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Extravasation of Blood and Blood Toxicity Drives Tubular Injury from RBC Trapping in Ischemic AKI. 血液外渗和血液毒性驱动缺血性AKI中红细胞捕获引起的肾小管损伤。
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2023-09-04 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad050
Sarah R McLarnon, Chloe Johnson, Jingping Sun, Qingqing Wei, Gabor Csanyi, Phillip O'Herron, Brendan Marshall, Priya Giddens, Jennifer C Sullivan, Amanda Barrett, Paul M O'Connor

Red blood cell (RBC) trapping is common in ischemic acute kidney injury (AKI) and presents as densely packed RBCs that accumulate within and engorge the kidney medullary circulation. In this study, we tested the hypothesis that "RBC trapping directly promotes tubular injury independent of extending ischemia time." Studies were performed on rats. Red blood cell congestion and tubular injury were compared between renal arterial clamping, venous clamping, and venous clamping of blood-free kidneys. Vessels were occluded for either 15 or 45 min with and without reperfusion. We found that RBC trapping in the medullary capillaries occurred rapidly following reperfusion from renal arterial clamping and that this was associated with extravasation of blood from congested vessels, uptake of blood proteins by the tubules, and marked tubular injury. To determine if this injury was due to blood toxicity or an extension of ischemia time, we compared renal venous and arterial clamping without reperfusion. Venous clamping resulted in RBC trapping and marked tubular injury within 45 min of ischemia. Conversely, despite the same ischemia time, RBC trapping and tubular injury were minimal following arterial clamping without reperfusion. Confirming the role of blood toward tubular injury, injury was markedly reduced in blood-free kidneys with venous clamping. Our data demonstrate that RBC trapping results in the rapid extravasation and uptake of blood components by tubular cells, causing toxic tubular injury. Tubular toxicity from extravasation of blood following RBC trapping appears to be a major component of tubular injury in ischemic AKI, which has not previously been recognized.

