bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating Single‐cell Transcriptome Dynamics of the Dorsal Motor Nucleus of the Vagus (DMV) in a Rat Model of Remote Ischemic‐Reperfusion Cardioprotection (RIPC)
Authors: Chong Weelic , Balycheva Marina , Schwaber James , Vadigepalli Rajanikanth 
Published: June 2021

The dorsal motor nucleus of the vagus (DMV) is one of the brainstem structures from which arises the vagus nerve, and is responsible for the vagal activity that protects the heart from reperfusion injury during an acute myocardial infarction. Remote ischemic‐reperfusion cardioprotection (RIPC) is a phenomenon known to protect the heart against injury via humoral and vagal mediation (Mastitskaya et al. 2012). It is hypothesized that RIPC cardioprotection may be mediated through changes in the gene expression of DMV neurons. However, the dynamics of gene expression in the DMV following RIPC is not known. Here, we performed RIPC by occluding the femoral artery, and using multiplex qPCR, we examined changes in gene expression of single cells taken from the DMV at several time points following RIPC. We conducted these experiments in both female and male rats and both left and right DMV. We also used a retrograde tracer to identify DMV neurons that travel to the heart and the gut, to identify different transcription profiles between these neuronal subpopulations. Our results show a distinct shift in transcriptomic identity of the neuronal subpopulations in the RIPC group over the sham controls. We conclude that there may be neuronal subpopulations in the DMV that are differentially activated following RIPC, which provides insights for translational applications of RIPC in decreasing reperfusion damage.Support or Funding InformationWe are supported by NIH NHLBI 5U01HL133360‐02 and NIH Director Office 3OT2OD023848. The funding sources played no role in study design, collection nor analysis of the data.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Adrenergic neurotransmission increases in obesity‐associated hypertension
Authors: Alula Kibrom , Fink Gregory , Xu Hui , Galligan James 
Published: June 2021

Obesity‐related hypertension (HTN) is a risk factor for cardiovascular disease, stroke, type 2 diabetes, and kidney failure. Adrenergic neurotransmission is mediated by norepinephrine (NE) released from sympathetic nerve terminals onto effector tissues. Neuroeffector junctions on vascular smooth muscle in the mesenteric artery (MA) are an essential site whereby adrenergic neurotransmission regulates vascular tone, blood pressure, and blood flow distribution. The effect of obesity on adrenergic control of blood pressure in the MA is not well established, so our aim was to elucidate if and how adrenergic neurotransmission is altered during the development of obesity. We hypothesized that adrenergic‐mediated arterial constriction increases in obese male Dahl salt‐sensitive (Dahl SS) rats. Male Dahl SS rats were fed control diet (CD; 10% fat) or high‐fat diet (HFD; 60% fat) beginning at 3 weeks (wks) of age. Experiments were conducted after rats were fed for 10, 17, and 24 wks to establish a relationship between adrenergic neurotransmission and HTN development. Body weight (BW) was greater in HFD rats at all time points. Mean arterial pressure (MAP; measured by tail‐cuff) was greater in HFD rats at only 17 and 24 wks. Neurogenic constriction of MA was studied ex vivo using electrical field stimulation, a pressure myograph, and video imaging. Constriction response curves were left‐shifted in MA only from 24‐week HFD rats compared to 10‐ and 17‐week HFD rats. Constriction was similar between CD and HFD rats at all time points. MA reactivity to exogenous NE was decreased in the 24‐week CD and HFD rats compared to younger rats. There was no difference in MA reactivity between CD and HFD rats. Adrenergic nerve density was higher in HFD rats compared to CD rats at 10 and 24 wks. It also increased in a 24‐week CD and HFD rats compared to younger rats. TH (NE marker)‐immunoreactive nerve intensity was similar between CD and HFD rats at all time points. Plasma NE was increased at 24 wks in CD and HFD rats compared to 10 and 17‐week rats. However, plasma NE was similar between CD and HFD at all time points. Tissue NE content (measured by HPLC) was not different between CD and HFD rats, although decreased at the 24‐week CD and HFD rats compared to 10 and 17‐week rats. α2‐adrenergic autoreceptor and NE transporter functions were not altered by the HFD. We conclude that HTN in HFD‐induced obesity is partly mediated by overactivity of adrenergic nerves in a time‐dependent manner.Support or Funding InformationMichigan State UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Impaired Regulation of Peripheral Blood Flow and Blood Pressure in Adults with Down Syndrome
Authors: Hilgenkamp Thessa , Wee Sang Ouk , Hong Kwangseok , Schroeder Elizabeth , Baynard Tracy , Fernhall Bo 
Published: June 2021

