TY  - JOUR
A1  - Vignon-Zellweger, Nicolas
A1  - Rahnenführer, Jan
A1  - Theuring, Franz
A1  - Hocher, Berthold
T1  - Analysis of cardiac and renal endothelin receptors by in situ hybridization in mice
JF  - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion
N2  - Background: Endothelin-1 (ET-1) is a multifunctional peptide, which is implicated in the renal and cardiac physicology as well as in many pathologies of these systems. ET-1's actions take place after the activation of two receptors: ETA and ETB. The expression of these receptors may be modulated during the pathologic process. The analysis of the distribution and level of expression of the receptors in animal models is therefore crucial.
 Methods: We developed a protocol for non-radioactive in situ hybridization for the mRNA of the two endothelin receptors on paraffin-embedded tissue using digoxigenin-labeled RNA probes.
 Results: In heart and kidney, the staining was reliable and specific. In a mouse model for endothelin/nitric oxide imbalance, cardiac ETB expression was reduced. The distribution of the receptors was in accordance with the actual knowledge. Differences in cell specific expression are discussed.
 Conclusions: We developed a protocol for the in situ hybridization of the endothelin receptors in mice. Given that the endothelin system is implicated in the development of many diseases, we believe that this protocol may be useful for a number of future preclinical studies.
KW  - Endothelin-1
KW  - endothelin receptors
KW  - in situ hybridization
KW  - mouse
Y1  - 2012
U6  - https://doi.org/10.7754/Clin.Lab.2012.120216
SN  - 1433-6510
VL  - 58
IS  - 9-10
SP  - 939
EP  - 949
PB  - Clin Lab Publ., Verl. Klinisches Labor
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Vickers, Steven P.
A1  - Cheetham, Sharon C.
A1  - Birmingham, Gareth D.
A1  - Rowley, Helen L.
A1  - Headland, Katie R.
A1  - Dickinson, Keith
A1  - Grempler, Rolf
A1  - Hocher, Berthold
A1  - Mark, Michael
A1  - Klein, Thomas
T1  - Effects of the DPP-4 Inhibitor, Linagliptin, in Diet-Induced obese rats  a comparison in Naive and Exenatide-Treated Animals
JF  - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion
N2  - Background: To assess the chronic effect of the DPP-4 inhibitor, linagliptin, alone, in combination with exenatide, and during exenatide withdrawal, in diet-induced obese (DIO) rats.
 Methods: Female Wistar rats were exposed to a cafeteria diet to induce obesity. Animals were then dosed with vehicle or linagliptin (3 mg/kg PO) orally once-daily for a 28 day period. In a subsequent study, rats received exenatide (either 3 or 30 mu g/kg/day) or vehicle by osmotic mini-pump for 28 days. In addition, groups of animals were dosed orally with linagliptin either alone or in combination with a 3 mu g/kg/day exenatide dose for the study duration. In a final study, rats were administered exenatide (30 mu g/kg/day) or vehicle by osmotic mini-pump for eleven days. Subsequently, exenatide-treated animals were transferred to vehicle or continued exenatide infusion for a further ten days. Animals transferred from exenatide to vehicle were also dosed orally with either vehicle or linagliptin. In all studies, body weight, food and water intake were recorded daily and relevant plasma parameters and carcass composition were determined.
 Results: In contrast to exenatide, linagliptin did not significantly reduce body weight or carcass fat in DIO rats versus controls. Linagliptin augmented the effect of exenatide to reduce body fat when given in combination but did not affect the body weight response. In rats withdrawn from exenatide, weight regain was observed such that body weight was not significantly different to controls. Linagliptin reduced weight regain after withdrawal of exenatide such that a significant difference from controls was evident.
 Conclusions: These data demonstrate that linagliptin does not significantly alter body weight in either untreated or exenatide-treated DIO rats, although it delays weight gain after exenatide withdrawal. This finding may suggest the utility of DPP-4 inhibitors in reducing body weight during periods of weight gain.
