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Megalin Knockout Reduces SGLT2 Expression and Sensitizes to Western Diet-induced Kidney Injury. Megalin基因敲除可减少SGLT2的表达,并对西方饮食诱导的肾损伤敏感。
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2024-07-11 DOI: 10.1093/function/zqae026
Elynna B Youm, Katherine E Shipman, Wafaa N Albalawy, Amber M Vandevender, Ian J Sipula, Youssef Rbaibi, Allison E Marciszyn, Jared A Lashway, Emma E Brown, Corry B Bondi, Cary R Boyd-Shiwarski, Roderick J Tan, Michael J Jurczak, Ora A Weisz

Megalin (Lrp2) is a multiligand receptor that drives endocytic flux in the kidney proximal tubule (PT) and is necessary for the recovery of albumin and other filtered proteins that escape the glomerular filtration barrier. Studies in our lab have shown that knockout (KO) of Lrp2 in opossum PT cells leads to a dramatic reduction in sodium-glucose co-transporter 2 (SGLT2) transcript and protein levels, as well as differential expression of genes involved in mitochondrial and metabolic function. SGLT2 transcript levels are reduced more modestly in Lrp2 KO mice. Here, we investigated the effects of Lrp2 KO on kidney function and health in mice fed regular chow (RC) or a Western-style diet (WD) high in fat and refined sugar. Despite a modest reduction in SGLT2 expression, Lrp2 KO mice on either diet showed increased glucose tolerance compared to control mice. Moreover, Lrp2 KO mice were protected against WD-induced fat gain. Surprisingly, renal function in male Lrp2 KO mice on WD was compromised, and the mice exhibited significant kidney injury compared with control mice on WD. Female Lrp2 KO mice were less susceptible to WD-induced kidney injury than male Lrp2 KO. Together, our findings reveal both positive and negative contributions of megalin expression to metabolic health, and highlight a megalin-mediated sex-dependent response to injury following WD.

Megalin(Lrp2)是一种多配体受体,可驱动肾近曲小管(PT)中的内细胞通量,是回收白蛋白和其他逃逸肾小球滤过屏障的滤过蛋白所必需的。我们实验室的研究表明,在负鼠近端肾小管细胞中敲除(KO)Lrp2 会导致钠葡萄糖共转运体 2(SGLT2)转录物和蛋白质水平的急剧下降,以及线粒体和代谢功能相关基因的差异表达。在 Lrp2 KO 小鼠中,SGLT2 转录物水平的降低幅度较小。在这里,我们研究了 Lrp2 KO 对喂食普通饲料(RC)或高脂肪、高精制糖的西式饮食(WD)的小鼠肾功能和健康的影响。尽管 SGLT2 的表达略有减少,但与对照组小鼠相比,两种饮食中 Lrp2 KO 小鼠的葡萄糖耐受性都有所提高。此外,Lrp2 KO 小鼠对 WD 诱导的脂肪增加有保护作用。令人惊讶的是,与服用 WD 的对照组小鼠相比,服用 WD 的雄性 Lrp2 KO 小鼠的肾功能受损,表现出明显的肾损伤。与雄性 Lrp2 KO 小鼠相比,雌性 Lrp2 KO 小鼠不易受到 WD 引起的肾损伤的影响。总之,我们的研究结果揭示了巨球蛋白表达对代谢健康的积极和消极贡献,并强调了巨球蛋白介导的对WD损伤的性别依赖性反应。
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引用次数: 0
Sex-Specific Effects of Cholesteryl Ester Transfer Protein (CETP) on the Perivascular Adipose Tissue. 胆固醇酯转移蛋白 (CETP) 对血管周围脂肪组织的性别特异性影响
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2024-07-11 DOI: 10.1093/function/zqae024
C M Lazaro, I N Freitas, V S Nunes, D M Guizoni, J A Victorio, H C F Oliveira, A P Davel

Cholesteryl ester transfer protein (CETP) increases the atherosclerosis risk by lowering HDL-cholesterol levels. It also exhibits tissue-specific effects independent of HDL. However, sexual dimorphism of CETP effects remains largely unexplored. Here, we hypothesized that CETP impacts the perivascular adipose tissue (PVAT) phenotype and function in a sex-specific manner. PVAT function, gene and protein expression, and morphology were examined in male and female transgenic mice expressing human or simian CETP and their non-transgenic counterparts (NTg). PVAT exerted its anticontractile effect in aortas from NTg males, NTg females, and CETP females, but not in CETP males. CETP male PVAT had reduced NO levels, decreased eNOS and phospho-eNOS levels, oxidative stress, increased NOX1 and 2, and decreased SOD2 and 3 expressions. In contrast, CETP-expressing female PVAT displayed increased NO and phospho-eNOS levels with unchanged NOX expression. NOX inhibition and the antioxidant tempol restored PVAT anticontractile function in CETP males. Ex vivo estrogen treatment also restored PVAT function in CETP males. Moreover, CETP males, but not female PVAT, show increased inflammatory markers. PVAT lipid content increased in CETP males but decreased in CETP females, while PVAT cholesterol content increased in CETP females. CETP male PVAT exhibited elevated leptin and reduced Prdm16 (brown adipocyte marker) expression. These findings highlight CETP sex-specific impact on PVAT. In males, CETP impaired PVAT anticontractile function, accompanied by oxidative stress, inflammation, and whitening. Conversely, in females, CETP expression increased NO levels, induced an anti-inflammatory phenotype, and preserved the anticontractile function. This study reveals sex-specific vascular dysfunction mediated by CETP.