Individuals with Down syndrome (DS) exhibit autonomic dysfunction in response to various sympathoexcitatory stimuli, with blunted responses in heart rate and blood pressure (BP). This abnormal central hemodynamic regulation may also affect peripheral blood flow regulation. Preliminary investigations suggest an impairment of brachial blood flow regulation in response to a sympathetic stimulus (−20 mmHg lower body negative pressure (LBNP)), but a larger sample is needed to confirm these findings.PURPOSETo investigate differences in brachial blood flow and BP in response to LBNP between individuals with DS and a control group.METHODSAfter 10 min of supine rest, participants with DS (n=19, 13 men, 24.0 ± 4.3 years) and age‐matched controls (n=30, 16 men, 24.2 ± 4.0 years) underwent 5 min of LBNP stimulation (−20 mmHg). Blood pressure and brachial blood flow were obtained for analysis in the last minute of baseline and LBNP. Mean flow velocity and arterial diameters were recorded with ultrasonography to determine brachial blood flow (BBF), forearm vascular conductance (FVC), and shear rate.RESULTSMean arterial pressure (MAP) decreased significantly in the DS group during the LBNP stimulus, with no change in the control group (interaction, p=0.027). The LBNP also produced differential blood flow responses between groups. Mean velocity (p=0.016), FBF (p=0.021), FVC (p=0.012), and shear rate (p=0.013) were different between groups at baseline and only decreased in response to LBNP in the controls (see table).CONCLUSIONYoung adults with DS exhibit reduced peripheral blood flow regulation in response to LBNP compared to controls, with an abnormal response in blood pressure to LBNP. Further research is required to explore the impact of this blunted sympathetic control of blood flow and blood pressure on exercise and work capacity.Support or Funding InformationThis work has been supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIH K99/R00 1 K99 HD092606‐01).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Renal hypertrophic signaling triggers activation of kidney immune response and accelerates cystogenesis in polycystic kidney disease
Authors: Saigusa Takamitsu , Huang Jifeng , He Lan , Yoder Bradley K , Zimmerman Kurt A , Bell P. Darwin 
Published: June 2021

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease with the predominant form resulting from mutations in the gene, PKD1. The disease severity is highly variable even among families with the same PKD1 gene mutation and factors other than genetics may affect cystogenesis. Protein load or unilateral nephrectomy (UNx: 1K) results in glomerular hyperfiltration and renal hypertrophy which both accelerates kidney cyst growth in PKD mice. Children with PKD that exhibit glomerular hyperfiltration were shown to have a higher rate of cyst growth and faster decline in kidney function. Thus, hypertrophic signaling in PKD may clinically be a risk factor to accelerate cystogenesis.MethodsTo test the effect of renal hypertrophy in PKD, we used adult tamoxifen inducible Pkd1flox/flox mice with or without CAGG‐cre. Three weeks after cre induction, first group of mice underwent sham surgery or UNx to accelerate cyst formation and observed for 3 or 6 weeks. The second group of mice were fed with either high protein (60%), normal protein (18%) or low protein diet (6%) for a total of 6 weeks. Mice from both UNx and modified protein diet group were sacrificed at the end of the experiment and kidneys were harvested for RNA‐seq, histology, inflammatory cytokines and flow cytometry for kidney immune cell sorting.ResultsAnalysis of RNA sequencing data revealed that 1K compared to intact two kidney (2K) Pkd1 deficient mice show differentially expressed genes involved in activating/recruiting macrophages and production of pro‐inflammatory cytokines during the hypertrophic signaling. 1K compared to 2K Pkd1 mice had increased number of resident macrophage (CD11blo, F4/80 hi) but not infiltrating macrophages (CD11bhi, F4/80lo), increased inflammatory cytokine production, and severe cystic kidneys. Pkd1 deficient mice that were given a high protein diet compared to a low protein diet, resulted in activation of kidney immune cells, recruitment of inflammatory cytokines and worsening kidney cysts.ConclusionsRenal hypertrophic signaling triggered by either UNx or protein load in adult Pkd1 mice activates kidney immune cells, inflammatory cytokine production and accelerates cyst growth.Support or Funding InformationNIH K08DK106465, P30 DK074038, T32AI007051This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Intrinsic Circadian Clock in Podocytes Controls the Glomerular Filtration Rate
Authors: Ansermet Camille , Centeno Gabriel , Pradervand Sylvain , Maillard Marc , Firsov Dmitri 
Published: June 2021

