bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regional Differences in Placental and Myoendometrial Vascularization and Placental and Fetal Development in Hypertensive‐Pregnancy
Authors: Dias‐Junior Carlos Alan , Ren Zongli , Zhu Minglin , Li Jun , Khalil Raouf A. 
Published: November 2023

Preeclampsia (PE) is a form of hypertensive‐pregnancy (HTN‐Preg) with unclear mechanism. General reduction of uterine perfusion pressure (RUPP) could be an initiating event leading to uteroplacental ischemia, abnormal angiogenic/anti‐angiogenic responses and HTN‐Preg. Additional regional differences in placental blood flow could further affect the pregnancy outcome and may be a factor in the increased risk of PE in twin or multiple pregnancy. To test the hypothesis that regional differences in uterine perfusion could affect uteroplacental vascularization and placental and fetal development, we compared the number and size of pups and placentae, and the number of placental and adjacent myoendometrial arteries in the proximal (prox‐U), middle (mid‐U) and distal (distal‐U) portions of the uterus (in relation to distance from the ovarian arteries) in normal pregnant (NP) and RUPP rats. Maternal blood pressure was higher (127±2 vs. 105±4mmHg), and uterine weight (3.2±0.1 vs. 4.6±0.2g), number of placentae (9.5±0.7 vs. 12.6±0.5), placenta weight (401±5 vs. 456±4mg), litter size (9.5±0.7 vs. 12.6±0.5), and pup weight (1.18±0.05 vs. 1.59±0.04g) were less in RUPP than NP group. Further examination of the RUPP uterus showed a decrease in the number and weight of placentae and pups in distal‐U (0.4±0.3, 210±120mg; 0.4±0.3, 1.16±0.51g) vs. prox‐U (1±0, 400±175mg; 1±0, 1.67±0.49g) and mid‐U (0.6±0.5, 337±184mg; 0.6±0.5, 1.58±0.46g). The number and diameter of placental arteries were smaller in distal‐U (2.6±0.5, 70±8μm) vs. prox‐U (5.0±0.4, 105±4μm) and mid‐U (5.0±0.5, 95±7μm) of RUPP rats. Also, the number of the adjacent myoendometrial arteries was less in distal‐U (1.3±0.04) vs. prox‐U (3.5±0.06) and mid‐U (2.5±0.04) of RUPP rats. No significant differences were observed in placentae and pups number and weight or number of placental and myoendometrial arteries in different uterine regions of NP group. Thus, in addition to the general reduction in placental and fetal development observed during uteroplacental ischemia, there is a greater decrease in placental and myoendometrial vascularization associated with greater placental and fetal growth restriction in distal‐U, suggesting regional differences in blood flow, placental perfusion and angiogenic responses in HTN‐Preg that could be a factor in the incidence of PE in multiple pregnancy.Support or Funding InformationThis work was supported by grants from National Heart, Lung, and Blood Institute (HL‐65998,HL‐111775).
ET‐1 and Nitric Oxide Stimulate Trans‐Epithelial Electrical Resistance (TER) in Inner Medullary Collecting Duct Cells
Authors: Arguello Alexandra M , Hyndman Kelly A , Goodchild Traci T , Pollock Jennifer S 
Published: November 2023

