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Scientific Reports Apr 2024P2X7 receptors mediate immune and endothelial cell responses to extracellular ATP. Acute pharmacological blockade increases renal blood flow and filtration rate,...
P2X7 receptors mediate immune and endothelial cell responses to extracellular ATP. Acute pharmacological blockade increases renal blood flow and filtration rate, suggesting that receptor activation promotes tonic vasoconstriction. P2X7 expression is increased in kidney disease and blockade/knockout is renoprotective. We generated a P2X7 knockout rat on F344 background, hypothesising enhanced renal blood flow and protection from angiotensin-II-induced renal injury. CRISPR/Cas9 introduced an early stop codon into exon 2 of P2rx7, abolishing P2X7 protein in kidney and reducing P2rx7 mRNA abundance by ~ 60% in bone-marrow derived macrophages. The M1 polarisation response to lipopolysaccharide was unaffected but P2X7 receptor knockout suppressed ATP-induced IL-1β release. In male knockout rats, acetylcholine-induced dilation of the renal artery ex vivo was diminished but not the response to nitroprusside. Renal function in male and female knockout rats was not different from wild-type. Finally, in male rats infused with angiotensin-II for 6 weeks, P2X7 knockout did not reduce albuminuria, tubular injury, renal macrophage accrual, and renal perivascular fibrosis. Contrary to our hypothesis, global P2X7 knockout had no impact on in vivo renal hemodynamics. Our study does not indicate a major role for P2X7 receptor activation in renal vascular injury.
Topics: Animals; Receptors, Purinergic P2X7; Angiotensin II; Male; Rats; Kidney; Rats, Inbred F344; Female; Gene Knockout Techniques; Macrophages; Acute Kidney Injury
PubMed: 38670993
DOI: 10.1038/s41598-024-59635-x -
BMC Nephrology Apr 2024Contrast-induced acute kidney injury (CI-AKI) has become the third leading cause of hospital-acquired AKI, which seriously threatens the health of patients. To date, the... (Review)
Review
Contrast-induced acute kidney injury (CI-AKI) has become the third leading cause of hospital-acquired AKI, which seriously threatens the health of patients. To date, the precise pathogenesis of CI-AKI has remained not clear and may be related to the direct cytotoxicity, hypoxia and ischemia of medulla, and oxidative stress caused by iodine contrast medium, which have diverse physicochemical properties, including cytotoxicity, permeability and viscosity. The latest research shows that microRNAs (miRNAs) are also involved in apoptosis, pyroptosis, and autophagy which caused by iodine contrast medium (ICM), which may be implicated in the pathogenesis of CI-AKI. Unfortunately, effective therapy of CI-AKI is very limited at present. Therefore, effective prevention of CI-AKI is of great significance, and several preventive options, including hydration, antagonistic vasoconstriction, and antioxidant drugs, have been developed. Here, we review current knowledge about the features of iodine contrast medium, the definition, pathogenesis, molecular mechanism, risk factors, prevention and treatment of CI-AKI.
Topics: Contrast Media; Humans; Acute Kidney Injury; Risk Factors; Antioxidants; MicroRNAs; Fluid Therapy; Apoptosis; Autophagy; Pyroptosis; Oxidative Stress; Iodine
PubMed: 38649939
DOI: 10.1186/s12882-024-03570-6 -
Advances in Kidney Disease and Health Mar 2024Acute kidney injury is a common complication of decompensated cirrhosis, frequently requires hospitalization, and carries a high short-term mortality. This population... (Review)
Review
Acute kidney injury is a common complication of decompensated cirrhosis, frequently requires hospitalization, and carries a high short-term mortality. This population experiences several characteristic types of acute kidney injury: hypovolemic-mediated (prerenal), ischemic/nephrotoxic-mediated (acute-tubular necrosis), and hepatorenal syndrome. Prerenal acute kidney injury is treated with volume resuscitation. Acute-tubular necrosis is treated by optimizing perfusion pressure and discontinuing the offending agent. Hepatorenal syndrome, a unique physiology of decreased effective arterial circulation leading to renal vasoconstriction and ultimately acute kidney injury, is treated with plasma expansion with albumin and splanchnic vasoconstrictors such as terlipressin or norepinephrine. Common acute stressors such as bleeding, infection, and volume depletion often contribute to multifactorial acute kidney injury. Even with optimal medical management, many clinicians are faced with the challenge of initiating renal replacement therapy in these patients. This article reviews the epidemiology, indications, and complex considerations of renal replacement therapy for acute kidney injury in decompensated cirrhosis.