KW  - Dipeptidyl peptidase 4 inhibitor
KW  - Linagliptin
KW  - obesity
KW  - weight loss
Y1  - 2012
U6  - https://doi.org/10.7754/Clin.Lab.2011.110919
SN  - 1433-6510
VL  - 58
IS  - 7-8
SP  - 787
EP  - 799
PB  - Clin Lab Publ., Verl. Klinisches Labor
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Taal, H. Rob
A1  - St Pourcain, Beate
A1  - Thiering, Elisabeth
A1  - Das, Shikta
A1  - Mook-Kanamori, Dennis O.
A1  - Warrington, Nicole M.
A1  - Kaakinen, Marika
A1  - Kreiner-Moller, Eskil
A1  - Bradfield, Jonathan P.
A1  - Freathy, Rachel M.
A1  - Geller, Frank
A1  - Guxens, Monica
A1  - Cousminer, Diana L.
A1  - Kerkhof, Marjan
A1  - Timpson, Nicholas J.
A1  - Ikram, M. Arfan
A1  - Beilin, Lawrence J.
A1  - Bonnelykke, Klaus
A1  - Buxton, Jessica L.
A1  - Charoen, Pimphen
A1  - Chawes, Bo Lund Krogsgaard
A1  - Eriksson, Johan
A1  - Evans, David M.
A1  - Hofman, Albert
A1  - Kemp, John P.
A1  - Kim, Cecilia E.
A1  - Klopp, Norman
A1  - Lahti, Jari
A1  - Lye, Stephen J.
A1  - McMahon, George
A1  - Mentch, Frank D.
A1  - Mueller-Nurasyid, Martina
A1  - O'Reilly, Paul F.
A1  - Prokopenko, Inga
A1  - Rivadeneira, Fernando
A1  - Steegers, Eric A. P.
A1  - Sunyer, Jordi
A1  - Tiesler, Carla
A1  - Yaghootkar, Hanieh
A1  - Breteler, Monique M. B.
A1  - Debette, Stephanie
A1  - Fornage, Myriam
A1  - Gudnason, Vilmundur
A1  - Launer, Lenore J.
A1  - van der Lugt, Aad
A1  - Mosley, Thomas H.
A1  - Seshadri, Sudha
A1  - Smith, Albert V.
A1  - Vernooij, Meike W.
A1  - Blakemore, Alexandra I. F.
A1  - Chiavacci, Rosetta M.
A1  - Feenstra, Bjarke
A1  - Fernandez-Banet, Julio
A1  - Grant, Struan F. A.
A1  - Hartikainen, Anna-Liisa
A1  - van der Heijden, Albert J.
A1  - Iniguez, Carmen
A1  - Lathrop, Mark
A1  - McArdle, Wendy L.
A1  - Molgaard, Anne
A1  - Newnham, John P.
A1  - Palmer, Lyle J.
A1  - Palotie, Aarno
A1  - Pouta, Annneli
A1  - Ring, Susan M.
A1  - Sovio, Ulla
A1  - Standl, Marie
A1  - Uitterlinden, Andre G.
A1  - Wichmann, H-Erich
A1  - Vissing, Nadja Hawwa
A1  - DeCarli, Charles
A1  - van Duijn, Cornelia M.
A1  - McCarthy, Mark I.
A1  - Koppelman, Gerard H.
A1  - Estivill, Xavier
A1  - Hattersley, Andrew T.
A1  - Melbye, Mads
A1  - Bisgaard, Hans
A1  - Pennell, Craig E.
A1  - Widen, Elisabeth
A1  - Hakonarson, Hakon
A1  - Smith, George Davey
A1  - Heinrich, Joachim
A1  - Jarvelin, Marjo-Riitta
A1  - Jaddoe, Vincent W. V.
A1  - Adair, Linda S.
A1  - Ang, Wei
A1  - Atalay, Mustafa
A1  - van Beijsterveldt, Toos
A1  - Bergen, Nienke
A1  - Benke, Kelly
A1  - Berry, Diane J.
A1  - Bradfield, Jonathan P.