In the renal collecting duct, it is the epithelial Na channel (ENaC) that is the rate‐limiting step for Na reabsorption. We recently reported, that collecting duct nitric oxide synthase‐1 (NOS1) is necessary for endothelin‐1 (ET‐1) dependent inhibition of ENaC activity. Loss of either ET‐1 or NOS1 expression specifically in the collecting duct generates a salt‐sensitive blood pressure phenotype. In the kidney, it is the IMCD that expresses the highest NOS activity in the kidney, and produces the most ET‐1 throughout the body. Previous studies demonstrating ENaC regulation in the collecting duct have utilized patch‐clamp electro‐physiology in the cortical collecting duct, however the inner medullary collecting duct (IMCD) is technically difficult to patch clamp. Thus, the purpose of this study was to utilize TER, which is inversely related to ion transport, to determine the effect of ET‐1 and NOS inhibition on IMCD ENaC activity. TER was measured with a volt‐ohmmeter and STX2 electrode. Transwell cell culture inserts were used, allowing mouse or rat IMCD cells to polarize. Both rat primary IMCD and mouse mIMCD‐3 exhibited amiloride‐sensitive ENaC inhibition. Amiloride (1 uM) increased TER (decreased ENaC activity) in rat IMCD cells (+5.27 ± 0.63%) and mIMCD‐3 cells (+9.53 ± 1.33%) compared to vehicle controls (+0.29 ±0.19%). ET‐1 (100 nM) stimulated a significant increase in TER for rat IMCD (+2.66‐‐ ± 0.23%) and mouse mIMCD‐3 cells (+3.25 ± 0.62%−) compared to vehicle, indicating an inhibition of ion transport. NOS inhibition (5 mM L‐NAME) also stimulated a significant decrease in TER in rat IMCD (−3.50 ± 0.5%) and mouse mIMCD‐3 cells (−8.35 ± 1.20%). The decrease in resistance, and therefore increase in ion transport, with NOS inhibition could not be reversed with the addition of ET‐1, indicating that the NOS system contributes to the tonic inhibition of ion transport in the IMCD. In conclusion, these data support the hypothesis that the ET‐1 and NOS systems regulate ion transport, most likely ENaC, in the IMCD of rats and mice.Support or Funding InformationNIHP01HL95499 and The University of Alabama at Birmingham Preparation for Graduate and Medical Education Program (PARADiGM) R25 HL120883
Impaired renal oxygenation in obese Zucker rats following orthopedic trauma
Authors: Xiang Lusha , Thompson Michael S , Mittwede Peter N 
Published: November 2023

Wepreviously found increased acute kidney injury (AKI) following orthopedictrauma in obese (OZ) as compared to lean Zucker rats (LZ), in agreement with results reported in lean and obese trauma patients. Impaired renal oxygenation due to elevated oxygen consumption (VO2) and/or decreased oxygen delivery(DO2) has been shown to be an important mechanism of AKI in in many critical illnesses, but few studies have investigated the mechanisms of AKI following orthopedic trauma, particularly in obesity. We hypothesized that the increased AKI in OZ following orthopedic trauma is associated with impaired renal oxygenation. Soft tissue injury, fibula fracture, and bone component injection were performed in both hind limbs in male LZ and OZ (~12wk old) to induce orthopedictrauma. A day later, food intake, circulating aldosterone, renal blood flow (RBF), GFR, and renal medullary glycogen levels were measured. Renal DO2 and VO2 were calculated from renal arterial and venous blood gases. Sodium (Na+) reabsorption was calculated based on GFR, plasma and urine [Na+], and urine output. Following trauma, RBF, GFR, Na+ filtration, renal DO2, and medullary glycogen levels were decreased in OZ but not in LZ. Food intake was markedly decreased in both LZ and OZ, which was associated with significantly increased Na+ reabsorption and aldosterone levels. However, compared to LZ, OZ exhibited lower Na+ uptake but higher aldosterone levels, renal VO2, and oxygen extraction ratio (VO2/DO2). These results suggest that trauma‐induced AKI in OZ is associated with impairments in renal oxygenation and the efficient oxygen utilization.Support or Funding InformationGrants: AHA‐12SDG12050525, National Institutes of HealthP20GM104357, HL‐51971, HL‐89581, and T32 HL‐105324.DoD Disclaimer: The opinions orassertions contained herin are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
Development of Renal Dysfunction in an Infant Model of Polymicrobial Sepsis
Authors: Sims Clark R , Gurley Patrick C , Mayeux Philip R 
Published: November 2023

