bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced epithelial sodium channel signaling in endothelial cells promotes arterial stiffness
Authors: Jia Guanghong , Aroor Annayya R. , Hill Michael A. , Yan Yang , Habibi Javad , Manrique Camila , Lastra Guido , Whaley‐Connell Adam , Jaisser Frederic , Sowers James R. 
Published: June 2021

Excessive epithelial sodium channel (ENaC) activation in endothelial cells (EnNaC) has been reported to increase oxidative stress and induce inflammation with associated cardiovascular abnormalities. Our previous research has demonstrated that global inhibition of ENaC signaling with amiloride prevented Western diet (WD)‐induced inflammation, fibrosis, endothelial dysfunction and vascular stiffness in mesenteric and coronary resistance arteries and aorta. However, the role of endothelium specific EnNaC activation in the pathogenesis of vascular stiffness has not been investigated. We posited that EnNaC activation promotes obesity‐ and mineralocorticoid receptor‐mediated vascular stiffness. Accordingly, we sought to determine if endothelium specific EnNaC alpha subunit KO would prevent vascular inflammation, vascular stiffness, and impairment of endothelium dependent relaxation. Female EnNaC and wild‐type littermate mice were fed with WD high in refined carbohydrates and saturated fat or a standard chow diet for 12 weeks. In a separate study, female mice were treated with aldosterone (250 μg/kg/day) via osmotic minipumps for 3 weeks. Selective deletion of EnNaC significantly mitigated WD‐induced ex vivo endothelial stiffness measured by atomic force microscopy and – impaired aortic endothelium dependent relaxation in response to acetylcholine (10−9–10−4 mol/L). In addition to reducing mineralocorticoid receptor mediated endothelial stiffness, EnNaC KO also mitigated aldosterone‐induced inward Na+ currents and EnNaC activity in isolated endothelial cells. Furthermore, EnNaC KO attenuated aldosterone‐induced endothelium permeability, vascular inflammation, endothelial stiffness, as well as aortic endothelium dependent relaxation. These data indicate that endothelial specific EnNaC activation mediates vascular endothelium dysfunction and prompts vascular stiffening.Support or Funding InformationJRS received funding from NIH (R01 HL73101‐01A and R01 HL107910‐01) and the Veterans Affairs Merit System (0018). Dr. Jia received funding from American Diabetes Association (Innovative Basic Science Award #1‐17‐IBS‐201).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Treating the Network: Application of a Combination of Two microRNA Inhibitors to the Brainstem Prevents Hypertension Development in the Spontaneously Hypertensive Rat
Authors: Gorky Jon , DeCicco Danielle , Achanta Sirisha , Schwaber James , Vadigepalli Rajanikanth 
Published: June 2021

We here test the concept that a disturbed function or disease state may result not from a single cause but from small changes in a network that are collectively significant, and that treatment might aim to correct these collective changes. We recently showed that development of hypertension (HTN) in the spontaneously hypertensive rat (SHR) model of human essential hypertension is accompanied by small changes in gene expression within a gene regulatory network, and that these changes potentially result from changes in microRNA expression levels tracking the development of HTN. These results led to the hypothesis that preventing the change in microRNA levels might prevent the development of HTN. We propose that hypertension is an emergent property of a network that has been pushed out of a normotensive equilibrium into a compensatory, yet ultimately pathological, state. In this work, we show that small perturbations in the gene regulatory networks in the brainstem by selectively blocking two microRNAs is sufficient to prevent development of hypertension in the SHR model. Furthermore, this effect appears driven by only modest changes in the expression of rate‐limiting genes, some of which are targets of these miRNAs, suggesting that the combination of genes that are targeted in the network is responsible for the effect rather than just one gene or another. While the use of anti‐sense oligonucleotides to treat hypertension is itself novel, the demonstration that hypertension is an emergent property an underlying network suggests that a new treatment paradigm altogether is needed.Support or Funding InformationFunding Sources: T32 AA007463‐28; U01 HL133360; R01 HL111621; SPARC‐OT2‐OD023848This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Palmitic Acid Induces Extracellular Vesicle Release in Human Renal Proximal Tubule Epithelial Cells
Authors: Cobbs Alyssa , Muthusamy Saravanakumar , Chen Xiaoming , Sims Joya , Chatterjee Radhika , Zhao Xueying 
Published: June 2021