Topics: Humans; Liver Cirrhosis; Acute Kidney Injury; Renal Replacement Therapy; Hepatorenal Syndrome
PubMed: 38649217
DOI: 10.1053/j.akdh.2024.01.003 -
Frontiers in Public Health 2024Previous physiology-driven pain studies focused on examining the presence or intensity of physical pain. However, people experience various types of pain, including...
BACKGROUND
Previous physiology-driven pain studies focused on examining the presence or intensity of physical pain. However, people experience various types of pain, including social pain, which induces negative mood; emotional distress; and neural activities associated with physical pain. In particular, comparison of autonomic nervous system (ANS) responses between social and physical pain in healthy adults has not been well demonstrated.
METHODS
We explored the ANS responses induced by two types of pain-social pain, associated with a loss of social ties; and physical pain, caused by a pressure cuff-based on multimodal physiological signals. Seventy-three healthy individuals (46 women; mean age = 20.67 ± 3.27 years) participated. Behavioral responses were assessed to determine their sensitivity to pain stimuli. Electrocardiogram, electrodermal activity, photoplethysmogram, respiration, and finger temperature (FT) were measured, and 12 features were extracted from these signals.
RESULTS
Social pain induced increased heart rate (HR) and skin conductance (SC) and decreased blood volume pulse (BVP), pulse transit time (PTT), respiration rate (RR), and FT, suggesting a heterogeneous pattern of sympathetic-parasympathetic coactivation. Moreover, physical pain induced increased heart rate variability (HRV) and SC, decreased BVP and PTT, and resulted in no change in FT, indicating sympathetic-adrenal-medullary activation and peripheral vasoconstriction.
CONCLUSION
These results suggest that changes in HR, HRV indices, RR, and FT can serve as markers for differentiating physiological responses to social and physical pain stimuli.
Topics: Adult; Humans; Female; Adolescent; Young Adult; Healthy Volunteers; Autonomic Nervous System; Pain; Emotions; Electrocardiography
PubMed: 38638471
DOI: 10.3389/fpubh.2024.1387056 -
Actas Espanolas de Psiquiatria Apr 2024Vascular dementia (VaD) is a prevalent neurodegenerative disease characterized by cognitive impairment due to cerebrovascular factors, affecting a significant portion of...
BACKGROUND
Vascular dementia (VaD) is a prevalent neurodegenerative disease characterized by cognitive impairment due to cerebrovascular factors, affecting a significant portion of the aging population and highlighting the critical need to understand specific targets and mechanisms for effective prevention and treatment strategies. We aimed to identify pathways and crucial genes involved in the progression of VaD through bioinformatics analysis and subsequently validate these findings.
METHODS
We conducted differential expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and Protein-Protein Interaction (PPI) analysis. We utilized pheochromocytoma 12 (PC12) cells to create an in vitro oxygen-glucose deprivation (OGD) model. We investigated the impact of overexpression and interference of adrenoceptor alpha 1D (ADRA1D) on OGD PC12 cells using TdT-mediated dUTP nick-end labeling (TUNEL), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot (WB), and Fluo-3-pentaacetoxymethyl ester (Fluo-3 AM) analysis.