胆固醇酯转移蛋白(CETP)会降低高密度脂蛋白胆固醇水平,从而增加动脉粥样硬化的风险。它还表现出与高密度脂蛋白无关的组织特异性效应。然而,CETP 作用的性双态性在很大程度上仍未得到研究。在这里,我们假设 CETP 以性别特异性的方式影响血管周围脂肪组织(PVAT)的表型和功能。我们对表达人或猿CETP的雌雄转基因小鼠及其非转基因小鼠(NTg)的PVAT功能、基因和蛋白表达以及形态进行了研究。PVAT在NTg雄性、NTg雌性和CETP雌性小鼠的主动脉中发挥了抗收缩作用,但在CETP雄性小鼠中却没有。CETP雄性PVAT的NO水平降低,eNOS和磷酸化-eNOS水平降低,氧化应激增加,NOX1和2表达增加,SOD2和3表达减少。相反,表达 CETP 的雌性 PVAT 的 NO 和磷酸化-eNOS 水平升高,NOX 表达量不变。抑制 NOX 和抗氧化剂 tempol 恢复了 CETP 雄性 PVAT 的抗收缩功能。体内外雌激素处理也恢复了 CETP 雄性 PVAT 的功能。此外,CETP 雄性而非雌性 PVAT 显示出炎症标记物的增加。CETP 雄性 PVAT 的脂质含量增加,而 CETP 雌性 PVAT 的脂质含量减少,而 CETP 雌性 PVAT 的胆固醇含量增加。CETP 雄性 PVAT 表现出瘦素升高和 Prdm16(棕色脂肪细胞标志物)表达降低。这些发现凸显了 CETP 性别特异性对 PVAT 的影响。在男性中,CETP 会损害 PVAT 的抗收缩功能,并伴有氧化应激、炎症和白化。相反,在女性中,CETP 的表达会增加 NO 水平,诱导抗炎表型,并保持抗收缩功能。这项研究揭示了 CETP 介导的具有性别特异性的血管功能障碍。
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引用次数: 0
Single Cell RNAseq Analysis of Cytokine-Treated Human Islets: Association of Cellular Stress with Impaired Cytokine Responsiveness. 细胞因子处理的人类胰岛的单细胞 RNAseq 分析:细胞压力与细胞因子反应能力受损的关系
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2024-07-11 DOI: 10.1093/function/zqae015
Jennifer S Stancill, Moujtaba Y Kasmani, Weiguo Cui, John A Corbett

Pancreatic β-cells are essential for survival, being the only cell type capable of insulin secretion. While they are believed to be vulnerable to damage by inflammatory cytokines such as interleukin-1 beta (IL-1β) and interferon-gamma, we have recently identified physiological roles for cytokine signaling in rodent β-cells that include the stimulation of antiviral and antimicrobial gene expression and the inhibition of viral replication. In this study, we examine cytokine-stimulated changes in gene expression in human islets using single-cell RNA sequencing. Surprisingly, the global responses of human islets to cytokine exposure were remarkably blunted compared to our previous observations in the mouse. The small population of human islet cells that were cytokine responsive exhibited increased expression of IL-1β-stimulated antiviral guanylate-binding proteins, just like in the mouse. Most human islet cells were not responsive to cytokines, and this lack of responsiveness was associated with high expression of genes encoding ribosomal proteins. We further correlated the expression levels of RPL5 with stress response genes, and when expressed at high levels, RPL5 is predictive of failure to respond to cytokines in all endocrine cells. We postulate that donor causes of death and isolation methodologies may contribute to stress of the islet preparation. Our findings indicate that activation of stress responses in human islets limits cytokine-stimulated gene expression, and we urge caution in the evaluation of studies that have examined cytokine-stimulated gene expression in human islets without evaluation of stress-related gene expression.

