bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pkd1 loss induces renal injury while strengthening colonic integrity in an early ADPKD model
Authors: Sedaka Randee , Lovelady Caleb , Shinde Sejal , Yamaguchi Shinobu , Saigusa Takamitsu 
Published: May 2023

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, initiated by a germline PKD1 mutation in nearly 80% of patients. Although polycystin-1 (PC-1), the protein encoded by PKD1, is vital to maintaining renal epithelial cell integrity, its role in the intestines has yet to be elucidated. Considering macrophage infiltration precedes accelerated cyst growth in Pkd1 knockout ( Pkd1KO) mice, and the intestines are the body’s largest reservoir of inflammatory cells, we hypothesized that loss of Pkd1 would weaken the intestinal epithelial cell barrier and increase inflammation, potentially preceding renal damage. Plasma, kidney, and intestines were collected from 11-12 week old male and female conditional Pkd1KO (CAGG-creER; tamoxifen-induced at 5-6 weeks) and flox (control) mice. Tissue was utilized for RT-PCR and immunohistochemistry. Plasma was used to measure intestinal permeability and monocyte chemoattractant protein-1 (MCP-1). Pkd1KO mice exhibited significantly elevated kidney-to-body weight ratio (flox: 4.68±0.22, KO: 6.83±0.20; n=6-9/group, P<0.001) and cyst ratio % (flox: 2.7±0.4%, KO: 20.6±1.2%; n=4-5/group, P<0.001) compared to flox mice. Likewise, expression of renal tubular injury markers, hepatitis A virus cellular receptor 1 (Havcr1) (flox: 1.00±0.26, KO: 2.83±0.41; n=6-9/group, P=0.003) and lipocalin 2 (Lcn2) (flox: 1.00±0.23, KO: 1.79±0.25; n=6-9/group, P=0.047) , were significantly increased in Pkd1KO over flox mice, with epithelial integrity marker tight junction protein 1 ( Tjp1) decreased (flox: 1.00±0.11, KO: 0.76±0.05; n=6-9/group, P=0.04). No overt physiological changes were observed in the intestines of either genotype. However, Pkd1KO mice had significantly reduced colonic epithelial cell permeability versus flox mice (flox: 1.00±0.08, KO: 0.50±0.10 AU; n=6-10/group, P<0.001), corresponding to elevated expression of colonic integrity markers occludin ( Ocln) (flox: 1.00±0.26, KO: 1.72±0.16; n=6-9/group, P=0.03), plasmalemma vesicle associated protein (Plvap) (flox: 1.00±0.14, KO: 1.45±0.14; n=6-9/group, P=0.045), and focal adhesion kinase (Ptk2) (flox: 1.00±0.15, KO: 1.40±0.12; n=6-9/group, P=0.05). Pkd1KO mice did not have altered pro-inflammatory or pro-fibrotic gene expression in the kidneys or the intestines compared to flox mice; nor were there differences in plasma MCP-1 levels. All in all, lack of Pkd1 strengthens the colonic epithelial barrier, while simultaneously increasing renal damage at this early timepoint, prior to cyst progression by inflammatory involvement. These studies were supported by NIH T32 DK007545 to RS and R03 DK119717 to TS. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Influence of ovariectomy on catecholamine synthesis in rats exposed to dexamethasone in utero
Authors: Martinez Monique , Madhavpeddi Lakshmi , Alvarez Jared , Hale Taben 
Published: May 2023

Previous studies have demonstrated that when pregnant rat dams are administered the synthetic glucocorticoid, dexamethasone (DEX), in late gestation, the female offspring exhibit altered autonomic regulation compared to females exposed to vehicle (Veh). This altered autonomic regulation is characterized by a reduced high frequency power component of heart rate variability and increased stress-responsive blood pressure and heart rate. Moreover, we have recently determined that heart rate in DEX-exposed females shows a greater reliance on sympathetic nervous system at rest and during stress, as compared to Veh-exposed rats. The purpose of the current project was to further investigate the effect of in-utero DEX exposure and gonadal steroid hormones on local autonomic regulation in adult female offspring. Specifically, we measured left ventricular and adrenal expression of tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), and catechol-o-methyltransferase (COMT) as indicators of sympathetic regulation. Pregnant dams were administered DEX (0.4mg/kg per day) or Veh on gestation days 18-21. At 9 weeks, the female