RESULTS
We found 187 differentially expressed genes (DEGs) in the red module that were strongly associated with VaD and were primarily enriched in vasoconstriction, G protein-coupled amine receptor activity, and neuroactive ligand-receptor interaction, mitogen-activated protein kinase (MAPK) signaling pathway, and cell adhesion. Among these pathways, we identified ADRA1D as a gene shared by vasoconstriction, G protein-coupled amine receptor activity, and neuroactive ligand-receptor interaction. The TUNEL assay revealed a significant decrease in PC12 cell apoptosis with ADRA1D overexpression (p < 0.01) and a significant increase in apoptosis upon silencing ADRA1D (p < 0.01). RT-qPCR and WB analysis revealed elevated ADRA1D expression (p < 0.001) and decreased phospholipase C beta (PLCβ) and inositol 1,4,5-trisphosphate receptor (IP3R) expression (p < 0.05) with ADRA1D overexpression. Moreover, the Fluo-3 AM assessment indicated significantly lower intracellular Ca2+ levels with ADRA1D overexpression (p < 0.001). Conversely, interference with ADRA1D yielded opposite results.
CONCLUSION
Our study provides a new perspective on the pathogenic mechanisms of VaD and potential avenues for therapeutic intervention. The results highlight the role of ADRA1D in modulating cellular responses to OGD and VaD, suggesting its potential as a target for VaD treatment.
Topics: Animals; Rats; Humans; Aged; Dementia, Vascular; Ligands; Neurodegenerative Diseases; Amines; Signal Transduction; GTP-Binding Proteins; Aniline Compounds; Xanthenes
PubMed: 38622006
DOI: 10.62641/aep.v52i2.1601 -
Cureus Mar 2024Retinopathy of prematurity (ROP) is a rare proliferative ocular condition that can happen in premature babies (born preterm <36 weeks) or who weigh <1.5 kg at birth... (Review)
Review
Retinopathy of prematurity (ROP) is a rare proliferative ocular condition that can happen in premature babies (born preterm <36 weeks) or who weigh <1.5 kg at birth (low birth weight babies). ROP is a major cause of childhood blindness. It is a premature disease since retina vascularization is completed only by 40 weeks of life. The survivability for preterm infants has increased owing to recent improvements in neonatal care during the past decade. As a result, the prevalence of ROP has risen concurrently. The abnormal development of blood vessels in the retina is the cause of this illness. It occurs in two phases, phases 1 and 2. Most preterm infants weighing <1.5 kg need supplemental oxygen for respiratory support at birth. This leads to the initiation of phase 1 (vasoconstrictive phase). Phase 1 is characterized by loss of maternal-fetal connection and hyperoxia due to supplemental oxygen therapy. Oxygen's vasoconstrictive and obliterative action is primarily observed in developing retinal vessels. The inhibition of vascular endothelial growth factor follows from this. Phase 2 (vasoproliferative phase) shows the dilatation and tortuosity of the bigger existing vessels together with neovascularization and proliferation of new vessels into the vitreous when the baby is shifted from respiratory support to room air. Now, the retina gets hypoxic, where the retina becomes more metabolically active but is yet minimally vascularized, leading to VEGF-induced vasoproliferation, which might result in retinal detachment. Patients with ROP face the danger of loss of vision. If correct and quick treatment is not provided, they might land into permanent blindness. Yet, ROP remains one of the most preventable causes of childhood blindness worldwide. Blindness caused by ROP can only be avoided if screening programs are readily available, pertinent, and appropriate. The initial stage in the therapy of ROP is the screening of premature neonates. Timely screening and management for ROP is important to avoid this irreversible loss of vision. The treatment is based on the severity of the disease. Management may include pharmacological interventions like intravitreal and anti-vascular endothelial growth factor and non-pharmacological interventions like laser surgery, vitrectomy, and scleral buckling. We conducted a thorough literature search of studies on pathogenesis, risk factors, classification, and various treatment options for retinopathy of prematurity in infants, using a mixture of pertinent keywords. Only those studies published in peer-reviewed journals between 2010 and 2023 and written in English were included. Duplicate studies, unavailable in full-text for free, or studies unrelated to our subject matter were excluded. After thoroughly evaluating the selected studies, the results were synthesized and presented narratively. This article sheds light on the pathogenesis of ROP, particularly its relation to oxygen use, screening, and potential therapeutic management of ROP. Today advances in screening techniques have improved the outcomes for infants with ROP. Still, ongoing research is needed to optimize management strategies and reduce the burden of this condition.