The circadian clock is a molecular mechanism that allows the kidney to continuously adjust specific glomerular and tubular functions to anticipate dramatic transitions induced in the internal body environment by circadian rhythms in activity and feeding.The role of the intrinsic renal circadian clocks in renal functions rhythmicity is still not fully understood and remains to be further characterized. In this study, we aimed to investigate the importance of the intrinsic circadian clock of podocytes in the circadian dynamic of the glomerular filtration rate (GFR). We showed that mice devoid of the circadian clock specifically in podocytes (Bmal1lox/lox/Nphs2‐rtTA/LC1 or cKO mice) lose the circadian rhythmicity of the GFR. Moreover, we observed significant alterations in excretion profiles of creatinine, electrolytes as well as in rhythmicity of plasma aldosterone levels in cKO mice. Finally, we demonstrated that the circadian clock in podocytes controls expression of various genes having a critical role in podocyte function and known to be involved in the pathogenesis of diverse glomerular diseases. Altogether, these results demonstrate that circadian clocks located in podocytes play a significant role in circadian rhythmicity of the GFR.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Atorvastatin does not ameliorate lithium‐induced nephrogenic diabetes insipidus in mice
Authors: Markussen Maria Linaa , Iervolino Anna , Rej Soham , Trepiccione Francesco , Christensen Birgitte Mønster 
Published: June 2021

Lithium (Li) is an important mood‐stabilizing drug used in the treatment of affective disorders. However, as a significant adverse effect patients can develop Nephrogenic Diabetes Insipidus (NDI). NDI is characterized by the inability of the kidney to concentrate urine in response to vasopressin, resulting in severe polyuria and an increased long‐term risk of chronic kidney disease. Li‐NDI is associated with downregulation of the water channel AQP2 and a cellular remodeling of the kidney collecting duct. Effective and safe treatment of Li‐NDI is still lacking. Statins are cholesterol‐lowering drugs, which appear to increase AQP2 membrane‐translocation and improve urine concentration ability in other NDI models.This project will investigate if atorvastatin is able to prevent the Li‐induced changes in mice using a mouse cortical collecting duct cell line (mCCD) and C57BL/6 mice.Biotinylation assays showed that acute (1hr) treatment with simvastatin (p<0.05) or fluvastatin (p<0.0001) increased AQP2 membrane accumulation compared to controls in the mCCD cells. This confirms that the mCCD cell line respond to acute statin treatment as shown before for these two statins in other cellular and animal models. In order to see whether chronic statin treatment abolish the effects of Li, cells were treated with Li and Li/atorvastatin for 48 hrs. Li reduced total AQP2 levels (p<0.01) compared to controls as expected, but combined Li/atorvastatin treatment did not prevent the Li‐induced downregulation of AQP2. Chronic (21 days) Li treatment of mice increased urine output (p<0.0001) and reduced urine osmolality (p<0.0001) compared to controls (receiving normal food). Atorvastatin (given in combination with Li for 21 days) decreased levels of triglycerides in the blood (p<0.05) compared to controls. Combined Li/atorvastatin treatment did not prevent the effects of Li on urine output and urine osmolality. In kidney inner medulla, western blotting showed that Li reduced total AQP2 levels (p<0.001) and increased pS261‐AQP2 levels (p<0.05), and further showed a tendency to pERK1/2 upregulation (p=0.06) compared to controls as shown previously. However, combined Li/atorvastatin treatment did not abolish any of these changes. Immunohistochemistry further showed that atorvastatin did not prevent the Li‐induced increase in intercalated cells and increased proliferation in the inner medulla.In conclusion, both chronic in vitro and in vivo experiments showed that atorvastatin does not appear to have positive effects on prevention of Li‐NDI in mice.Support or Funding InformationDanish Medical Research Council, Beckett Fonden, Aase and Ejnar Danielsens Fonden, Knud and Edith Eriksens MindefondThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of adrenomedullin in mediating water reabsorption in rat inner medullary collecting ducts
Authors: Wang Yanhua , Ma Fuying , Klein Janet D 
Published: June 2021