A1  - Charoen, Pimphen
A1  - Coin, Lachlan
A1  - Cousminer, Diana L.
A1  - Das, Shikta
A1  - Davis, Oliver S. P.
A1  - Elliott, Paul
A1  - Evans, David M.
A1  - Feenstra, Bjarke
A1  - Flexeder, Claudia
A1  - Frayling, Tim
A1  - Freathy, Rachel M.
A1  - Gaillard, Romy
A1  - Geller, Frank
A1  - Groen-Blokhuis, Maria
A1  - Goh, Liang-Kee
A1  - Guxens, Monica
A1  - Haworth, Claire M. A.
A1  - Hadley, Dexter
A1  - Hebebrand, Johannes
A1  - Hinney, Anke
A1  - Hirschhorn, Joel N.
A1  - Holloway, John W.
A1  - Holst, Claus
A1  - Hottenga, Jouke Jan
A1  - Horikoshi, Momoko
A1  - Huikari, Ville
A1  - Hypponen, Elina
A1  - Iniguez, Carmen
A1  - Kaakinen, Marika
A1  - Kilpelainen, Tuomas O.
A1  - Kirin, Mirna
A1  - Kowgier, Matthew
A1  - Lakka, Hanna-Maaria
A1  - Lange, Leslie A.
A1  - Lawlor, Debbie A.
A1  - Lehtimaki, Terho
A1  - Lewin, Alex
A1  - Lindgren, Cecilia
A1  - Lindi, Virpi
A1  - Maggi, Reedik
A1  - Marsh, Julie
A1  - Middeldorp, Christel
A1  - Millwood, Iona
A1  - Mook-Kanamori, Dennis O.
A1  - Murray, Jeffrey C.
A1  - Nivard, Michel
A1  - Nohr, Ellen Aagaard
A1  - Ntalla, Ioanna
A1  - Oken, Emily
A1  - O'Reilly, Paul F.
A1  - Palmer, Lyle J.
A1  - Panoutsopoulou, Kalliope
A1  - Pararajasingham, Jennifer
A1  - Prokopenko, Inga
A1  - Rodriguez, Alina
A1  - Salem, Rany M.
A1  - Sebert, Sylvain
A1  - Siitonen, Niina
A1  - Sovio, Ulla
A1  - St Pourcain, Beate
A1  - Strachan, David P.
A1  - Sunyer, Jordi
A1  - Taal, H. Rob
A1  - Teo, Yik-Ying
A1  - Thiering, Elisabeth
A1  - Tiesler, Carla
A1  - Uitterlinden, Andre G.
A1  - Valcarcel, Beatriz
A1  - Warrington, Nicole M.
A1  - White, Scott
A1  - Willemsen, Gonneke
A1  - Yaghootkar, Hanieh
A1  - Zeggini, Eleftheria
A1  - Boomsma, Dorret I.
A1  - Cooper, Cyrus
A1  - Estivill, Xavier
A1  - Gillman, Matthew
A1  - Grant, Struan F. A.
A1  - Hakonarson, Hakon
A1  - Hattersley, Andrew T.
A1  - Heinrich, Joachim
A1  - Hocher, Berthold
A1  - Jaddoe, Vincent W. V.
A1  - Jarvelin, Marjo-Riitta
A1  - Lakka, Timo A.
A1  - McCarthy, Mark I.
A1  - Melbye, Mads
A1  - Mohlke, Karen L.
A1  - Dedoussis, George V.
A1  - Ong, Ken K.
A1  - Pearson, Ewan R.
A1  - Pennell, Craig E.
A1  - Price, Thomas S.
A1  - Power, Chris
A1  - Raitakari, Olli T.
A1  - Saw, Seang-Mei
A1  - Scherag, Andre
A1  - Simell, Olli
A1  - Sorensen, Thorkild I. A.
A1  - Timpson, Nicholas J.
A1  - Widen, Elisabeth
A1  - Wilson, James F.
A1  - Ang, Wei
A1  - van Beijsterveldt, Toos
A1  - Bergen, Nienke
A1  - Benke, Kelly
A1  - Berry, Diane J.