PubMed: 38618439
DOI: 10.7759/cureus.56168 -
Pulmonary Circulation Apr 2024Pulmonary arterial hypertension (PAH) is driven by pathologies associated with increased metabolism such as pulmonary revascularization, vasoconstriction and smooth...
Pulmonary arterial hypertension (PAH) is driven by pathologies associated with increased metabolism such as pulmonary revascularization, vasoconstriction and smooth muscle cell proliferation in pulmonary artery wall. 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) is an imaging technique sensitive to glucose metabolism and might be considered as a non-invasive method for diagnosis due to significant role of inflammation in idiopathic pulmonary artery hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH). The present study aimed to investigate the role of PET/CT imaging of patients with IPAH and CTEPH as an alternative diagnosis method. Demographic characteristics, FDG uptake in lungs, pulmonary artery and right ventricle (RV) of 17 patients (10 IPAH, 7 CTEPH), and 30 controls were evaluated. PET scanning, 6-min walk test, pro-BNP level, right heart catheterization of patients were performed both at the onsert and after 6-month PAH specific treatment. IPAH and CTEPH patients had significantly higher left lung FDG ( = 0.006), right lung FDG ( = 0.004), right atrial (RA) FDG ( < 0.001) and RV FDG ( < 0.001) uptakes than controls. Positive correlation was detected between the RV FDG uptake and the mean pulmonary artery pressure (mPAP) ( = 0.7, = 0.012) and between the RA FDG uptake and the right atrial pressure (RAP) ( = 0.5, = 0.02). Increased RV FDG and RA FDG uptakes predicts the presence of pulmonary hypertension and correlates with mPAP and RAP, respectively, which are important indicators in the prognosis of PAH. Further studies are required whether FDG PET imaging can be used to diagnose or predict the prognosis of pulmonary hypertension.
PubMed: 38618292
DOI: 10.1002/pul2.12363 -
Placenta Jun 2024Placenta-associated pregnancy complications, including pre-eclampsia (PE) and intrauterine growth restriction (IUGR) are conditions postulated to originate from initial...
INTRODUCTION
Placenta-associated pregnancy complications, including pre-eclampsia (PE) and intrauterine growth restriction (IUGR) are conditions postulated to originate from initial failure of placentation, leading to clinical sequelae indicative of endothelial dysfunction. Vascular smooth muscle aberrations have also been implicated in the pathogenesis of both disorders via smooth muscle contractility and relaxation mediated by Myosin Light Chain Phosphatase (MLCP) and the oppositional contractile action of Myosin Light Chain Kinase. PPP1R12A is a constituent part of the MLCP complex responsible for dephosphorylation of myosin fibrils. We hypothesize that alternative splicing of micro-exons result in isoforms lacking the functional leucine zipper (LZ) domain which may give those cells expressing these alternative transcripts a tendency towards contraction and vasoconstriction.
METHODS
Expression was determined by qRT-PCR. Epigenetic profiling consisted of bisulphite-based DNA methylation analysis and ChIP for underlying histone modifications.
RESULTS
We identified several novel transcripts with alternative micro-exon inclusion that would produce LZ- PPP1R12A protein. qRT-PCR revealed some isoforms, including the PPP1R12A canonical transcript, are differentially expressed in placenta biopsies from PE and IUGR samples compared to uncomplicated pregnancies.
DISCUSSION
We propose that upregulation of PPP1R12A expression in complicated pregnancies may be due to enhanced promoter activity leading to increased transcription as a response to physiological stress in the placenta, which we show is independent of promoter DNA methylation.
Topics: Female; Humans; Pregnancy; Alternative Splicing; Fetal Growth Retardation; Placenta; Myosin-Light-Chain Phosphatase; Pre-Eclampsia; Exons; DNA Methylation; Adult
PubMed: 38615553
DOI: 10.1016/j.placenta.2024.04.005 -
International Journal of Molecular... Mar 2024Both the endothelial (eNOS) and the neuronal (nNOS) isoforms of constitutive Nitric Oxide Synthase have been implicated in vascular dysfunctions in Alzheimer's disease...