Lipotoxicity, an accumulation of intracellular lipid metabolites, has been proposed as an important pathogenic mechanism leading to kidney dysfunction in the context of metabolic disease. Palmitate, a predominant lipid derivative, can cause lipoapoptosis and the release of inflammatory extracellular vesicles (EVs) in hepatocytes. This study was aimed to investigate whether free fatty acid palmitate could increase EV release in renal tubular epithelial cells. A human proximal tubule epithelial cell line, HK‐2, was incubated with 1% bovine serum albumin (BSA), BSA‐conjugated palmitic acid (PA, 250 μM), BSA‐conjugated oleic acid (OA, 250 μM), or diluent (control) for 24 hours. The released EVs were isolated by ultracentrifugation, then characterized and quantified by immunoblot and nanoparticle‐tracking analysis (NTA). To examine the uptake of EVs by tubular cells, isolated EVs were further labelled and applied to HK‐2 cells. According to the NTA, the size distribution of HK‐2‐derived EVs was 30–200 nm with a similar mode size in all four groups. Interestingly, incubation of HK‐2 cells with 1%BSA alone significantly increased the release of EVs compared to the vehicle control. Moreover, BSA‐induced EV release was further increased by approximately two‐fold in the presence of PA, whereas EV production was not significantly changed by the addition of OA. PA (250 μM)‐enhanced EV release in HK‐2 is independent of cell apoptosis since apoptosis‐related proteins were not different between BSA and BSA‐PA groups. Both confocal microscopy and flow cytometry analyses confirmed that labeled lipid‐induced EVs were taken up by HK‐2 cells. Collectively, our results indicate that saturated fatty acid palmitate stimulates EV release from HK‐2 cells. Lipid‐induced EVs may serve as an untapped source to evaluate novel signaling pathways contributing to nephropathy progression.Support or Funding InformationNIH Diabetes and Digestive Kidney Disease Grant Number: R25DK1136559MSM Interdisciplinary Sleep/Clinical Cardiovascular Research Training Program (T32)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Reno‐protective effects of everolimus vs. bone marrow‐derived stem cells in rat model of glomerulonephritis
Authors: Zedan Mohamed M. , Mansour Ahmed K. , Bakr Ashraf A. , Sobh Mohamed A. , Baban Babak , Elmarakby Ahmed A. 
Published: June 2021

Glomerular endothelial injury and effectiveness of glomerular endothelial repair play a crucial role in the progression of renal disease. Recent studies suggest that progenitor cells could be an effective tool to enhance glomerular endothelial repair. We hypothesize that bone marrow‐derived stem cells (BMDSCs) attenuate experimental glomerulonephritis by restoring glomerular endothelial barrier function through improving the repair process. Anti‐Thy1 glomerulonephritis was induced in male Sprague Dawley rats by a single injection of an antibody against Thy1, which is mainly expressed on glomerular mesangial cells. Rats were then treated with the immunosuppressant everolimus daily or injected with bone marrow‐derived endothelial progenitor cells after one week of injection of anti‐Thy1 (n=6–7). After nine days of injection of anti‐Thy1, glomerular albumin permeability and albuminuria were significantly increased when compared to control group (P< 0.05). Everolimus was superior to BMDSCs in attenuating the increase in glomerular albumin permeability and albuminuria in anti‐Thy1 injected rats. Only everolimus treatment significantly reduced the markers of glomerular injury, nephrinuria and podocalyxin excretion levels, in anti‐Thy1 injected rats (nephrinuria was 0.4± 0.1 vs. 0.8± 0.02 mg/day and podocalyxin excretion was 7± 1 vs. 11± 1 μg/day in everolimus treated vs. untreated anti‐Thy1 injected rats, P< 0.05). Injection of Anti‐Thy1 induced hypercellular glomeruli with loss of Bowman space and variable number of lymphocyte when compared to control. Everolimus treatment partially restored Anti‐Thy1 renal pathophysiological changes whereas BMDSCs had no significant effect. Everolimus treatment also reduced the number of renal T cells and macrophage and lowered IL‐17 and caspase 3 expression levels in the anti‐Thy1 injected rat. These data suggest that everolimus early treatment preserves glomerular endothelial barrier function in anti‐Thy1‐induced glomerulonephritis via anti‐apoptotic and anti‐inflammatory mechanisms.Support or Funding InformationThis work was supported by American Heart Association scientist development grant and intramural grant from Augusta University To Dr. Ahmed A. ElmarakbyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
In‐Common And Unique Gene Expression Patterns In Acute Kidney Injury Of Different Aetiology Implicates MYC‐Pathway In Damage Progression
Authors: Hultström Michael , Jönsson Sofia , Agic Mediha Becirovic 
Published: June 2021

