bluuebunny/crossref_metadata_2025_split huggingface dataset:
Central Terminals of Trigeminal Nerves that Innervate the Nose and Nasal Passages Colocalize with Medullary Dorsal Horn Neurons Activated during Voluntary Diving in Rats
Authors: McCulloch Paul , Margosiak Malgorzata , DiNovo Karyn 
Published: June 2021

Underwater submersion in mammals initiates the diving response, an autonomic cardiorespiratory reflex that includes apnea, a parasympathetically‐mediated bradycardia, and a sympathetically‐mediated increase in total peripheral resistance. The initial synapse of this reflex occurs within the ventral medullary dorsal horn (MDH) of the spinal trigeminal nucleus caudalis. The anterior ethmoidal and nasopalatine nerves, trigeminal nerves that innervate the internal nasal passages, also send their central terminations to the ventral MDH. The objective of this research was to detect colocalization of secondary MDH neurons activated by voluntary diving with the central terminations of the trigeminal nerves innervating the internal nasal passages. MDH activated neurons were identified by Fos protein production, while central terminals of the trigeminal nerves were located by the transganglionic tracer Wheat Germ Agglutinin (WGA). Sprague‐Dawley rats (N=12) were trained to voluntarily dive through a 5 m underwater Plexiglas maze. After training, 6 rats then received WGA injections into the anterior ethmoidal nerve, while 6 rats received WGA injections into the nasopalatine nerve. Four days post‐WGA injection, 3 rats from each nerve injection group performed 12 dive trials over 1 hour to activate brainstem neurons and initiate Fos production; 3 rats from each nerve injection group were non‐diving controls. Brainstem tissue from all rats was immunohistochemically processed to visualize both Fos and WGA, and was inspected using a Nikon C1 confocal microscope and Nikon Eclipse Ti2 inverted fluorescent microscope. Results indicate repetitive voluntary diving increases the number of Fos‐positive neurons within the ventral tip of the superficial MDH and adjacent paratrigeminal nucleus. WGA results show central termination sites from both the anterior ethmoidal and nasopalatine nerves within this same MDH location. Additionally, MDH Fos‐positive neurons from diving animals show extensive colocalization with WGA injected into both the anterior ethmoidal nerve and nasopalatine nerve compared to non‐diving control rats. We conclude both the anterior ethmoidal and nasopalatine nerves can provide afferent information necessary to activate MDH neurons during initiation of the mammalian diving response.Support or Funding InformationSupported by MWU Intramural funding (PFM) and CGS MBS program (MM)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Enhancement of Hypothalamic Corticotrophin Releasing Hormone Signal Contributes to Elevated Sympathetic Outflow in Spontaneous Hypertension Rat
Authors: Zhou Jing‐Jing , Shao Jian‐Ying , Ma HuiJie , Pan Hui‐Lin , Li De‐Pei 
Published: June 2021