offspring underwent an OVX or Sham surgery. At 12 weeks, these rats were euthanized on diestrus and the left ventricles and adrenals were processed and subjected to western blot analysis to quantify protein expression of interest. TH expression tended to be reduced in left ventricle (0.57-fold, p>0.05) yet increased (1.5-fold, p>0.05) in adrenal gland in rats prenatally exposed to DEX. In both cases, there was no difference in expression of TH between vehicle and DEX rats following OVX. DBH expression was not different in adrenal gland, regardless of prenatal exposure or OVX. However, in the left ventricle, OVX resulted in an overall reduction in DBH expression that reached statistical significance in the DEX OVX rats (-50%, p=0.0079 vs Veh Sham). COMT expression was not influenced by prenatal DEX or OVX in the left ventricle. Taken together, the findings reveal a differential regulation of catecholamine synthesis in adrenal gland as compared to the left ventricle of the heart. The findings suggest that local regulation of catecholamine synthesis does not underlie our previous findings of increased sympathetic nervous system activation of females exposed to DEX in utero. Additional investigation of cardiac beta-adrenergic receptor expression, as well measures of the central autonomic nervous system circuitry, may provide further insight into the sex-dependent impact of DEX and gonadal hormones on local autonomic regulation. NIH U54 MH118919, University of Arizona Clinical Translational Sciences, Maximizing Student Development Graduate Access Fellowship This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Dynamic Regulation of Order Lipid Meso-domains in the Capillary Endothelial Cell Membrane
Authors: Franco Cristian , Gonzales Albert 
Published: May 2023

The structure and function of ion channels are sensitive to direct interactions with lipids of the membrane and to the biophysical properties of the membrane microenvironment, such that membrane fluidity, lateral pressure profile, and thickness can modulate the channels. Cholesterol plays a significant role in regulating membrane fluidity and is capable of phase separation where cholesterol will spontaneously separate into its own domain, which is partially responsible for developing two distinct domains within the membrane. These ordered domains are regions of high cholesterol and low fluidity, and the disordered domains are regions of low cholesterol and high fluidity. Here we examine and provide evidence of the presence of ordered cholesterol membrane domains in capillary endothelial cells. We will test the hypothesis that capillary endothelial cell ordered domains function as a signaling hub for different phospholipids regulating ion channel function. Using the isolated retinal vasculature, confocal microscopy, and fluorescent Bodipy-cholesterol, a marker of ordered lipid domains, we observed large regions approximately 2.3± 0.9 μm long of cholesterol ordered meso-domains within capillary endothelial cells and not the feeding arteriole. To determine the dynamic nature of these meso-domains, we used membrane-disordering drugs to disrupt the organization of membrane lipids. The ordered meso-domains display dynamic membrane disordering by ethanol and can re-cluster into the large ordered meso-domains. In addition, we observed that the critical signaling phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) co-localized with the ordered meso-domains. To determine the cooperativity between these lipid molecules, we examined the effects of ethanol-dependent disordering of cholesterol on the membrane localization of PIP2. In addition, we examined the effects of PIP2 depletion with the G-protein couple receptor agonist, U46619, on the disordered state of the cholesterol meso-domains. These data suggest that ordered meso-domains might play a role as a signaling hub affecting the membrane fluidity and bioavailability of signaling lipids modulating ion channel function in capillary endothelial cell. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Super-resolution ultrasound imaging -- creating 3D in vivo images of the renal microvasculature
Authors: Sørensen Charlotte Mehlin , Soegaard Stinne , Andersen Sofie , Taghavi Iman , Nielsen Michael , Jensen Jørgen 