Sepsis‐induced acute kidney injury increases mortality from 25% to nearly 45% in infants. We used a clinically relevant cecal ligation and puncture (CLP) sepsis model in rat pups 17–19 days old (developmentally comparable to a 5 to 6‐month‐old human infant) to characterize the development of renal dysfunction. Renal injury was assessed using intravital video microscopy (IVVM), blood urea nitrogen (BUN), and glomerular filtration rate (GFR) at 4, 6, and 18h following CLP. Temperature was measured as an indicator of Systemic Inflammatory Response Syndrome. Temperature was decreased as early as 6h following CLP and remained decreased through 18h. Lactate, an indicator of general organ hypoperfusion and hypoxia, was nearly doubled as early as 4h following CLP and remained elevated through 18h. IVVM analysis of the renal microcirculation showed a significant decrease in the percentage of continuously flowing capillaries (72% to 36%) and an increase in the percentage of capillaries with no flow (2% to 26%) at 6h following CLP that persisted through 18h. Clinically, measurement of BUN is used to assess renal function when GFR is difficult to measure. In this model, BUN was significantly increased by 4h following CLP and was increased even further by 18h. GFR is the gold standard measurement of renal function and it was measured using non‐invasive transcutaneous measurements of sinistrin clearance in conscious rat pups. GFR was decreased 50% as early as 4h following CLP and remained decreased through 18h. These findings show that this model of polymicrobial sepsis produces early and sustained renal dysfunction suggesting it could be used in preclinical studies to evaluate new targeted therapies for sepsis‐induced renal injury in infants.Support or Funding InformationCRS supported by T32 GM106999, F31DK104533, AHA PRE20450050; PRM supported by AHA 15GRNT2508025 and UAMS Medical Research Foundation; PCG supported by ASPET Institutional SURF Award 2015.
Muc1 Modulates the Beta‐Catenin Protective Pathway During Ischemia‐Reperfusion Injury
Authors: Al‐bataineh Mohammad M , Kinlough Carol L , Pastor‐Soler Nuria M , Sutton Timothy A , Poland Paul A , Mang Henry E , Gendler Sandra J , Madsen Cathy S , Singh Sucha , Bastacky Sheldon I , Monga Satdarshan P , Hughey Rebecca P 
Published: November 2023

The HIF‐1 and β‐catenin protective pathways represent the two most significant cellular responses that are activated in response to acute kidney injury. We previously reported that murine Mucin 1 (Muc1) protects kidney function and morphology in a mouse model of ischemia‐reperfusion injury (IRI) by stabilizing HIF‐1α, enhancing HIF‐1 downstream signaling and thereby preventing metabolic stress (Pastor‐Soler et al. 2015 Am. J. Physiol. Renal Physiol. 308, F1452‐F1462). We asked if Muc1 regulates the β‐catenin protective pathway during IRI as published data indicate that (i) β‐catenin is found in co‐immunoprecipitates with human MUC1 in extracts of both cultured cells and tissues, (ii) β‐catenin nuclear targeting is MUC1‐dependent in cultured human cells, and (iii) MUC1 prevents β‐catenin phosphorylation by glycogen synthase kinase 3β (GSK3b) and thereby β‐catenin degradation. Using our same mouse model of IRI, and by using immunohistochemistry and immunoblotting of kidney tissue, we found that levels of active GSK3β were significantly lower in kidneys of control mice compared to Muc1 KO mice. Consequently, β‐catenin was significantly increased at 24 and 72 h recovery and appeared in the nuclear fraction at 72 h in control mouse kidneys. Both β‐catenin induction and nuclear targeting were absent in Muc1 KO mice. In accord with these data, we also found downstream induction of β‐catenin pro‐survival factors (activated Akt, survivin, transcription factor TCF4 and its downstream target cyclin D1) and repression of pro‐apoptotic factors (p53, active Bax and cleaved caspase 3) in control mouse kidneys that were absent or aberrant in kidneys of Muc1 KO mice. Altogether, the data clearly indicate that Muc1 protection during AKI proceeds by enhancing both the HIF‐1 and β‐catenin protective pathways.Support or Funding InformationThis work was supported by National Institutes of Health (NIH) Grants DK‐099345 (to T. A. Sutton), DK‐084184 (to N. M. Pastor‐Soler), CA‐64389 (to S. J. Gendler), DK‐62277, DK‐100287, and DK‐095498 (to S. P. Monga), DK‐097889 (to M. M. Al‐bataineh), DK107632, DK‐079307 (Pilot Project) and Samuel and Emma Winters Foundation grant (to R. P. Hughey), and P30‐DK079307 (to the Microscopy Core N. M. Pastor‐Soler and S. Bastacky).
Role of Nox4 and p67phox in ROS production in response to increased tubular flow in the mTAL of Dahl salt‐sensitive (SS) rats
Authors: Zheleznova Nadezhda N , Yang Chun , Cowley Allen W 
Published: November 2023