A1  - Bradfield, Jonathan P.
A1  - Charoen, Pimphen
A1  - Coin, Lachlan
A1  - Cousminer, Diana L.
A1  - Das, Shikta
A1  - Elliott, Paul
A1  - Evans, David M.
A1  - Frayling, Tim
A1  - Freathy, Rachel M.
A1  - Gaillard, Romy
A1  - Groen-Blokhuis, Maria
A1  - Guxens, Monica
A1  - Hadley, Dexter
A1  - Hottenga, Jouke Jan
A1  - Huikari, Ville
A1  - Hypponen, Elina
A1  - Kaakinen, Marika
A1  - Kowgier, Matthew
A1  - Lawlor, Debbie A.
A1  - Lewin, Alex
A1  - Lindgren, Cecilia
A1  - Marsh, Julie
A1  - Middeldorp, Christel
A1  - Millwood, Iona
A1  - Mook-Kanamori, Dennis O.
A1  - Nivard, Michel
A1  - O'Reilly, Paul F.
A1  - Palmer, Lyle J.
A1  - Prokopenko, Inga
A1  - Rodriguez, Alina
A1  - Sebert, Sylvain
A1  - Sovio, Ulla
A1  - St Pourcain, Beate
A1  - Standl, Marie
A1  - Strachan, David P.
A1  - Sunyer, Jordi
A1  - Taal, H. Rob
A1  - Thiering, Elisabeth
A1  - Tiesler, Carla
A1  - Uitterlinden, Andre G.
A1  - Valcarcel, Beatriz
A1  - Warrington, Nicole M.
A1  - White, Scott
A1  - Willemsen, Gonneke
A1  - Yaghootkar, Hanieh
A1  - Boomsma, Dorret I.
A1  - Estivill, Xavier
A1  - Grant, Struan F. A.
A1  - Hakonarson, Hakon
A1  - Hattersley, Andrew T.
A1  - Heinrich, Joachim
A1  - Jaddoe, Vincent W. V.
A1  - Jarvelin, Marjo-Riitta
A1  - McCarthy, Mark I.
A1  - Pennell, Craig E.
A1  - Power, Chris
A1  - Timpson, Nicholas J.
A1  - Widen, Elisabeth
A1  - Ikram, M. Arfan
A1  - Fornage, Myriam
A1  - Smith, Albert V.
A1  - Seshadri, Sudha
A1  - Schmidt, Reinhold
A1  - Debette, Stephanie
A1  - Vrooman, Henri A.
A1  - Sigurdsson, Sigurdur
A1  - Ropele, Stefan
A1  - Coker, Laura H.
A1  - Longstreth, W. T.
A1  - Niessen, Wiro J.
A1  - DeStefano, Anita L.
A1  - Beiser, Alexa
A1  - Zijdenbos, Alex P.
A1  - Struchalin, Maksim
A1  - Jack, Clifford R.
A1  - Nalls, Mike A.
A1  - Au, Rhoda
A1  - Hofman, Albert
A1  - Gudnason, Haukur
A1  - van der Lugt, Aad
A1  - Harris, Tamara B.
A1  - Meeks, William M.
A1  - Vernooij, Meike W.
A1  - van Buchem, Mark A.
A1  - Catellier, Diane
A1  - Gudnason, Vilmundur
A1  - Windham, B. Gwen
A1  - Wolf, Philip A.
A1  - van Duijn, Cornelia M.
A1  - Mosley, Thomas H.
A1  - Schmidt, Helena
A1  - Launer, Lenore J.
A1  - Breteler, Monique M. B.