Published: May 2023

Aim: Our overall aim is to create 3D in vivo microvascular imaging of the renal vasculature in healthy and diabetic rats in real time. Methods-1: Super-resolution ultrasound imaging (SRUS) using intravascular microbubbles (MBs) can generate in vivo images of the renal microcirculation. Spatially separated MBs are followed over numerous image frames to create anatomical vascular images showing MB direction and velocity. Presently, images with a resolution of 50 μm are obtainable. Results-1: As diabetes mellitus is associated with micro- and macrovascular diseases also affecting the kidneys we used SRUS on Zucker Diabetic Fat rats (ZDF) aged 12-, 20- and 40-weeks. We show a significant decrease in vascular density in the cortex at week 12 before onset of proteinuria when compared to age-matched lean Zucker rats. At week 20 vascular density decreased in the outer medulla and inner medulla. No significant changes were found in vascular tortuosity. However, the SRUS images are collected over several minutes, and are challenged by tissue motion and the lack of real-time imaging. The fragile MBs limit emission pressure and thus scan depth. Hypothesis: We hypothesize that tracking erythrocytes instead of MBs will reduce these obstacles and make the method non-invasive. Resolution and scan depth will increase and scan time will shorten. This will allow an easy transition into the clinic. Results-2: Using this innovative method, we have generated images of healthy rat kidneys. Within 24 seconds, we can create an image of the renal vasculature showing the vasa recta (the capillary network penetrating the medulla) and the arcuate and cortical radial arteries. μCT scans have verified the structure of the vascular tree. However, even at these short scan times, there is considerable tissue motion from heart-beat, respiration etc. moving the image out of plane. To clearly image the true microcirculation, 3D imaging is needed. We have recently obtained this amazing step and made a 3D in vivo scan of a healthy rat kidney. The project is funded by an ERC Synergy Grant SURE, project no. 854796. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Decentering and baroreflex sensitivity in adults with elevated blood pressure
Authors: Bishop Reagan , Thivierge Grant , Larson Robert , Durocher John 
Published: May 2023

Previous studies have linked the ability to decenter, a non-judgmental view of emotions, with lower arterial stiffness and better nocturnal blood pressure dipping in adults. It is unknown however if autonomic regulation of blood pressure is linked to decentering. Therefore, the purpose of this study was to determine if decentering ability is related to cardiovagal or sympathetic baroreflex sensitivity. Thirty-three adults (age 25±6 years; BMI 25±3 kg/m2) with resting blood pressure ≥120/80 mmHg volunteered for this study. All participants had a BMI <30 kg/m2, and had no history of smoking, diabetes, or prescriptions for blood pressure or cardiac function. Participants completed an 11-item experiences questionnaire to evaluate decentering, and then were equipped for a supine autonomic evaluation. The autonomic evaluation included continuous recording of heart rate via 3-lead ECG, muscle sympathetic nerve activity (MSNA) via microneurography, and beat-to-beat blood pressure via finger photoplethysmography. Cardiovagal baroreflex sensitivity (n=33) included estimation of vagal activation by evaluating up-up relationships between systolic arterial pressure (SAP) and R-R intervals of the ECG. Vagal withdrawal was also estimated via the down-down relationships between SAP and R-R intervals. Spontaneous sympathetic baroreflex sensitivity (n=26) was evaluated by evaluating the relationship between changes in diastolic arterial pressure (DAP) in 3 mmHg bins vs. changes in MSNA burst incidence (i.e., bursts / 100 heart beats). Results from 2-tailed Pearson correlation analyses revealed that there was not a relationship between decentering and vagal activation (r=-0.07; p=0.71) or between decentering and vagal withdrawal (r=-0.28; p=0.12). Likewise, there was no relationship between decentering and sympathetic baroreflex sensitivity (r=0.10; p=0.64). Our findings suggest that there is not a clear link between decentering and autonomic regulation of blood pressure as estimated through both cardiovagal and baroreflex sensitivity. NIH (1R15HL140596-01); Nils K. Nelson Endowment Fund This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