Reactive Oxygen Species (ROS) in the renal outer medulla play an important role in the development of salt‐sensitive hypertension. NADPH oxidases (Nox) are the major source of ROS production in the kidney. We have examined the contribution of Nox4 and p67phox, related to the most abundant isoforms of NADPH‐oxidase Nox4 and Nox2 in the kidney, to the ROS production in response to sodium delivery and tubular flow in medullary thick ascending limb (mTAL) isolated from Dahl salt‐sensitive (SS) rats. We have shown in our previous studies that SSNox4−/− and SSp67phox−/− mutant rats exhibited a significant reduction of salt‐induced hypertension compared to SS rats after 21 day of 4.0% NaCl and a large reduction of albuminuria, tubular casts, and glomerular injury. In this study we have shown that increase in mTAL luminal flow stimulates cellular hydrogen peroxide (H2O2) and superoxide (O2·−), as well as mitochondrial H2O2 production in SS rats indicated by changes in fluorescence of sensitive dyes for detection of ROS (PF6‐AM, DHE, Mito‐PY1). In the present study we have determined that deletion of Nox4 (SSNox4−/−) resulted in significant reduction of intracellular H2O2 compared to SS in response to increased luminal flow in mTAL isolated from rats fed a 4% NaCl diet for 3 days. Deletion of the p67phox subunit in SS rat (SSp67phox−/−) also decreased H2O2 production compared to SS but to a lesser extent than that observed in mTAL of Nox4 rats (SSNox4−/−). There were no differences between cellular O2·− production in mTAL of SSNox4−/− rats compared to SS. However there was a significant decrease in cellular O2·− production in mTAL of mutant SSp67phox−/− rats. We conclude from this study that Nox4 is a major player in the production of cellular H2O2 in response to increased mTAL tubular flow of the SS rat whereas the p67phox subunit of Nox2 is involved in cellular O2·− production. Neither Nox4 nor the p67phox subunit of Nox2 seems to contribute to the mitochondrial H2O2 production in response to increased mTAL luminal flow.Support or Funding InformationHL 122662HL 082798
Angiotensin II Type 2 Receptor Agonist C21 Reduces Kidney Damage And Improves Renal Tubular Functions In High Sodium Diet‐Fed Obese Zucker Rats
Authors: Patel Sanket Niranjanbhai , Hussain Tahir 
Published: November 2023

Salt‐sensitivity has been implicated in chronic kidney damage (CKD) and impairing renal function, particularly in obesity. Earlier we have reported blood‐pressure and oxidative stress reducing effects of angiotensin AT2 receptor (AT2R) agonist C21 in kidney of high sodium diet (HSD)‐fed obese Zucker rat (OZR). Present study tested the effects of C21 on indices of renal function in HSD‐fed OZR. Obese rats were fed normal sodium diet (NSD) or 4% HSD for 14 days, with/without C21 (1 mg/kg/day) delivered subcutaneously via osmotic pump. Compared to NSD controls, HSD rats exhibited severe glomerulosclerosis, interstitial fibrosis, decline in estimated glomerular filtration rate (GFR), and an increase in urinary leak and activity of N‐acetyl‐β‐D‐glucosaminidase, a lysosomal enzyme and a marker of tubular damage, which were all improved by C21. C21 treatment reduced protein‐to‐creatinine (uPcr), albumin‐to‐creatinine (uAcr) as well as fractional excretion of protein (FEpro) and albumin (FEalb) in HSD‐fed OZR, which is independent of changes in protein recycling receptors – megalin and cubilin. HSD intake has also altered renal excretory and reabsorptive capacity as evident by elevated plasma urea nitrogen‐to‐creatinine (UN‐to‐cr) and fractional excretion of urea nitrogen (FEUN), and reduced urine‐to‐plasma creatinine (UPcr), which were modestly, but insignificantly, improved by C21. Collectively, we conclude that AT2R agonist C21 reduced glomerular protein leak and preserved lysosomal function and thus reduced exposure of nephrotic proteins to tubular lumen suggesting a potential role of AT2R in protecting glomerulus and renal tubules during HSD intake in obesity.Support or Funding InformationAcknowledgement: This study was supported by NIH R01 grant DK61578 to TH
Renal‐tubular NEDD4‐2 action is fundamental for renal adaptation during potassium deficiency
Authors: Staub Olivier , Basquin Denis , Roy Ankita , Stifanelli Matteo , Rajaram Renuga Devi , Maillard Marc , Subramanya Arohan R , Al‐Qusairi Lama 
Published: November 2023