Both the endothelial (eNOS) and the neuronal (nNOS) isoforms of constitutive Nitric Oxide Synthase have been implicated in vascular dysfunctions in Alzheimer's disease (AD). We aimed to explore the relationship between amyloid pathology and NO dynamics by comparing the cerebrospinal fluid (CSF) levels of nNOS and eNOS of 8 healthy controls (HC) and 27 patients with a clinical diagnosis of Alzheimer's disease and isolated CSF amyloid changes, stratified according to APOE ε genotype (APOE ε3 = 13, APOE ε4 = 14). Moreover, we explored the associations between NOS isoforms, CSF AD biomarkers, age, sex, cognitive decline, and blood-brain barrier permeability. In our cohort, both eNOS and nNOS levels were increased in APOE ε3 with respect to HC and APOE ε4. CSF eNOS inversely correlated with CSF Amyloid-β42 selectively in carriers of APOE ε3; CSF nNOS was negatively associated with age and CSF p-tau only in the APOE ε4 subgroup. Increased eNOS could represent compensative vasodilation to face progressive Aβ-induced vasoconstriction in APOE ε3, while nNOS could represent the activation of NO-mediated plasticity strategies in the same group. Our results confirm previous findings that the APOE genotype is linked with different vascular responses to AD pathology.
Topics: Humans; Alzheimer Disease; Apolipoprotein E3; Apolipoprotein E4; Amyloidogenic Proteins; Genotype; Protein Isoforms
PubMed: 38612537
DOI: 10.3390/ijms25073725 -
Diagnostics (Basel, Switzerland) Mar 2024This study aimed to precisely investigate the effects of intensive physical exercise on retinal microvascular regulation in healthy volunteers through adaptive optics...
This study aimed to precisely investigate the effects of intensive physical exercise on retinal microvascular regulation in healthy volunteers through adaptive optics retinal camera (AO) measurement. We included healthy volunteers (11 men and 14 women) aged 20.6 ± 0.9. The heart rate (HR) and systolic and diastolic blood pressures (SBP, DBP) were recorded before and after a submaximal physical exertion of continuously riding a training ergometer. The superior temporal retinal artery measurements were captured using the AO-rtx1 (Imagine Eyes, Orsay, France) without pupil dilation. We compared measures of vessel diameter (VD), lumen diameter (LD), two walls (Wall 1, 2), wall-to-lumen ratio (WLR), and wall cross-sectional analysis (WCSA) before and immediately after the cessation of exercise. Cardiovascular parameter results: After exercise, SBP, DBP, and HR changed significantly from 130.2 ± 13.2 to 159.7 ± 15.6 mm Hg, 81.2 ± 6.3 to 77.1 ± 8.2 mm Hg, and 80.8 ± 16.1 to 175.0 ± 6.2 bpm, respectively ( < 0.002). Retinal microcirculation analysis showed no significant decrease in LD, Wall 1 after exercise: from 96.0 ± 6.8 to 94.9 ± 6.7 ( = 0.258), from 11.0 ± 1.5 to 10.4 ± 1.5 ( = 0.107), respectively, and significant reduction in VD from 118.5 ± 8.3 to 115.9 ± 8.3 ( = 0.047), Wall 2 from 11.5 ± 1.0 to 10.7 ± 1.3 ( = 0.017), WLR from 0.234 ± 0.02 to 0.222 ± 0.010 ( = 0.046), WCSA from 3802.8 ± 577.6 to 3512.3 ± 535.3 ( = 0.016). The AO is a promising technique for investigating the effects of exercise on microcirculation, allowing for the tracking of changes throughout the observation. Intensive dynamic physical exertion increases blood pressure and heart rate and causes the vasoconstriction of small retinal arterioles due to the autoregulation mechanism.
PubMed: 38611623
DOI: 10.3390/diagnostics14070710