The paraventricular nucleus (PVN) of the hypothalamus is crucially involved in the regulation of blood pressure and sympathetic outflow in hypertension. The PVN contains neurons synthesizing corticotrophin releasing hormone (CRH), a neuropeptide that is critical in regulating neuroendocrine and cardiovascular functions in physiological and disease conditions. The mRNA and protein expression levels are significantly increased in the hypothalamus in patients with primary hypertension. However, the role of hypothalamic CRH signal in the elevated sympathetic vasomotor tone in hypertension remains unknown. In this study, we tested a hypothesis that enhanced hypothalamic CRH signals contributes to elevated sympathetic vasomotor tone in primary hypertension. Western blotting analysis by using PVN tissues revealed that CRH receptor (CRHR) 1 expression level was significantly higher in male adult spontaneously hypertensive rats (SHRs) than in Wistar‐Kyoto (WKY) rats. However, CRHR1 expression level in the PVN was not significantly affected by lowing ABP by celiac ganglionectomy in SHRs. In brain slice preparation, bath application of CRH induced a significantly greater membrane depolarization and an increase in the firing rate of spinally projecting PVN neurons in SHRs than in WKY rats. A CRHR1 antagonist NBI 35965, not CRHR2 antagonist antisauvagine‐30, decreased the basal firing rate of spinally projecting PVN neurons in SHRs but not in WKY rats. However, CRH did not change neither the miniature inhibitory post‐synaptic currents nor the miniature excitatory post‐synaptic currents of labeled PVN neurons in both SHRs and WKY rats. Furthermore, bilateral microinjection of CRH into the PVN induced dose‐dependently greater increases in arterial blood pressure (ABP), heart rate (HR), and renal sympathetic activity (RSNA) in anesthetized SHRs than in WKY rats. CRH‐induced sympathoexcitatory effect was eliminated by microinjection of NBI 35965 but not antisauvagine‐30. Microinjection of NBI 35965 into the PVN significantly reduced basal ABP, HR, and RSNA in SHRs. These data suggest that upregulation of CRFR1 receptor in the PVN is involved in hyperactivity of spinally projecting PVN neurons and contributes to the elevated sympathetic outflow in essential hypertension.Support or Funding InformationSupported by grants from National Institutes of Health (HL139523 and HL142133).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Group III Metabotropic Glutamate Receptors Regulate Excitability of Hypothalamic Presympathetic Neurons and Sympathetic Output in Hypertension
Authors: Zhou Jing‐Jing , Pachuau Judith , Li De‐Pei , Pan Hui‐Lin 
Published: June 2021

Enhanced glutamatergic input to the hypothalamic paraventricular nucleus (PVN) contributes to the development of hypertension. Group III metabotropic glutamate receptors (mGluRs) are expressed in the PVN. In the present study, we determined the role of group III mGluRs in the control of the excitability of spinally projecting PVN neurons and sympathetic outflow in hypertension. We found that stimulation of group III mGluRs with L‐(+)‐2‐amino‐4‐phosphonobutyric acid (L‐AP4) consistently inhibited the firing activity of PVN neurons in normotensive WKY rats. However, L‐AP4 inhibited 37%, but excited 48%, of spinally projecting PVN neurons in spontaneously hypertensive rats (SHRs). Both the inhibitory and excitatory effects of L‐AP4 on the firing activity were abolished by the group III mGluR antagonist CPPG. Inclusion of GDP‐β‐S in the intracellular recording solution eliminated the excitatory effect of L‐AP4 on the firing activity of PVN neurons in SHRs, but it did not significantly change the inhibitory effect of L‐AP4 on PVN neurons in WKY rats or SHRs. L‐AP4 significantly reduced the frequency of spontaneous excitatory postsynaptic currents of PVN neurons in both WKY rats and SHRs. Interestingly, pretreatment of brain slices with the group I mGluR agonist DHPG converted the L‐AP4 effect on PVN neurons from inhibitory to excitatory in WKY rats. Also, L‐AP4 consistently inhibited PVN neurons in SHRs after treatment with the group I mGluR antagonist MPEP. In addition, microinjection of L‐AP4 into the PVN dose‐dependently decreased arterial Bp and lumbar sympathetic nerve activity (LSNA) in WKY rats and SHRs. Microinjection of L‐AP4 in the presence of MPEP produced a more significant reduction in arterial BP and LSNA than did with microinjection of L‐AP4 alone in SHRs. These findings suggest that group III mGluRs in the PVN regulate the synaptic plasticity and excitability of PVN presympathetic neurons and sympathetic vasomotor activity in hypertension. The signaling of postsynaptic group III mGluRs is influenced by increased group I mGluR activity in PVN presympathetic neurons in hypertension. Supported by NIH grants HL131161 and HL142133.Support or Funding InformationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Phenotyping a Mouse with Vascular Smooth Muscle Specific Deletion of the Gamma Subunit of the Epithelial Sodium Channel (γENaC)
Authors: Hasan Mahpara , Mutchler Stephanie , Tan Roderick J , Kohan Donald E , Kleyman Thomas R 
Published: June 2021