红细胞(RBC)捕获在缺血性急性肾损伤(AKI)中很常见,表现为密集的RBC,积聚在肾髓质循环中并使其充血。在这项研究中,我们检验了“红细胞捕获直接促进肾小管损伤,而不依赖于延长缺血时间”的假设。比较无血肾的肾动脉夹闭、静脉夹闭和静脉夹闭之间的红细胞充血和肾小管损伤。血管闭塞15或45 min再灌注和不灌注。我们发现,肾动脉夹闭再灌注后,髓质毛细血管中的红细胞捕获迅速发生,这与充血血管中的血液外渗、肾小管对血液蛋白的摄取以及明显的肾小管损伤有关。为了确定这种损伤是由于血液毒性还是缺血时间延长,我们比较了未再灌注的肾静脉和动脉夹闭。静脉夹闭导致红细胞滞留,并在45分钟内造成明显的肾小管损伤 缺血分钟。相反,尽管缺血时间相同,但动脉阻断后无再灌注,红细胞捕获和肾小管损伤最小。证实了血液对肾小管损伤的作用,通过静脉夹闭,无血肾脏的损伤显著减少。我们的数据表明,红细胞捕获导致肾小管细胞快速外渗和吸收血液成分,导致毒性肾小管损伤。红细胞捕获后血液外渗引起的肾小管毒性似乎是缺血性AKI肾小管损伤的主要组成部分,这一点以前尚未得到认识。
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引用次数: 0
Intermittent Hypoxia and Respiratory Plasticity: The Good, the Bad, and the Unknown. 间歇性缺氧与呼吸可塑性:好的、坏的和未知的。
Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-04 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad045
Andrew William Sheel
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引用次数: 0
Beliefs Made It into Science: Believe It or Not. 信仰使它成为科学:信不信由你。
Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-02 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad049
Rüdiger J Seitz, Raymond F Paloutzian
© t n c long-standing discourse in philosophy dating back to antiqity concerns the nature of beliefs and believing. Until today, he notion “belief” has been of importance in philosophy, as evient from the definition of knowledge as justified true belief. In act, the notion “belief” was understood as a topic of resear c h ocused on people’s attitudes or opinions about what was or was ot true in the w orld. 1 Resear c h questions were summarized by he formula “ S A that P ,” where S denotes the mental state, A he attitude of a putati v el y rational a gent, and P the v erball y xpr essed pr oposition r eflecting the belief. 1 By contrast, the tudy of beliefs was generally assumed to be incompatible with he natural sciences. Ver y r ecentl y, howev er, the term “belief” as been described as to be used widespread in the cogniti v e cience literature to explain human reasoning and behavior. 2 pecifically, it has been described that beliefs act as fundamenal hypotheses about the world that result from any amount of ogniti v e pr ocessing and ar e held with any degr ee of certainty. 3 hus, beliefs are apparently not propositions expressed by conciousl y aw ar e , so-called r ational agents, but, on the contrary, eterminants of people’s spontaneous and intuiti v e behavior in complex world, as highlighted in a recent interdisciplinary esear c h topic. 4 Here , w e put the implications of the recent dvancements in this rapidly evolving field in perspective for the ciences and beyond.
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引用次数: 0
Deficiency of phosphatidylethanolamine synthesis: consequences for skeletal muscle. 磷脂酰乙醇胺合成不足:对骨骼肌的影响。
Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-01 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad044
Robin Elaine Duncan
hosphatidylethanolamine (PE) is a major gl ycer ophospholipid PL) in cellular and organellar membranes, and dysregulation of E synthesis has been associated with ener gy o v er-stora ge and nsulin resistance. 1 Due to the small size of its ethanolamine eadgr oup r elati v e to the v olume occupied by its long and, in articular, unsaturated fatty acyl side chains (which impart a kink” to the molecule), PE forms a conical shape. 2 This moleclar structure is key to sculpting the curv atur e of the inner layer f cellular and organellar membranes, where PE is quantitati v el y he most abundant type of PL. 3 In organelles where a high degree of membrane curv atur e s critical for the translation of structure to function, such s in the cristae that form the inner mitochondrial memranes, increases in PE content can impr ov e performance, hile losses can result in dysfunction that is so critical as o be incompatible with cellular and organismal life. 4 While his provides a direct connection between PE and the conrol of energy metabolism, recent studies demonstrate addiional roles for this gl ycer olipid in the regulation of wholeody metabolic homeostasis that are both complex and overlaping. For example, PE is primarily synthesized in the Kennedy athw ay thr ough the cytidine diphosphate (CDP)-ethanolamine athw ay, wher e CTP:phosphoethanolamine c ytid ylyltr ansfer ase Pcyt2) catalyzes the second and rate-limiting step. Because iacylgl ycer ol (DAG) is a substrate in the third and final step f the PE-K ennedy pathw ay, limitations in Pcyt2 activity are ssociated with reduced utilization, and therefore increased t
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引用次数: 0
Circulating Tetraspanins: From Markers to Mechanisms Driving Systemic Exercise Adaptation. 循环四合蛋白:从标记物到驱动系统运动适应的机制。
Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-01 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad048
Darby S Easterday, Daniel S Lark
Exercise impr ov es cardiometa bolic health thr ough a range of systemic [ie , bey ond w orking skeletal muscle (SkM)] mec ha-nisms typically attributed to small molecules and peptide hormones. Recent discoveries have shown that the abundance and cargo of circulating small extracellular vesicles (sEVs) like exosomes ar e alter ed by exer cise , but linking these c hanges to SkM-deri v ed systemic exercise adaptations has been challenging. A key barrier to linking SkM sEVs to exercise adaptations is determining which of the hundreds of molecules that may be transported by SkM sEVs have functional relevance in the context of exer cise . One surprisingly untested str ate gy is to start with the most abundant sEV car go . Tetraspanins like CD81 are tr ansmembr ane protein hallmarks of sEVs. To date, CD81 has only been described as an sEV marker, not an instrument of sEV function. However, ∼ 30 yr of resear c h has established CD81 as a tr ansmembr ane adaptor protein that influences a variety of cellular functions by altering the organization of r ece ptor pr oteins within membranes. Multiple groups
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引用次数: 0
Angiogenic Microvascular Wall Shear Stress Patterns Revealed Through Three-dimensional Red Blood Cell Resolved Modeling. 通过三维红细胞解析模型揭示的血管生成微血管壁剪切应力模式。
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2023-08-29 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad046
Mir Md Nasim Hossain, Nien-Wen Hu, Maram Abdelhamid, Simerpreet Singh, Walter L Murfee, Peter Balogh