The adaptation to K+ deficiency requires high coordination between organs involved in K+ homeostasis including kidney, muscle and liver. However, how the kidney performs functional and molecular changes to ensure K+ retention is not well understood. Here, we show that the ubiquitin‐protein ligase NEDD4‐2, known as a negative regulator of ENaC, NCC and more recently WNK1, is essential for the adaptation of the kidney to potassium deficiency. Our analyses revealed that the induciblerenal‐tubular NEDD4‐2 (NEDD4‐2Pax8/LC1) mice have normal K+homeostasis when challenged by high K+ (HKD) or low K+ (LKD)diet for one week. Upon longer exposure to LKD (2 weeks), mutant mice exhibited hypokalemia together with increased urinary K+ loss. Under the sehypokalemic conditions, increase of the large, Ca2+‐activated K+channel BK and decrease of ROMK protein levels and membrane localization are observed in NEDD4‐2Pax8/LC1 mice. SPAK‐mediated NCC phosphorylation was enhanced in the knock‐out animals with no change in total NCC. Moreover, the mutant mice showed increased WNK1 signaling in the CNT and the CD, which may explain these deregulations. In addition, ENaC expression and activity were both enhanced in the mutant mice. Interestingly, IP injection of Benzamil, anENaC inhibitor, restored K+ loss in NEDD4‐2Pax8/LC1 mice. Altogether, our data strongly suggest that NEDD4‐2plays an essential role in K+ retention via coordination of K+ channels including BK and ROMK on the one hand and of Na+ transporters including ENaC and NCC on the other hand.Support or Funding InformationSwiss National Science Foundation grant 310030_159735 (to OS), Swiss Kidney.ch NCCR (to OS), National Institutes of Health grant DK098145 (to ARS). LAQ was supported by a fellowship of the Marie Curie Co‐funding IKPP (International Fellowship Program on Integrative Kidney Physiology and Pathophysiology).
Histamine stimulates mucus secretion through IL‐4 induced TMEM16A in human nasal epithelium
Authors: Cho Hyung‐Ju , Lee Yong Hyuk , Kim Chang‐Hoon , Yoon Joo‐Heon 
Published: November 2023

BackgroundHistamine released from mast cells is an important mediator of allergic reaction, and mucus hypersecretion is a major allergic symptom.ObjectiveWe studied whether histamine directly induces mucus secretion from epithelial cells or submucosal glands (SMG) in human and pig nasal epithelium.MethodsThe short circuit current (Isc) change in response was determined in cultured primary human nasal epithelial (HNE) cells using Ussing chamber experiment. Freshly excised nasal mucosae were harvested from patients who were classified into AR and non‐AR group to quantify mucus secretion from individual SMGs using bubble method. The expression of H1R, H2R, and H3R in human nasal turbinates was identified using in situ hybridization. Pig nasal and tracheal tissues were also investigated.ResultsHistamine induced a modest alteration of Isc in HNE cells with increasing intracellular calcium but no gland secretion. Pretreatment of IL‐4 augmented histamine response that was suppressed by TMEM16A inhibitor. The expression of H1R, H2R, and H3R was identified in human nasal epithelium by in situ hybridization. However, H1R or H2R was not noted in SMG. In pig airway tissues, histamine was a potent secretagogue that directly induced robust responses, indicating a species‐difference from human.ConclusionH1R agonist induces modest anion secretion under normal condition but the response was enhanced under IL‐4 stimulation that might be related to mucus hypersecretion in allergic rhinitis. We first elucidated histamine‐induced mucus secretion in synergy with IL‐4 through TMEM16A in human nasal epithelium.Support or Funding InformationSupported by grants NRF‐2013R1A1A 1010151 to H. J. Cho from the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology.
Characterizing TRPA1 and TRPV1 in Isolated Mouse Cardiac Myocytes
Authors: Andrei Spencer , Sinharoy Pritam , Bratz Ian N. , Damron Derek S 
Published: November 2023