Adrenomedullin (ADM) increases water permeability in the inner medullary collecting duct by mediating aquaporin‐2 (AQP2) phosphorylation. It is generally considered to be a backup system for vasopressin. We investigated whether adrenomedullin stimulates osmotic water permeability through cAMP and/or protein kinase A (PKA). RNA sequencing and western analysis showed that ADM and its receptors, calcitonin‐receptor‐like receptor (CRLR) and receptor‐activity‐modifying proteins 2 or 3 (RAMP2 or RAMP3) are highly expressed in the inner medullary collecting ducts of control rats. No mRNA expression was seen for RAMP1. We measured water permeability in inner medullary collecting ducts of rats by tubule perfusion with and without treatment with the PDE4 inhibitor roflumilast or the PKA inhibitor H89. ADM significantly increased osmotic water permeability from 251.4 ± 58.1 to 383.4 ± 73.2 μm/s (n=4, p<0.05). Roflumilast (30nM) further increased ADM‐stimulated osmotic water permeability to 472.7 ± 84.9 μm/s (n=4, p<0.05). Inhibition of PKA by H89 decreased ADM‐stimulated osmotic water permeability from 225.4 ± 57.3 to 179.7 ± 49.6 μm/s (n=3, p<0.05). Western analysis with phospho‐specific antibody showed that ADM significantly increased phosphorylation of AQP2 at serine 256 and decreased phosphorylation of AQP2 at serine 261. We conclude that ADM and its receptors are expressed in inner medulla and that the mechanism of ADM stimulation of water reabsorption involves cAMP and activation of PKA. Further, our results suggest that ADM may represent a complimentary method for vasopressin in regulating water homeostasis.Support or Funding InformationThis work was supported by Emory URC grant 00067457, and AHA Career Development Grant #18CDA34060053.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
TRPC6 deficiency causes obesity and metabolic dysfunction
Authors: Bailey Kandice , Wang Zhen , Moak Sydney P. , Dai Xuemei , Fu Yiling , do Carmo Jussara M. , da Silva Alexandre A. , Hall John E. 
Published: June 2021