The wall shear stress (WSS) exerted by blood flowing through microvascular capillaries is an established driver of new blood vessel growth, or angiogenesis. Such adaptations are central to many physiological processes in both health and disease, yet three-dimensional (3D) WSS characteristics in real angiogenic microvascular networks are largely unknown. This marks a major knowledge gap because angiogenesis, naturally, is a 3D process. To advance current understanding, we model 3D red blood cells (RBCs) flowing through rat angiogenic microvascular networks using state-of-the-art simulation. The high-resolution fluid dynamics reveal 3D WSS patterns occurring at sub-endothelial cell (EC) scales that derive from distinct angiogenic morphologies, including microvascular loops and vessel tortuosity. We identify the existence of WSS hot and cold spots caused by angiogenic surface shapes and RBCs, and notably enhancement of low WSS regions by RBCs. Spatiotemporal characteristics further reveal how fluctuations follow timescales of RBC "footprints." Altogether, this work provides a new conceptual framework for understanding how shear stress might regulate EC dynamics in vivo.

流经微血管毛细血管的血液所施加的壁剪切应力(WSS)是新血管生长或血管生成的既定驱动因素。这种适应是健康和疾病中许多生理过程的核心,然而真实血管生成微血管网络中的三维(3D)WSS特征在很大程度上是未知的。这标志着一个重大的知识差距,因为血管生成自然是一个3D过程。为了推进目前的理解,我们使用最先进的模拟对流经大鼠血管生成微血管网络的3D红细胞(RBCs)进行了建模。高分辨率流体动力学揭示了在内皮下细胞(EC)尺度上发生的3D WSS模式,这些模式源于不同的血管生成形态,包括微血管环和血管扭曲。我们确定了由血管生成表面形状和RBCs引起的WSS热点和冷点的存在,并且RBCs显著增强了低WSS区域。时空特征进一步揭示了波动如何遵循RBC“足迹”的时间尺度。总之,这项工作为理解剪切应力如何在体内调节EC动力学提供了一个新的概念框架。
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引用次数: 0
Magnitude and Mechanism of Phrenic Long-term Facilitation Shift Between Daily Rest Versus Active Phase. 在日常休息期和活动期之间的膈肌长期促进转变的程度和机制。
Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-08 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad041
Alexandria B Marciante, Yasin B Seven, Mia N Kelly, Raphael R Perim, Gordon S Mitchell

Plasticity is a fundamental property of the neural system controlling breathing. One key example of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a persistent increase in phrenic nerve activity elicited by acute intermittent hypoxia (AIH). pLTF can arise from distinct cell signaling cascades initiated by serotonin versus adenosine receptor activation, respectively, and interact via powerful cross-talk inhibition. Here, we demonstrate that the daily rest/active phase and the duration of hypoxic episodes within an AIH protocol have profound impact on the magnitude and mechanism of pLTF due to shifts in serotonin/adenosine balance. Using the historical "standard" AIH protocol (3, 5-min moderate hypoxic episodes), we demonstrate that pLTF magnitude is unaffected by exposure in the midactive versus midrest phase, yet the mechanism driving pLTF shifts from serotonin-dominant (midrest) to adenosine-dominant (midactive). This mechanistic "flip" results from combined influences of hypoxia-evoked adenosine release and daily fluctuations in basal spinal adenosine. Since AIH evokes less adenosine with shorter (15, 1-min) hypoxic episodes, midrest pLTF is amplified due to diminished adenosine constraint on serotonin-driven plasticity; in contrast, elevated background adenosine during the midactive phase suppresses serotonin-dominant pLTF. These findings demonstrate the importance of the serotonin/adenosine balance in regulating the amplitude and mechanism of AIH-induced pLTF. Since AIH is emerging as a promising therapeutic modality to restore respiratory and nonrespiratory movements in people with spinal cord injury or ALS, knowledge of how time-of-day and hypoxic episode duration impact the serotonin/adenosine balance and the magnitude and mechanism of pLTF has profound biological, experimental, and translational implications.