RationaleTransient receptor potential channels of the ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) subtypes are extensively coexpressed in dorsal root ganglions and other heterologous systems; however, expression, localization and function of these ion channels within primary isolated adult mouse ventricular cardiomyocytes (MVCs) has not been established.ObjectiveSince the localization of TRPA1 and TRPV1 on cardiomyocytes has not been reported, we aimed to determine the expression patterns of the ion channels on MVCs and further studied channel‐specific agonistic effects on intracellular free calcium concentrations.Methods and ResultsWestern blot, immunocytochemistry and intracellular free calcium measurements were used to determine localization and function of the ion channels. Immunoblot analysis of MVCs revealed the presence of TRPA1 and TRPV1 at protein levels. Moreover, TRPA1 and TRPV1 were coexpressed at the Z‐discs, costameres and intercalated discs, which was demonstrated with immunocytochemistry using α‐actinin (Z‐disc marker) and vinculin (costamere/intercalated disc marker). Furthermore, both allyl isothiocyanate (AITC), a TRPA1 agonist, and capsaicin, a TRPV1 agonist, dose‐dependently increased intracellular calcium influx. Real‐time measurements of intracellular free calcium concentrations revealed that AITC and capsaicin elicited transient influxes of calcium on cardiomyocytes stained with Fura‐2AM.ConclusionsIn summary, these findings demonstrate functional TRPA1 and TRPV1 ion channels on MVCs.Support or Funding InformationThis work was supported by departmental funds and grants from NIH HL60571 to D.D.
Respiratory Adaptations to High‐Altitude Hypoxia in Deer Mice (Peromyscus maniculatus)
Authors: Ivy Catherine , Scott Graham 
Published: November 2023

The unremitting hypoxia at high altitudes challenges small endotherms to extract enough oxygen from the environment to survive, exercise, and generate enough heat for thermoregulation. We compared the control of breathing and pulmonary gas‐exchange between highland and lowland populations of deer mice to determine the physiological specializations important for living in high‐altitude hypoxia. Mice were acclimated to normoxia or hypobaric hypoxia (simulating hypoxia at ~4300 m elevation) for 4–5 months. The hypoxic ventilatory response (HVR) was measured using whole‐body and restraint plethysmography in response to step‐wise decreases in inspired O2 fraction. Hypoxia acclimation enhanced the HVR in lowlanders, such that total ventilation and arterial saturation were higher across a range of inspired O2. Hypoxia acclimation also made breathing pattern more effective in lowlanders, as reflected by higher tidal volumes and lower breathing frequencies at a given total ventilation, and it allowed lowlanders to maintain higher heart rates in deep hypoxia. In contrast, hypoxia acclimation had no effect on these traits in highlanders, who exhibited a fixed HVR and breathing pattern that was similar to hypoxia‐acclimated lowlanders, and highlanders also maintained higher arterial saturations in hypoxia than lowlanders. In contrast, hypoxia acclimation similarly enhanced the hypercapnic ventilatory response (measured in normoxia during step‐wise increases in inspired CO2, from 0% to 6%) in both populations. Therefore, ventilatory acclimatization to hypoxia is absent in highland deer mice, which have a fixed HVR that is effective for gas exchange, through a mechanism that appears independent of evolved changes in the plasticity of CO2 chemosensitivity.Support or Funding InformationSupported by NSERC of Canada.