A1  - DeCarli, Charles
T1  - Common variants at 12q15 and 12q24 are associated with infant head circumference
JF  - Nature genetics
N2  - To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
Y1  - 2012
U6  - https://doi.org/10.1038/ng.2238
SN  - 1061-4036
VL  - 44
IS  - 5
SP  - 532
EP  - +
PB  - Nature Publ. Group
CY  - New York
ER  - 
TY  - JOUR
A1  - Sun, Sheng-Yun
A1  - Huang, Jin
A1  - Meng, Min-Jie
A1  - Lu, Jia-Hai
A1  - Hocher, Berthold
A1  - Liu, Kang-Li
A1  - Yang, Qin-He
A1  - Zhu, Xiao-Feng
T1  - Improvement of lipid profile and reduction of body weight by Shan He Jian Fei Granules in high fat diet-induced obese rats
JF  - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion
N2  - Background: The goal was to study lipid profiles (TG, TC, LDL, HDL), effects on serum leptin, and fat tissue adiponectin, and resistin as well as body weight effects of Shan He Jian Fei Granules (SHJFG) in rats on a high fat diet.
 Methods: Rats were randomly divided into five groups: normal control group fed with normal fat diet, rats on high fat diet receiving low dosage, middle dosage, high dosage of Shan He Jian Fei Granules (SHJFG) as well as a high fat diet group receiving placebo. Rats were treated for 8 weeks. Body weight and naso-anal length of each rat were recorded and Lee's index was calculated. Serum TG, TC, LDL, HDL and leptin concentrations were analyzed. The gene expressions of adiponectin and resistin in adipose tissues were tested by RT-PCR.
 Results: Compared to the high-fat diet group, body weights, Lee's indexes, weight of fat tissues and serum TG, TC, LDL and leptin of SHJFG groups significantly decreased (p<0.05), whereas mRNA expressions of adiponectin and resistin of SHJFG groups significantly increased (p<0.05).
 Conclusions: SHJFG could significantly lower body weight and serum TG, TC, and LDL of obese rats. The effects of SHJFG in lowering leptin synthesis and raising mRNA expression of adiponectin and resistin in fat tissues may act as part of the mechanisms in lowering body weight of obese rats. Further studies are needed to demonstrate whether SHJFG may also reduce overall cardiovascular morbidity and mortality like other lipid lowering drugs.
KW  - obesity
KW  - high-fat diet
KW  - Shan He Jian Fei Granules (SHJFG)
KW  - lipid
KW  - adiponectin
KW  - resistin
KW  - leptin
Y1  - 2012
SN  - 1433-6510
VL  - 58
IS  - 1-2
SP  - 81
EP  - 87
PB  - Clin Lab Publ., Verl. Klinisches Labor
CY  - Heidelberg
ER  - 
TY  - CHAP
A1  - Sharkovska, Y.
A1  - Alter, Markus L.
A1  - Reichetzeder, Christoph
A1  - Tsuprykov, Oleg
A1  - Klein, T.
A1  - Hocher, Berthold
T1  - DPP-4 inhibition with linagliptin delays the progression of diabetic nephropathy in db/db mice
T2  - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
Y1  - 2012
SN  - 0012-186X
SN  - 1432-0428
VL  - 55
IS  - 5
SP  - S20
EP  - S20
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Schmerbach, K.
A1  - Kalk, Philipp.
A1  - Wengenmayer, Christina
A1  - Lucht, K.
A1  - Unger, T.
A1  - Hocher, Berthold
A1  - Thoene-Reineke, C.
T1  - Renal outcome in equipotent Antihypertensive Treatment with Telmisartan, Ramipril and in combination in SHR-SP Rats
JF  - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion
N2  - Background: The ONTARGET trial revealed an association of ACEI/ARB combination treatment (telmisartan and ramipril) with adverse renal outcome versus respective monotherapy; preclinical evidence regarding renal outcome in ACEI/ARB combination treatment is scarce.
 Methods: Spontaneously hypertensive stroke prone rats (SHR-SP) rats on a salt-rich diet were randomly allocated to 4 groups: SHR (untreated, n = 24), SHR + telmisartan (SHR-T, 2.39 +/- 0.69 mg/kg bw; n = 27), SHR + ramipril (SHR-R, 6.28 +/- 3.48 mg/kg bw; n = 27) and combination treatment (SHR-TR, 0.51 +/- 0.14 mg/kg bw; same dose for telmisartan and ramipril; n = 26). Study duration was 12 weeks, blood pressure was assessed weekly and doses were adjusted to maintain equal blood pressure. Finally, blood and urine samples were obtained and kidneys were harvested for histological studies.