High sodium diet and intestinal permeability in young, healthy adults
Authors: Kaseman Kathryn , Smiljanec Katarina , Lobene Andrea , Axler Michael , Lennon Shannon 
Published: May 2023

High sodium diets (HSD) have been shown to both increase blood pressure (BP) and lead to gut dysbiosis in adults. Gut dysbiosis can increase intestinal permeability (IP), allowing for translocation of bacteria and their products into the systemic circulation. There, bacteria and their products are recognized by the immune system and can activate pro-inflammatory pathways such as TH17 in a dose dependent manner. HSD has been shown to activate those pathways and increase BP in men. However, the effect of a HSD on IP has not been explored as a potential mechanism of HSD induced BP changes. The objective of this research was to investigate if a HSD can increase IP and inflammatory markers. We hypothesized that plasma concentrations of two common biomarkers of IP, zonulin and LPS binding protein (LBP), and proinflammatory TH17 lymphocytes would increase, while anti-inflammatory Treg lymphocytes would decrease on a HSD compared to a recommended sodium diet (RSD). Twenty-seven healthy participants (15W/12M, age 24±3 yrs, BP 112±9/65±6 mmHg) underwent a 10-day HSD (6,900mg sodium/d, supplemented by salt pills) and a 10-day RSD (2,300 mg sodium/d) intervention in randomized order. On day 9 of each intervention, participants collected urine and wore an ambulatory BP monitor for 24hr. Blood was collected to measure plasma zonulin and LBP by ELISA. TH17 and Treg populations were characterized from PBMCs by flow cytometry. Paired t-tests were used to compare variables on day 9 between diets. Pearson correlations were used to assess the relation between markers of IP and BP. Twenty-four-hour sodium excretion was increased on the HSD (RSD: 135±57 mmol/24h, HSD: 290±68 mmol/24h, p<0.0001). Mean 24-hr SBP (RSD: 116±10, HSD: 117±11 p=0.70) and DBP (RSD: 66±6 mmHg, HSD: 66±5 mmHg, p=0.84) were not different between diets. Plasma zonulin concentrations (RSD: 2.6±1.6 ng/ml, HSD: 2.6±1.5 ng/ml p=0.88) and LBP concentrations (RSD: 3.2±1.7 μg/ml, HSD: 3.2±1.8 μg/ml, p=0.72) were not different between diets. The TH17/Treg ratio was not different between diets (RSD: 0.54±0.51, HSD: 0.41±0.38; p=0.21) however the ratio was inversely associated with zonulin (r=-0.57 p=0.04), and LBP (r=-0.61; p=0.012) on HSD when controlling for age and sex but not on RSD (all p>0.05). These data suggest that 10 days of a HSD did not change IP, BP or T lymphocyte populations in young, healthy individuals. However, the TH17/Treg ratio was associated with zonulin and LBP suggesting that the immune system may respond to changes in IP. Future research is needed to determine whether a HSD can affect IP and inflammation in salt sensitive populations. NIH Grants R01 HL145055 and P20GM113125 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Right ventricular function in hearts of a mouse model of Duchenne muscular dystrophy following increased ventricular load
Authors: Lambert Michelle , Behrmann Andrew , Nourian Zahra , Nyanyo Keith , Hanft Laurin , Krenz Maike , McDonald Kerry , Domeier Timothy 
Published: May 2023

Duchenne muscular dystrophy (DMD) is an X-linked recessive myopathy caused by mutations in the gene encoding dystrophin. Dystrophin is present in striated muscle cells and stabilizes the sarcolemma to mitigate contraction-induced damage. The main cause of death in DMD is cardiopulmonary failure by age 30. Diaphragmatic weakness in DMD causes restrictive lung disease and excessive afterload on the right ventricle (RV). Thus, RV dysfunction in DMD patients is typically observed early in disease progression. The objective of this study was to investigate ex vivo RV function in a mouse model of muscular dystrophy and test the hypothesis that RV function is impaired following a sustained increase in ventricular preload and afterload. Right-ventricular pressure