Transient receptor potential cation channel C (TRPC) is a group of receptor‐operated cation channels that modulate cell Ca2+ influx. TPRC6 is a subunit of the TRPC family that is expressed in the brain. However, the role of TRPC6 in controlling metabolic and cardiovascular functions remains unknown. In this study, we investigated the impact of genetic TRPC6 deletion on energy balance, metabolic and cardiovascular functions, and anorexic responses to leptin. Metabolic phenotypes including body weight (BW), food intake (FI), body fat/lean composition, energy expenditure (EE), respiratory quotient (RQ), responses to acute leptin injection as well as cardiovascular parameters including blood pressure (BP) and heart rate (HR) were measured by telemetry in male and female TRPC6 null and B6/129 control mice (n=7/per group and sex). TRPC6 null mice were heavier than control mice from 6 to 16 weeks of age when fed a standard diet (39.5±1.5 vs 31.1±1.2 g in males and 31.1±1.2 vs 22.9±1.0 g in females at 16 weeks of age, p<0.05). EchoMRI scans showed that the higher BW of TRPC6 null mice was mainly due to increased body fat compared to controls (30.0 vs 22.6 % of fat mass/BW in males and 32.7 vs 21.0 % in females at 16 weeks of age), and was associated with increased FI (3.4±0.1 vs 2.7±0.2 g/day in males and 2.7±0.1 vs 2.0±0.1 g/day in females at 16 weeks of age, p<0.05). EE, assessed by indirect calorimetry, was significantly reduced in TRPC6 null mice (0.108±0.003 vs 0.205±0.012 kcal/12h/g in males and 0.178±0.005 vs 0.217±0.006 kcal/12h/g in females at 17 weeks of age, p<0.05) and was accompanied by significantly reduced 24‐h average RQ (0.80±0.01 vs 0.89±0.01 in males and 0.77±0.01 vs 0.84± 0.01 in females at 17 weeks of age, p<0.05) when compared to male and female controls. Acute leptin injections (5 mg/kg, i.p. at 18 weeks of age) reduced 24‐hr FI by 41% and 32 % in male and female control mice, respectively, while only 8 % and 18 % reductions in FI were observed in male and female TRPC6 null mice. BP and HR measured by telemetry for 5 consecutive days at 22 weeks of age were similar in TRPC6 null mice and control mice (MAP: 111±2 vs 108±2 in males and 103±3 vs 108±3 in females; HR: 541±9 vs 526±14 in males and 552±4 vs 552±27 in females). Our results indicate that TRPC6 plays an important role in normal control of FI, BW and energy balance as well as for normal anorexic responses to leptin. Although TRPC6 deficiency caused obesity and metabolic abnormalities, BP and HR did not increase suggesting that TRPC6 may be an important link between obesity and hypertension.Support or Funding InformationNHLBI PO1HL51971, NIGMS P20GM104357 and U54GM115428, and NIDDK R00DK113280This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
New Methods for Analysis and Interpretation of Obesity Experiments
Authors: Banks Alexander , Corrigan June 
Published: June 2021

We report here the first data repository for experiments of obesity and body weight change. Modern obesity research depends upon indirect calorimetry systems to allow for state‐of‐the‐art experimental measurement of energy expenditure and food intake. These systems generate a flood of raw data that require time‐consuming manual manipulation for formatting, outlier detection, statistical interpretation, and visualization. Analysis of calorimetry experiments requires an onerous and specialized statistical treatment to account for differences in body mass and body composition. As such, controversies have emerged on the appropriate treatment of the data generated by these experiments, fundamentally challenging some published conclusions. We recently described a free web‐based tool, CalR, for analysis of experiments using indirect calorimetry to measure physiological energy balance. CalR simplifies the process to import raw data files, generate plots, and determine the most appropriate statistical tests for interpretation of diverse experimental designs including those of obesity and thermogenesis. Critically, CalR can read in data files from all experimental setups and produce a standardized output file.A recent effort to promote transparency and increase the rigor of the scientific process, especially regarding biostatistical analysis and improving reproducibility, has created an atmosphere receptive towards novel tools that assist in achieving these goals. Many forms of large scale datasets have central repositories, including that for microarray, RNA‐seq, and proteomics experiments. Here describe the first repository for indirect calorimetry experiments, populated by reference data from more than 30,000 individual mice from the International Mouse Phenotype Consortium (IMPC). By uploading data, in the standard CalR format to the repository, users can see how their experiments compare to the reference data. Furthermore, the user‐supplied data can be shared with the public as a lasting resource. This new system will provide the transparency necessary to enhance consistency, rigor, and reproducibility in studies of obesity and energy balance.Support or Funding Information‘Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (MMPC, www.mmpc.org) under the MICROMouse Program, grants DK076169 and DK115255.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.