Acute kidney injury (AKI) is a syndrome that may be caused by a number of different diseases. The existence of renal biomarkers that work for many kinds of AKI indicate that there may be an underlying common molecular pathway by which AKI causes progression of chronic kidney disease (CKD). By comparing six high‐quality microarray studies of renal gene expression after AKI in models of different diseases (gram negative sepsis, gram positive sepsis, ischemia‐reperfusion, malignant hypertension, rhabdomyolysis and cisplatin toxicity) a total of 5254 genes were differentially expressed in at least one of the AKI models. 66% we only found in one of the models showing that there are unique features to AKI depending on the precipitating disease. There were in‐common features in the form of four genes that were differentially expressed in all six models, 49 in at least five, and 215 were in‐common between at least four models. The in‐common genes included many of the known biomarkers and damage associated molecular patterns (DAMPs) indicating that these are an integral part of the molecular response to AKI of any etiology. The most connected gene in the network was MYC, which suggests that it may be a central regulator of renal gene expression in AKI. The outlining of this molecular network may be useful for understanding the progression from AKI to chronic kidney disease, but also for identifying new potential biomarkers.Support or Funding InformationThe study was supported by grants from the Swedish Heart and Lung Foundation, and the Swedish Society for Medical Research.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Metabolic acidosis inhibits AMPK function in kidney cells
Authors: Pastor‐Soler Nuria M. , Rajani Roshan , Mancino Valeria , Omi Kazuhiro , Hallows Kenneth R. 
Published: June 2021

The metabolic sensor AMP‐activated protein kinase (AMPK) is stimulated by cellular metabolic depletion. We have shown that AMPK activation inhibits kidney membrane transport proteins. AMPK‐activated processes protect kidney cells from further metabolic depletion and damage. AMPK is tightly regulated, and its pharmacological activation can protect kidneys from superimposed injury, such as acute kidney injury (AKI). Conversely, AMPK is inhibited in chronic kidney disease (CKD). Therefore, pharmacologic AMPK activators are proposed as therapies to slow CKD progression. However, the mechanisms by which AMPK may promote kidney survival are unclear. CKD results in metabolic acidosis (MA) due to the inability of kidneys to excrete non‐volatile acid. MA, if untreated, has severe health sequelae such as worsening of kidney function. We hypothesized that there is cross‐talk between acid‐base status and AMPK signaling, and that dysregulation of AMPK function by MA disrupts kidney regeneration in the setting of CKD. We used kidney epithelial cell lines in culture and adult male C57BL/6 mice (WT) and AMPKβ1‐KO mice for our experiments. Cells were exposed to media at either pH 7.3–7.4 (control) or 6.9–7.0 (acidic) for 3 d ± an AMPK activator (last 16 h). We found that, as compared to cells grown at pH 7.4, kidney cells grown in acidic media have reduced baseline AMPK activity and blunted pharmacologic AMPK activation. We then evaluated changes in AMPK function in WT mice fed a normal diet vs. WT mice given 1.5% saccharin ± 0.28 M NH4Cl in drinking water for 2 mo. To evaluate the AMPK pathway in kidney tissue, we examined levels of phosphorylation of acetyl CoA carboxylase (pACC) by immunoblot. Mice on the acidogenic diet developed MA without significant weight loss compared to mice on the control diet (blood pH 7.2 vs 7.3 ± 0.01). In mice after UNX, the superimposed MA induced a statistically significant decrease in pACC, compared to mice with UNX on a control diet. We also evaluated differences in BUN in WT vs. AMPKβ1‐KO mice 3 mos. after sham surgery or UNX, a model for reduced kidney mass. Both WT and KO mice post‐UNX had significant worsening of kidney function (higher BUN) compared to sham‐operated mice of the same genotype. However, we did not observe any significant differences in BUN between WT and KO mice following sham or UNX. Our results point to worsening in kidney function post‐UNX and to a direct inhibition of the AMPK pathway in the setting of reduced kidney mass and MA. This AMPK inhibition may be detrimental to kidney regeneration in these settings.Support or Funding InformationKeck School of Medicine of USC; USC/UKRO Kidney Research CenterThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Aerobic exercise training prevents renal lipotoxicity associated with insulin resistance in mice
Authors: Muller Cynthia Rodrigues , Américo Anna Laura Viacava , Pereira Renata Oliveira , Matsumoto Alice Jackeline , Fiorino Patricia , Evangelista Fabiana Sant'Anna 
Published: June 2021