The epithelial sodium channel (ENaC) has an important role in mediating myogenic tone of blood vessels. Previous studies found that mice with whole body knockdown of bENaC had an increased blood pressure, thought to be due to the loss of myogenic tone in the renal vasculature leading to inflammation and glomerular damage. However, because these results were obtained in an animal with global suppression of bENaC expression, the contributions of vascular smooth muscle (VSM) ENaC cannot be separated from effects of suppressed ENaC expression at other sites. To address this concern, we generated a VSM ENaC knockout animal using cre‐lox technology. Contrary to the bENaC hypomorphs, these mice did not have increased baseline blood pressure, as measured by radiotelemetry. Our preliminary results do not show significant differences in the myogenic response of the mesenteric or thoracodorsal arteries as assessed by pressure myography, however, the vessels do have greater angiotensin II‐mediated vasoconstriction. Preliminary results reveal that VSM ENaC KO mice exhibited increased glomerular filtration rate (GFR) at baseline, and that the knockouts had more proteinuria following a 4‐week treatment with high salt diet and aldosterone. However, wild type and VSM ENaC KO mice had similar responses to renal ischemia reperfusion injury, as assessed by serum creatinine and message levels for kidney injury markers NGAL and Kim1. Taken together, these data reveal that VSM gENaC may be playing a distinct role from that of bENaC, potentially only contributing to the myogenic response in the microvasculature of the kidney under conditions of stress.Support or Funding InformationNIH P30 2P30DK079307‐11, NIH T32 2T32DK061296‐16This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Chronic Intermittent Hypoxia Promotes Glomerular Hyperfiltration, Reductions in Renal Blood Flow, and Upregulation of Renal A2B Receptor Expression
Authors: Kious Kiefer W. , Twohey Stephanie C.E. , Keomanivong Faithe E. , Neidermann Sarah E. , Dirkman Jacob J. , Marcus Noah J. 
Published: June 2021

Background/SignificanceSleep apnea (SA) is associated with hypertension and chronic kidney disease. Changes in adenosine signaling associated with chronic intermittent hypoxia (CIH) during apneic episodes may alter glomerular hemodynamics and contribute to hyperfiltration. In addition, increased signaling through the adenosine type 2B receptor (A2B) may promote inflammation and contribute to renal damage and eventual declines in renal function.HypothesisWe hypothesized that short‐term exposure to CIH would promote increased glomerular filtration rate and upregulation of A2B, IL‐6, NGAL, and α‐smooth muscle actin (SMA) expression in the kidney.MethodsAdult male Sprague Dawley rats were exposed to 10 days CIH (60 sec. FiO2 10%, 120 sec. FiO2 21%) for 8h/d. Glomerular filtration rate (GFR) was measured transdermally (Medibeacon) pre‐ and post‐CIH, and post‐CIH (or sham) renal blood flow (RBF) was measured using Transonic flow probes (2% isoflurane, FiO2 21% and 10%). Cortical and medullary expression of A2B, IL‐6, NGAL, and α‐smooth muscle actin (SMA) was measured via western blot.ResultsWeight‐corrected RBF decreased modestly (15%) after 10 days of CIH (1.89±0.13 mL/min/g vs. 1.42±0.16 mL/min/g, p<0.05). In contrast weight‐corrected GFR increased by 80% from pre‐ to post‐CIH measurements (3.1±0.27 mL/min/g vs. 5.5±0.51 mL/min/g, p<0.05). Renal cortical A2B (1.0±0.09 sham vs. 1.42±0.15 CIH, p<0.05) and IL‐6 (1.0±0.11 sham vs. 1.56±0.21 CIH, p<0.05) and medullary NGAL (1.0±0.22 sham vs. 2.68±0.65 CIH, p<0.05) expression was increased in CIH relative to sham tissue. SMA was not significantly different between groups.ConclusionsIntermittent hypoxia induces glomerular hyperfiltration and upregulation of renal A2B/pro‐inflammatory pathways, which in turn may precede renal injury.Support or Funding InformationSupported by a grant from NHLBI (R15 HL138600‐01 to NJM)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Postprandial Effects on ENaC‐Mediated Sodium Absorption
Authors: Klemens Christine A , Blass Gregory A , Brands Michael , Palygin Oleg , Staruschenko Alexander 
Published: June 2021

