hydrophobic pocket), they can also be used as carriers for bioactives. In this study, conjugates between beta-lactoglobulin (beta-lg), and a bioactive metabolite from Brassicaceae vegetables, allyl isothiocyanate (AITC) were formed. Heat aggregation behavior (85 degrees C, 15 min), foaming and emulsifying properties of conjugates, at pH 4.0 and 7.1, were evaluated. Conjugates were formed by incubating beta-lg (0.5 mM) with AITC (0.05-20 mM) in water at pH 8.5 and room temperature. AITC primarily reacted with beta-lg's free thiol group (K-D = 0.2 +/- 0.1 mM) and thereafter with its amino groups (K-D 10.8 +/- 3.4 mM). AITC binding destabilized secondary and tertiary structure of beta-lg at pH 7.1, whereas induced molten globule conformation at pH 4.0. Conjugation reduced the heat aggregation of beta-lg at pH 7.1, while promoting it at pH 4.0. Conjugates adsorbed faster to air/water and oil/water interfaces at pH 4.0 than at pH 7.1. After 30 min, air/water surface tension was lower at pH 4.0 (47 mN m(-1)) than at pH 7.1 (57 mN m(-1)), while the surface tension of the oil/water interface was 8 mN m(-1) at both pHs. Foams produced with beta-lg-AITC conjugates at pH 4.0 exhibited higher volume and liquid stabilities compared to foams obtained at pH 7.1. Emulsions formed with conjugates at both pHs were destabilized by creaming due to flocculation, but coalescence was prevented. This study revealed that whey protein could potentially be used for the delivery of isothiocyanates in the form of foam or emulsion-based products. KW - beta-Lactoglobulin KW - Allyl isothiocyanate KW - Molecular structure KW - Heat aggregation KW - Foaming properties KW - Emulsifying properties Y1 - 2011 U6 - https://doi.org/10.1016/j.foodhyd.2010.08.018 SN - 0268-005X VL - 25 IS - 4 SP - 694 EP - 706 PB - Elsevier CY - Oxford ER -