Insulin resistance is associated with lipid accumulation in the kidney which leads to lipotoxicity, inflammation and renal damage. We investigated the potential of aerobic exercise training (AET) to prevent renal lipotoxicity in mice with diet‐induced insulin resistance. Adult male C57BL6/J mice were assigned into chow‐fed controls (C, n=5), cafeteria diet (CAF, n=5), chow‐fed trained (T, n=5), and cafeteria diet plus trained (CAFT, n=5). The standard chow diet contained 4% of kilocalories from fat, 55% from carbohydrate and 22% from proteins (Nuvilab®, Paraná, Brazil). The cafeteria diet contained 18.7% of kilocalories from fat, 56% from carbohydrate and 14.8% from proteins. AET was performed simultaneously with diet and consisted of 8‐wk running session of 60 min at 60% of maximal speed, 5 days/wk. Experimental procedures were approved by Ethics Committee from Faculty of Medicine of University of São Paulo (#18/2014). Cafeteria diet induced insulin resistance in CAF group compared to C group during insulin tolerance test, which was counteracted by AET in CAFT group. Histological analysis showed that CAF group increased intra‐renal lipid deposition (4.12 ± 0.48 %/area) compared to C group (1.70 ± 0.55 %/area), and that AET was able to prevent this increase in CAFT group (2.11 ± 0.51 %/area). Immunohistochemistry measurement revealed no difference in the expression of TGF‐β, Collagen IV and fibronectin. In the western blot analysis, CAF (2.12 ± 0.7 % vs. C) and CAFT (2.74 ± 0.5 % vs. C) groups showed a tendency (p=0.07) to increase the expression of IL‐6 compared to C group (1 ± 0.07 % vs. C). Furthermore, there was an increase in TNF‐α expression in the CAF (1.72 ± 0.05 % vs. C) and CAFT (1.46 ± 0.02 % vs. C) compared to C group. In conclusion, our results showed that cafeteria diet was able to induce renal lipotoxicity associated with insulin resistance and AET was efficient to prevent this damage independent of inflammatory profile changes.Support or Funding InformationFinancial Support: FAPESP # 2015/04948‐4.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
APOL1‐like gene insertion associated with increased blood pressure in the African Green Monkey
Authors: Rhoads Megan K. , Weaver Chelsea C. , Osborn Jeffrey L. 
Published: June 2021