 Results: Blood pressure in untreated rats rose to a maximum of 239 mmHg, whereas in all treatment groups it remained stable betvveen 140 and 150 mmHg. Mortality was 50% in the untreated group, whereas all treatment groups survived completely. Renal function - as indicated by plasma urea and cystatin c - was significantly worse in SHR-TR animals compared to all other groups. With plasma creatinine a similar trend was observed. All treatment options significantly decreased albuminuria. Renal glomerulosclerosis was decreased by monotherapy, whereas combination therapy failed to have a significant effect. Interstitial fibrosis was decreased to a similar extent by all treatment options.
 Conclusions: ACEI/ARB combination treatment failed to render significant additional benefits on renal outcome in hypertensive rats when compared to monotherapy. Instead our data indicate that dual RAAS blockade might have an adverse effect on kidney function and histology when compared to monotherapy in salt-loaded SHR-SP.
KW  - Renal failure
KW  - angiotensin receptor blockers
KW  - ACE inhibitors
KW  - telmisartan
KW  - ramipril
Y1  - 2012
U6  - https://doi.org/10.7754/Clin.Lab.2011.110622
SN  - 1433-6510
VL  - 58
IS  - 7-8
SP  - 625
EP  - 633
PB  - Clin Lab Publ., Verl. Klinisches Labor
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Rokutan, Hirofumi
A1  - Suckow, Christian
A1  - von Hähling, Stephan
A1  - Strassburg, Sabine
A1  - Bockmeyer, Barbara
A1  - Döhner, Wolfram
A1  - Waller, Christiane
A1  - Bauersachs, Johann
A1  - von Websky, Karoline
A1  - Hocher, Berthold
A1  - Anker, Stefan D.
A1  - Springer, Jochen
T1  - Furosemide induces mortality in a rat model of chronic heart failure
JF  - International journal of cardiology
N2  - Objectives: In an experimental heart failure model, we tested the hypothesis that furosemide causes excess mortality.
 Background: Post-hoc analysis of large clinical heart failure trails revealed that furosemide treatment might be associated with worsening of morbidity and even mortality in heart failure patients.
 Methods and results: Myocardial infarction was induced in 7 +/- 1 week old male Wistar rats by ligation of the left coronary artery. In study 1, animals were randomly assigned to treatment with furosemide (10 mg/kg/d via drinking water, n = 33) or placebo (n = 33) starting 18 days after surgery. In study 2, animals received furosemide from day 18 and were then randomized to ongoing treatment with either furosemide only (n = 38) or furosemide plus ACE-inhibitor Ramipril (1 mg/kg/d, n = 38) starting on day 42. In study 1 survival rate in the furosemide group was lower than in the placebo group (hazard ratio {HR} 3.39, 95% confidence interval {CI} 1.14 to 10.09, p = 0.028). The furosemide group had a lower body weight (-6%, p = 0.028) at the end of the study and a higher sclerosis index of the glomeruli (+9%, p=0.026) than the placebo group. Wet lung weight, infarct size, and cardiac function were similar between the groups. In study 2, the furosemide group had a higher mortality rate than the furosemide + ramipril group (HR 4.55, 95% CI 2.0 to 10.0, p = 0.0003).
 Conclusion: In our rat model of heart failure furosemide, provided at a standard dose, was associated with increased mortality. This increased mortality could be prevented by additional administration of an ACE-inhibitor.
KW  - Angiotensin converting enzyme inhibitor
KW  - Furosemide
KW  - Heart failure
KW  - Loop diuretics
KW  - Mortality
Y1  - 2012
U6  - https://doi.org/10.1016/j.ijcard.2011.03.005
SN  - 0167-5273
VL  - 160
IS  - 1
SP  - 20
EP  - 25
PB  - Elsevier
CY  - Clare
ER  - 
TY  - JOUR
A1  - Ott, Ina M.