Recent studies have suggested that postprandial increases in insulin directly contribute to reduced urinary sodium (Na+) excretion by altering renal Na+ transport. While there are a number of renal transporters that respond to insulin stimulation, which of these transporters are involved in this Na+ sparing mechanism under normal physiological conditions is not fully established. The epithelial sodium channel (ENaC) is the rate limiting step for sodium reabsorption in the distal nephron and its regulation by insulin is well established; however, the regulatory effect of acute hyperinsulinemia (as would result from a meal) on ENaC under normal conditions is still being debated. The main objective of this study was to test the contribution of ENaC as well as other Na+ transporters to the increase in renal Na+ reabsorption following a meal. To test this, we used fasted Sprague Dawley rats that had been given a high carbohydrate supplement to simulate a meal and analyzed changes to ENaC activity as well as expression of other renal transporters involved in sodium homeostasis. Postprandial changes in circulating renin‐angiotensin‐aldosterone system (RAAS) hormones known to enhance ENaC activity were also tested. We found that 4 hours post carbohydrate stimulus, ENaC open probability increased relative to controls in split‐open isolated collecting duct tubules (0.34 ±0.06 vs. 0.70 ± 0.07, n≥5, p<0.01), while the number of channels at the surface and total ENaC α‐ and β‐subunit levels remained unchanged. We also examined expression levels of the Na+‐Cl− cotransporter (NCC), Na+‐K+‐2Cl− cotransporter (NKCC2), and Na+‐K+‐ATPase (NKA). While there were no significant differences in expression of NCC or NKCC2 in either group, NKA expression in the postprandial group was significantly increased (1.0 ± 0.08 vs. 1.62 ± 0.10, n=5, p<0.001). Additionally, using mass spectrometry‐based analysis, we interrogated different metabolites of RAAS signaling between the stimulated and fasted rats and found no significant changes in aldosterone or angiotensin metabolite levels. These results suggest that acute hyperinsulinemia following a meal increases ENaC activity independent of the RAAS signaling cascade. Our study demonstrates that ENaC and NKA regulation via insulin is a likely contributor to an evolutionary mechanism for preserving sodium and volume loss after a meal, and that this regulation is distinct from classical ENaC regulation by RAAS.Support or Funding InformationT32 HL134643; R35 HL135749, HL56259This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
ENaC activation by bile acids depends on specific moieties, but not on membrane permeability
Authors: Wang Xue‐Ping , Im Seohyun Janice , Ertem Merve , Balchak Deidra M , Montalbetti Nicolas , Carattino Marcelo D , Ray Evan C , Kashlan Ossama B 
Published: June 2021

The epithelial sodium channel (ENaC) mediates Na+ transport in several epithelia, including the aldosterone‐sensitive distal nephron, distal colon, and biliary epithelium. Numerous factors regulate the activity of the channel, including extracellular ligands, post‐translational modifications, and membrane‐resident lipids. Bile acids are abundant in the biliary tree and intestinal tract, and can be elevated in the urine of patients with advanced liver disease. Using Xenopus oocytes, we found that bile acids both activated and inhibited mouse ENaC, dependent on the bile acid. Whether bile acids were activating or inhibiting depended on the position and stereochemistry of specific moieties. Taurine conjugated bile acids had stronger effects than their more membrane permeant unconjugated counterparts, suggesting that bile acids regulate ENaC extracellularly. Bile acids that increased ENaC currents had a hydroxyl group at position 12, facing the hydrophilic side. Bile acids that decreased ENaC currents had a hydroxyl group at position 6. Bile acid dependent activation of ENaC currents was mildly voltage‐dependent, suggesting that regulation occurs in the outer leaflet of the membrane. Bile acids also regulated ENaC in a cortical collecting duct cell line, mirroring results in Xenopus oocytes. These results suggest that bile acids interact directly with ENaC near the interface between the outer leaflet and the extracellular solution.Support or Funding InformationThis work was supported by NIDDK, National Institutes of Health, Grant R01 DK098204 (to O.B.K), and a grant from the Pittsburgh Liver Research Center. The Pittsburgh Center for Kidney Research was supported by Grant DK P30 DK079307 from NIDDK, National Institutes of Health.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
MARCKS Expression and Localization in the Aged Kidney of Hypertensive 129Sv Mice
Authors: Malik Zeeshan S. , Schramm Whitney C. , Liu Lauren P. , Chacko Kevin M. , Alli Abdel A. 
Published: June 2021