End stage renal disease affects 660,000 adults in the United States and disproportionally affects people of African descent. Studies have identified two alleles in the apolipoprotein L1 (APOL1) gene that are expressed in high frequency in African‐ American populations and may contribute to a 4–5 fold increased incidence of end stage renal disease (ESRD) in this demographic. The African Green Monkey (AGM, Chlorocebus aethiops sabaeus) is an Old World monkey species that develops spontaneous hypertension and is indigenous from the regions of Africa from which the two APOL1 alleles are known to exist in humans. We have recently reported that the AGM exhibits renal glomerular and vascular pathologies in conjunction with significant spontaneous hypertension. Furthermore, we report elsewhere that this spontaneous hypertension in the AGM is associated with significant proteinuria even when the animals are prehypertensive; suggesting that altered renal glomerular and/or tubular function in regulating protein excretion may precede the development of spontaneous hypertension in the AGM. This study hypothesized that gene sequence changes in the APOL1‐like gene region may be expressed in the AGM and are associated with increased blood pressure and altered renal function, similar to the human population. DNA was extracted from whole blood or frozen tissue in 44 adult males and the APOL1‐like gene region was sequenced. Bioinformatic analysis identified a 6 nucleotide insertion at base 329 that was positively associated with increased systolic blood pressures (p<0.05). Within the cohort, 2 animals were found to be homozygous for the sequenced insertion (mean ± SE SBP: 206.6±0.1 mmHg), 10 animals were heterozygous (SBP: 136.6±14.6 mmHg), and 32 animals did not have the insertion (SBP: 135.7± 7 mmHg). This data suggests that the insertion in the APOL1‐like gene may affect blood pressure regulation (and/or kidney function) in the AGM, providing a novel and exciting nonhuman primate model to study the progression of ESRD in a non‐human primate species that expresses variations within the APOL1 gene, which is known to correlate with early onset ESRD in African Americans. Ongoing studies are focused on increasing the AGM cohort size, adding normotensive and hypertensive females to the sequenced cohort, and collection of renal functional data on all sequenced animals to determine the effect of the APOL1‐like insertion on kidney function and blood pressure regulation in the AGM.Support or Funding InformationFunding provided by Biomedical Science Research Group, LLC.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
EXERCISE TRAINING DOES NOT ALTER PROSTATE TUMOR CELL GROWTH IN RAT SERUM OR PROSTATE CONDITIONED MEDIA
Authors: Ardery Savannah , Horn Andrew , Opoku‐Acheampong Alexander , Baumfalk Dryden , Behnke Brad 
Published: June 2021

Prostate cancer is the second leading cause of cancer‐related deaths in men in the United States with tumor aggressiveness (i.e., metastatic potential, ability to infiltrate surrounding tissue) being negatively related to patient prognosis and survivorship. Although there is promising data that exercise training may alter the tumor microenvironment to facilitate conventional treatment, the effects of exercise on prostate cancer growth is equivocal. Key facets of tumor aggressiveness include the ability of the tumor to spread (infiltrate) to surrounding tissue as well as for tumor cells to survive in the general circulation. Thus, we hypothesize that exercise training changes the tumor growth‐supporting environment of prostate tissue as well as blood serum to slow the migration of prostate cancer cells. The effects of exercise training on serum and prostate conditioned media (PCM) upon migration of prostate cancer cells in vitro was evaluated in this study. Blood serum was collected, and conditioned media was prepared from the prostates of sedentary (n = 10) and moderate‐intensity exercise‐trained (treadmill exercise for 5 days/week at 15 m/min, 15° incline for 60 min/day for 10–11 weeks; n = 10) male Copenhagen rats (~6 mo old). Cell migration of Dunning R‐3327 AT‐1 prostate cancer cells was determined via cell exclusion zone assay using serum, serum and fetal bovine serum (FBS), and prostate conditioned media from both rat groups for 24–96 hours. There was no significant difference in cell migration between serum alone, serum and FBS, or PCM from exercise‐trained rats compared to sedentary control, respectively, at any time point (e.g., PCM @96 hrs, Exercised Trained 514 ± 35 vs. Sedentary 508 ± 37 cells/field, p > 0.05). Although there is evidence suggesting exercise training can mitigate the pro tumor growth environment of adipose tissue, our data does not support an effect of exercise training on the tumor growth‐supporting environment of the prostate from in vitro measures. Future studies, using a more physiological oxygen range for in vitro tumor cell growth and/or conducted in vivo, are needed to corroborate or refute these initial results.Support or Funding InformationAmerican Cancer Society RSG‐14‐150‐1‐CCE (BJB)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.