可塑性是控制呼吸的神经系统的一个基本特性。呼吸运动可塑性的一个关键例子是膈长期易化(pLTF),这是由急性间歇性缺氧(AIH)引起的膈神经活动的持续增加。pLTF可以分别由血清素和腺苷受体激活引发的不同细胞信号级联产生,并通过强大的串扰抑制相互作用。在这里,我们证明,由于血清素/腺苷平衡的变化,AIH方案中的每日休息/活动期和缺氧发作的持续时间对pLTF的大小和机制有着深远的影响。使用历史上的“标准”AIH方案(3-5分钟中度缺氧发作),我们证明pLTF的大小在活动中期与休息中期不受暴露的影响,但驱动pLTF从血清素主导(休息中期)转变为腺苷主导(活动中期)的机制。这种机制性的“翻转”是缺氧引起的腺苷释放和脊髓基底腺苷每日波动的综合影响的结果。由于AIH在较短(15,1分钟)的缺氧发作中引起较少的腺苷,因此由于腺苷对血清素驱动的可塑性的限制减少,中脑pLTF被放大;相反,在中期活动期升高的背景腺苷抑制血清素占主导地位的pLTF。这些发现证明了血清素/腺苷平衡在调节AIH诱导的pLTF的幅度和机制中的重要性。由于AIH正在成为一种很有前途的治疗方式,可以恢复脊髓损伤或ALS患者的呼吸和非呼吸运动,因此了解一天中的时间和缺氧发作持续时间如何影响血清素/腺苷平衡以及pLTF的大小和机制具有深远的生物学、实验和翻译意义。
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引用次数: 0
Genetic Ablation of Prorenin Receptor in the Rostral Ventrolateral Medulla Influences Blood Pressure and Hydromineral Balance in Deoxycorticosterone-Salt Hypertension. 脱氧皮质酮盐性高血压患者延髓腹外侧区肾素原受体基因消融对血压和水盐平衡的影响。
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2023-08-07 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad043
Natalia M Mathieu, Eva M Fekete, Patricia C Muskus, Daniel T Brozoski, Ko-Ting Lu, Kelsey K Wackman, Javier Gomez, Shi Fang, John J Reho, Connie C Grobe, Ibrahim Vazirabad, Gary C Mouradian, Matthew R Hodges, Jeffrey L Segar, Justin L Grobe, Curt D Sigmund, Pablo Nakagawa

Non-enzymatic activation of renin via its interaction with prorenin receptor (PRR) has been proposed as a key mechanism of local renin-angiotensin system (RAS) activation. The presence of renin and angiotensinogen has been reported in the rostral ventrolateral medulla (RVLM). Overactivation of bulbospinal neurons in the RVLM is linked to hypertension (HTN). Previous studies have shown that the brain RAS plays a role in the pathogenesis of the deoxycorticosterone (DOCA)-salt HTN model. Thus, we hypothesized that PRR in the RVLM is involved in the local activation of the RAS, facilitating the development of DOCA-salt HTN. Selective PRR ablation targeting the RVLM (PRRRVLM-Null mice) resulted in an unexpected sex-dependent and biphasic phenotype in DOCA-salt HTN. That is, PRRRVLM-Null females (but not males) exhibited a significant delay in achieving maximal pressor responses during the initial stage of DOCA-salt HTN. Female PRRRVLM-Null subsequently showed exacerbated DOCA-salt-induced pressor responses during the "maintenance" phase with a maximal peak at 13 d on DOCA-salt. This exacerbated response was associated with an increased sympathetic drive to the resistance arterioles and the kidney, exacerbated fluid and sodium intake and output in response to DOCA-salt, and induced mobilization of fluids from the intracellular to extracellular space concomitant with elevated vasopressin. Ablation of PRR suppressed genes involved in RAS activation and catecholamine synthesis in the RVLM but also induced expression of genes involved in inflammatory responses. This study illustrates complex and sex-dependent roles of PRR in the neural control of BP and hydromineral balance through autonomic and neuroendocrine systems. Graphical abstract.