Essential hypertension remains a major public health problem and there is an increase in its prevalence with age. An upregulation in the expression and activity of the renal epithelial sodium channel (rENaC) plays a key role in the development of essential hypertension. MARCKS protein plays an essential role in the positive regulation of rENaC by stabilizing the actin cytoskeleton and increasing the availability of PIP2 at the apical plasma membrane. The goal of this study was to determine whether MARCKS protein expression and association with the actin cytoskeleton is augmented in the aged kidney of hypertensive 129Sv mice. 129Sv mice were aged for 12 months before being subject to salt loading (8% NaCl) for 4 weeks to induce hypertension. Blood pressure was measured by tail cuff and electrolytes in the urine were measured using an electrolyte analyzer. The kidneys were harvested for proteins and the expression of total MARCKS and phospho‐MARCKS was measured by Western blotting and densitometric analysis. Immunohistochemistry was performed to assess the localization of MARCKS and the actin cytoskeleton protein filamin A. The expression of total MARCKS protein increased while phospho‐MARCKS protein expression decreased in kidney cortex lysates from aged 129Sv mice with hypertension compared to aged 129Sv mice without hypertension. The colocalization between MARCKS and filamin A in kidney tubules was augmented in hypertensive aged mice compared to controls. These data indicate MARCKS expression and its function is augmented in the pathogenesis of hypertension in the aged kidney.Support or Funding InformationThis project was funded by the U.S. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (Grant K01 DK099617; to A.A.A.) and the University of Florida College of Medicine.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sex Differences in Aged Hypertensive 129Sv Mice
Authors: Liu Lauren P. , Chacko Kevin M. , Schramm Whitney C. , Malik Zeeshan S. , Alli Abdel A. 
Published: June 2021

Salt‐sensitive hypertension has become an enormous public health problem due to the recent increase of dietary salt intake in many countries. It is already known that female sex hormones have a protective effect regarding the increase of blood pressure. However, little is known about sex differences in the aged kidney. The goal of this study was to determine whether or not there are differences in blood pressure, ENaC alpha protein expression, and filamin protein expression in the aged kidneys of salt‐sensitive male mice when compared to female mice after salt loading. Male and female 129Sv mice were aged for 12 months and maintained on a normal salt diet (0.4% NaCl) before being salt loaded (8% NaCl) for 4 weeks. During this time, blood pressure was measured by tail cuff and electrolytes in the urine were measured using an electrolyte analyzer. Protein expression of ENaC alpha and filamin were measured by Western blotting and immunohistochemistry. The difference in blood pressure before and after salt loading was greater in the aged male 129Sv mice compared to the females. Before and after salt loading, the male mice showed higher urinary sodium levels than the female mice. There were no differences observed in urinary potassium levels between the male and female mice. Although ENaC alpha protein expression did not change, filamin A protein expression was augmented in the hypertensive aged male mice compared to the females. This data suggests that there are sex differences in the aged kidneys of hypertensive 129Sv mice that do not involve changes in ENaC alpha protein expression but may involve changes in actin cytoskeleton associated proteins.Support or Funding InformationThis project was funded by the U.S. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (Grant K01 DK099617; to A.A.A.) and the University of Florida College of Medicine.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.