A1  - Alter, Markus L.
A1  - von Websky, Karoline
A1  - Kretschmer, Axel
A1  - Tsuprykov, Oleg
A1  - Sharkovska, Yuliya
A1  - Krause-Relle, Katharina
A1  - Raila, Jens
A1  - Henze, Andrea
A1  - Stasch, Johannes-Peter
A1  - Hocher, Berthold
T1  - Effects of Stimulation of Soluble Guanylate Cyclase on Diabetic
 Nephropathy in Diabetic eNOS Knockout Mice on Top of Angiotensin II
 Receptor Blockade
JF  - PLOS ONE
N2  - The prevalence of diabetes mellitus and its complications, such as diabetic nephropathy (DN), is rising worldwide and prevention and treatment are therefore becoming increasingly important. Therapy of DN is particularly important for patients who do not adequately respond to angiotensin receptor blocker (ARB) treatment. Novel approaches include the stimulation of soluble guanylate cyclase (sGC) as it is reported to have beneficial effects on cardiac and renal damage. We aimed to investigate the effects of the sGC stimulator riociguat and ARB telmisartan on kidney function and structure in a hypertensive model of diabetic nephropathy. Seventy-six diabetic male eNOS knockout C57BL/6J mice were randomly divided after having received streptozotocin: telmisartan (1 mg/kg/d), riociguat (3 mg/kg/d), riociguat+telmisartan (3+1 mg/kg/d), and vehicle. Fourteen mice were used as non-diabetic controls. Treatment duration was 11 weeks. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan insignificantly reduced blood pressure by 5.9 mmHg compared with diabetic controls (111.2 +/- 2.3 mmHg vs. 117.1 +/- 2.2 mmHg; p = 0.071). Treatment with riociguat both alone and in combination with telmisartan led to a significant reduction of blood pressure towards diabetic vehicle (105.2 +/- 2.5 mmHg and 105.0 +/- 3.2 mmHg, respectively, vs. 117.1 +/- 2.2 mmHg). Combined treatment also significantly decreased albuminuria compared with diabetic controls (47.3 +/- 9.6 mu g/24 h vs. 170.8 +/- 34.2 mu g/24 h; p = 0.002) reaching levels similar to those of non-diabetic controls (34.4 +/- 10.6 mu g/24 h), whereas the reduction by single treatment with either telmisartan (97.8 +/- 26.4 mu g/24 h) or riociguat (97.1 +/- 15.7 mu g/24 h) was not statistically significant. The combination treatment led to a significant (p < 0.01) decrease of tissue immunoreactivity of malondialdehyde, as consequence of reduced oxidative stress. In conclusion, stimulation of sGC significantly reduced urinary albumin excretion in diabetic eNOS knockout mice treated already with ARB. Thus, this new drug class on top of standard ARBs administration may offer a new therapeutic approach for patients resistant to ARB treatment.
Y1  - 2012
U6  - https://doi.org/10.1371/journal.pone.0042623
SN  - 1932-6203
VL  - 7
IS  - 8
PB  - PUBLIC LIBRARY SCIENCE
CY  - SAN FRANCISCO
ER  - 
TY  - JOUR
A1  - Nair, Anil V.
A1  - Hocher, Berthold
A1  - Verkaart, Sjoerd
A1  - van Zeeland, Femke
A1  - Pfab, Thiemo
A1  - Slowinski, Torsten
A1  - Chen, You-Peng
A1  - Schlingmann, Karl Peter
A1  - Schaller, Andre
A1  - Gallati, Sabina
A1  - Bindels, Rene J.
A1  - Konrad, Martin
A1  - Hönderop, Joost G.