肾素通过与前肾素受体(PRR)相互作用的非酶激活已被认为是局部肾素-血管紧张素系统(RAS)激活的关键机制。据报道,在延髓头端腹外侧区(RVLM)存在肾素和血管紧张素原。RVLM中球螺旋体神经元的过度激活与高血压(HTN)有关。先前的研究表明,脑RAS在脱氧皮质酮(DOCA)盐HTN模型的发病机制中发挥作用。因此,我们假设RVLM中的PRR参与RAS的局部激活,促进DOCA盐HTN的发展。靶向RVLM的选择性PRR消融(PRRRVLM Null小鼠)导致DOCA盐HTN出现意外的性别依赖性和双相表型。也就是说,在DOCA盐HTN的初始阶段,PRRRVLM Null雌性(但不是雄性)在实现最大升压反应方面表现出显著延迟。雌性PRRRVLM Null随后在“维持”阶段表现出加重的DOCA盐诱导的升压反应,在DOCA盐作用13天时达到最大峰值。这种加剧的反应与对阻力小动脉和肾脏的交感神经驱动增加有关,对DOCA盐的反应加剧了液体和钠的摄入和输出,并诱导液体从细胞内到细胞外空间的动员,同时血管加压素升高。PRR的消融抑制了RVLM中参与RAS激活和儿茶酚胺合成的基因,但也诱导了参与炎症反应的基因的表达。本研究阐明了PRR在通过自主神经和神经内分泌系统对BP和水盐平衡的神经控制中的复杂和性别依赖性作用。图形摘要。
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引用次数: 0
Breaking New Ground: The Crucial Role of Animal Research in the Advancement of Rhabdomyolysis-Induced AKI Treatment and Prevention. 开拓新天地:动物研究在促进横纹肌溶解症诱导的AKI治疗和预防中的关键作用。
Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-07-26 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad039
Marharyta Semenikhina, Joshua H Lipschutz, Oleg Palygin
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引用次数: 0
Computational Modeling of Substrate-Dependent Mitochondrial Respiration and Bioenergetics in the Heart and Kidney Cortex and Outer Medulla. 心、肾皮质和外髓质基质依赖性线粒体呼吸和生物能量学的计算模型。
Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-07-25 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad038
Shima Sadri, Xiao Zhang, Said H Audi, Allen W Cowley, Ranjan K Dash

Integrated computational modeling provides a mechanistic and quantitative framework to characterize alterations in mitochondrial respiration and bioenergetics in response to different metabolic substrates in-silico. These alterations play critical roles in the pathogenesis of diseases affecting metabolically active organs such as heart and kidney. Therefore, the present study aimed to develop and validate thermodynamically constrained integrated computational models of mitochondrial respiration and bioenergetics in the heart and kidney cortex and outer medulla (OM). The models incorporated the kinetics of major biochemical reactions and transport processes as well as regulatory mechanisms in the mitochondria of these tissues. Intrinsic model parameters such as Michaelis-Menten constants were fixed at previously estimated values, while extrinsic model parameters such as maximal reaction and transport velocities were estimated separately for each tissue. This was achieved by fitting the model solutions to our recently published respirometry data measured in isolated rat heart and kidney cortex and OM mitochondria utilizing various NADH- and FADH2-linked metabolic substrates. The models were validated by predicting additional respirometry and bioenergetics data, which were not used for estimating the extrinsic model parameters. The models were able to predict tissue-specific and substrate-dependent mitochondrial emergent metabolic system properties such as redox states, enzyme and transporter fluxes, metabolite concentrations, membrane potential, and respiratory control index under diverse physiological and pathological conditions. The models were also able to quantitatively characterize differential regulations of NADH- and FADH2-linked metabolic pathways, which contribute differently toward regulations of oxidative phosphorylation and ATP synthesis in the heart and kidney cortex and OM mitochondria.

综合计算建模提供了一个机制和定量框架来表征线粒体呼吸和生物能量学对不同代谢底物的反应。这些改变在影响心脏和肾脏等代谢活跃器官的疾病的发病机制中起着关键作用。因此,本研究旨在开发和验证心脏、肾脏皮层和髓质外侧(OM)线粒体呼吸和生物能量学的热力学约束集成计算模型。这些模型结合了主要生化反应和转运过程的动力学以及这些组织线粒体的调节机制。诸如Michaelis-Menten常数之类的内在模型参数被固定在先前估计的值,而诸如最大反应和传输速度之类的外在模型参数被分别估计用于每个组织。这是通过将模型溶液与我们最近发表的呼吸测量数据进行拟合来实现的,这些数据是利用各种NADH-和FADH2相关的代谢底物在分离的大鼠心脏和肾脏皮层以及OM线粒体中测量的。通过预测额外的呼吸测量和生物能量学数据来验证模型,这些数据不用于估计外部模型参数。该模型能够预测不同生理和病理条件下组织特异性和底物依赖性线粒体出现的代谢系统特性,如氧化还原状态、酶和转运蛋白通量、代谢产物浓度、膜电位和呼吸控制指数。该模型还能够定量表征NADH和FADH2相关代谢途径的差异调节,这些代谢途径对心脏、肾脏皮层和OM线粒体中氧化磷酸化和ATP合成的调节有不同的贡献。
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引用次数: 1
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Function (Oxford, England)
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