development (Pdev) and rate of pressure decay (dP/dtMin) were monitored in isolated perfused hearts of 2-6 month normal (C57BL/6, n=5) and dystrophic (mdx4CV, n=5) male mice. Measurements were obtained under unloaded conditions and during right-ventricular load challenge (10 mmHg preload; 20 mmHg afterload). Coronary effluent lactate dehydrogenase (LDH) levels were measured following 30 minutes of sustained load challenge to assess cardiac damage. Our results show dystrophic hearts exhibited greater RV Pdev than normal hearts under unloaded conditions (24±2 mmHg mdx4CV vs 15±2 mmHg C57BL/6, P=0.015). In response to load challenge, Pdev increased (P<0.05) in both groups, but it was similar between dystrophic and normal hearts (32±1 mmHg mdx4CV vs 33±3 mmHg C57BL/6). Rate of pressure decay was similar between dystrophic and normal hearts under both conditions. Levels of LDH following load challenge were higher (P<0.05) in dystrophic versus normal hearts. In conclusion, in the absence of ventricular load RV contractile function was enhanced in dystrophic hearts. With RV load both dystrophic and normal hearts exhibited similar contractile function, yet sustained load challenge increased cellular damage in dystrophic versus normal hearts. National Institutes of Health, University of Missouri School of Medicine, University of Missouri System This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Increased nitric oxide-soluble guanylyl cyclase signaling improves endurance capacity and contracting skeletal muscle oxygenation in healthy female rats
Authors: Weber Ramona , Schulze Kiana , Hageman K. Sue , Musch Timothy , Poole David 
Published: May 2023

Introduction: During exercise skeletal muscle blood flow and O2 delivery (Q̇O2) as well as mitochondrial oxygen uptake (V̇O2) are regulated, in part, by nitric oxide (NO)-soluble guanylyl cyclase (sGC) signaling. Exercise-induced metabolic adaptations within skeletal muscle lead to a higher Q̇O2-V̇O2 ratio (measured as increased interstitial partial pressure of O2, PO2 is), which is driven partly via increases in NO bioavailability. The sGC activator BAY 60-2770 augments downstream NO signaling by targeting the heme-free sGC enzyme, which constitutes 20-60% of sGC in healthy smooth muscle cells. We tested the hypotheses that sGC activator BAY 60-2770 administration would increase skeletal muscle oxygenation (spinotrapezius PO2 is) and enhance endurance capacity. Methods: Healthy female Sprague-Dawley rats (n=6) performed a baseline time-to-exhaustion (TTE) exercise protocol and were then randomly assigned to vehicle (V) or sGC activator (sGC) groups. sGC rats were administered 0.3 mg/kg b.i.d for five days via oral gavage. Following the dosing regimen, repeated TTE testing determined running endurance capacity on a motor-driven treadmill. On a subsequent day, the PO2 is at rest and its temporal profile following the onset of 1 Hz twitch contractions in the spinotrapezius muscle were measured using phosphorescence quenching under pentobarbital anesthesia. Results: sGC rats evidenced a 34% increase in TTE (p < 0.05) compared to V rats. There was no statistical difference in arterial blood gases and pH or heart rate and mean arterial pressure between groups during anesthesia (p > 0.05). Phosphorescence quenching revealed a significant increase in PO2 is at rest and during contractions (p < 0.05) in sGC versus V rats. Conclusions: These findings demonstrate that increasing downstream NO signaling via augmented sGC activity has the potential to improve endurance exercise capacity and skeletal muscle oxygenation at rest and during contractions in female rats. Further studies will focus on increasing the sample size to assess the robustness of these observations and investigate whether there is any pertinent sexual dimorphism in sGC signaling. We will also resolve corollary molecular signaling pathways that might be upregulated by chronic sGC activation which may positively impact skeletal muscle contractile function and exercise performance. This work was supported, in part, by the National Institute of Aging (1 R15 AG 078060) and a SMILE Award from Kansas State College of Veterinary Medicine. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.