T1  - Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy
JF  - Proceedings of the National Academy of Sciences of the United States of America
N2  - Hypomagnesemia affects insulin resistance and is a risk factor for diabetes mellitus type 2 (DM2) and gestational diabetes mellitus (GDM). Two single nucleotide polymorphisms (SNPs) in the epithelial magnesium channel TRPM6 ((VI)-I-1393, (KE)-E-1584) were predicted to confer susceptibility for DM2. Here, we show using patch clamp analysis and total internal reflection fluorescence microscopy, that insulin stimulates TRPM6 activity via a phosphoinositide 3-kinase and Rac1-mediated elevation of cell surface expression of TRPM6. Interestingly, insulin failed to activate the genetic variants TRPM6 ((VI)-I-1393) and TRPM6((KE)-E-1584), which is likely due to the inability of the insulin signaling pathway to phosphorylate TRPM6(T-1391) and TRPM6(S-1583). Moreover, by measuring total glycosylated hemoglobin (TGH) in 997 pregnant women as a measure of glucose control, we demonstrate that TRPM6((VI)-I-1393) and TRPM6((KE)-E-1584) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6((VI)-I-1393) and TRPM6((KE)-E-1584) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6.
KW  - kidney
KW  - distal convoluted tubule
KW  - transient receptor potential
KW  - vesicular trafficking
Y1  - 2012
U6  - https://doi.org/10.1073/pnas.1113811109
SN  - 0027-8424
VL  - 109
IS  - 28
SP  - 11324
EP  - 11329
PB  - National Acad. of Sciences
CY  - Washington
ER  - 
TY  - JOUR
A1  - Li, Jian
A1  - Wang, Zi-Neng
A1  - Chen, You-Peng
A1  - Dong, Yun-Peng
A1  - Shuai, Han-Lin
A1  - Xiao, Xiao-Min
A1  - Reichetzeder, Christoph
A1  - Hocher, Berthold
T1  - Late gestational maternal serum cortisol is inversely associated with fetal brain growth
JF  - Neuroscience & biobehavioral reviews : official journal of the International Behavioral Neuroscience Society
N2  - To analyze the association between fetal brain growth and late gestational blood serum cortisol in normal pregnancy.Blood total cortisol was quantified at delivery in 432 Chinese mother/child pairs. Key inclusion criteria of the cohort were: no structural anomalies of the newborn, singleton pregnancy, no alcohol abuse, no drug abuse or history of smoking no hypertensive disorders and no impairment of glucose tolerance and no use of steroid medication during pregnancy. Differential ultrasound examination of the fetal body was done in early (gestational day 89.95 +/- 7.31), middle (gestational day 160.17 16.12) and late pregnancy (gestational day 268.89 +/- 12.42). Newborn's cortisol was not correlated with any of the ultrasound measurements during pregnancy nor with birth weight. Multivariable regression analysis, considering timing of the ultrasound examination, the child's sex, maternal BMI, maternal age, maternal body weight at delivery, the timing of cortisol measurement and maternal uterine contraction states, revealed that maternal serum total cortisol was significantly negative correlated with ultrasound parameters describing the fetal brain: late biparietal diameter (R-2 =0.512, p =0.009), late head circumference (R-2 = 0.498, p= 0.001), middle biparietal diameter (R-2= 0.819, p = 0.013), middle cerebellum transverse diameter R-2 = 0.76, p= 0.014) and early biparietal diameter(R-2 = 0.819, p = 0.013). The same analysis revealed that birth weight as well as ultrasound parameters such as abdominal circumference and femur length were not correlated to maternal cortisol levels.
 In conclusion, our study demonstrates that maternal cortisol secretion within physiological ranges may be inversely correlated to fetal brain growth but not to birth weight. It remains to be demonstrated whether maternal cortisol secretion negatively influencing fetal brain growth translates to adverse neurological outcomes in later life.
KW  - Brain development
KW  - Fetal programming
KW  - Cortisol Maternal cortisol
KW  - Head circumference
KW  - Biparietal diameter
Y1  - 2012
U6  - https://doi.org/10.1016/j.neubiorev.2011.12.006
SN  - 0149-7634
VL  - 36
IS  - 3
SP  - 1085
EP  - 1092
PB  - Elsevier
CY  - Oxford
ER  -