胰岛β细胞是唯一能够分泌胰岛素的细胞类型,对胰岛β细胞的存活至关重要。虽然人们认为它们容易受到白细胞介素-1β(IL-1β)和γ干扰素(IFN-γ)等炎症细胞因子的损害,但我们最近发现细胞因子信号在啮齿动物β细胞中的生理作用包括刺激抗病毒和抗微生物基因表达以及抑制病毒复制。在本研究中,我们利用单细胞 RNA 测序技术研究了细胞因子刺激下人类胰岛基因表达的变化。令人惊讶的是,与我们之前在小鼠体内观察到的结果相比,人类胰岛细胞对细胞因子暴露的整体反应明显减弱。对细胞因子有反应的一小部分人胰岛细胞表现出IL-1β刺激的抗病毒鸟苷酸结合蛋白的表达增加,就像在小鼠中一样。大多数人的胰岛细胞对细胞因子没有反应,这种缺乏反应与核糖体蛋白编码基因的高表达有关。我们进一步将 RPL5 的表达水平与应激反应基因相关联,当 RPL5 高水平表达时,可预测所有内分泌细胞对细胞因子的反应失败。我们推测,供体的死因和分离方法可能会导致胰岛制备过程中的应激反应。我们的研究结果表明,人类胰岛中应激反应的激活限制了细胞因子刺激基因的表达,因此我们呼吁在评估那些未评估应激相关基因表达就检测人类胰岛中细胞因子刺激基因表达的研究时要谨慎。
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引用次数: 0
Brain Ballet: The Choreography of Left-Right Neuroendocrine Signals in Injury. 大脑芭蕾:损伤中左右神经内分泌信号的编排。
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2024-07-11 DOI: 10.1093/function/zqae022
Marshall T Holland, Bryan Becker
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引用次数: 0
Society Note - 'How Do We Clean Up the Scientific Record?' 社会说明--"我们如何清理科学记录?
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2024-06-11 eCollection Date: 2024-01-01 DOI: 10.1093/function/zqae028
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引用次数: 0
Rethinking Ischemic Acute Kidney Injury as Nephrotoxicity. 将缺血性急性肾损伤视为肾毒性的再思考
Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-17 eCollection Date: 2024-01-01 DOI: 10.1093/function/zqae020
David M Pollock
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引用次数: 0
High Salt Remodels Kidney Metabolism: Metabolite Fuel, Fate, and Signals. 高盐重塑肾脏代谢:代谢物燃料、命运和信号
Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-29 eCollection Date: 2024-01-01 DOI: 10.1093/function/zqae006
Moritz Lassé, Markus M Rinschen
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引用次数: 0
Epigenetic Regulation of Autophagy in Bone Metabolism. 骨代谢中自噬的表观遗传调控
Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-27 eCollection Date: 2024-01-01 DOI: 10.1093/function/zqae004
Yazhou Zhang, Qianqian Wang, Hongjia Xue, Yujin Guo, Shanshan Wei, Fengfeng Li, Linqiang Gong, Weiliang Pan, Pei Jiang

The skeletal system is crucial for supporting bodily functions, protecting vital organs, facilitating hematopoiesis, and storing essential minerals. Skeletal homeostasis, which includes aspects such as bone density, structural integrity, and regenerative processes, is essential for normal skeletal function. Autophagy, an intricate intracellular mechanism for degrading and recycling cellular components, plays a multifaceted role in bone metabolism. It involves sequestering cellular waste, damaged proteins, and organelles within autophagosomes, which are then degraded and recycled. Autophagy's impact on bone health varies depending on factors such as regulation, cell type, environmental cues, and physiological context. Despite being traditionally considered a cytoplasmic process, autophagy is subject to transcriptional and epigenetic regulation within the nucleus. However, the precise influence of epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNA expression, on cellular fate remains incompletely understood. The interplay between autophagy and epigenetic modifications adds complexity to bone cell regulation. This article provides an in-depth exploration of the intricate interplay between these two regulatory paradigms, with a focus on the epigenetic control of autophagy in bone metabolism. Such an understanding enhances our knowledge of bone metabolism-related disorders and offers insights for the development of targeted therapeutic strategies.

骨骼系统对于支持身体机能、保护重要器官、促进造血和储存必需矿物质至关重要。骨骼平衡包括骨密度、结构完整性和再生过程等方面,对骨骼功能的正常发挥至关重要。自噬是一种降解和回收细胞成分的复杂细胞内机制,在骨代谢中发挥着多方面的作用。它将细胞废物、受损蛋白质和细胞器封存在自噬体中,然后进行降解和再循环。自噬对骨骼健康的影响因调节、细胞类型、环境线索和生理背景等因素而异。尽管自噬传统上被认为是一个细胞质过程,但它在细胞核内受到转录和表观遗传的调控。然而,表观遗传调控(包括 DNA 甲基化、组蛋白修饰和非编码 RNA 表达)对细胞命运的确切影响仍不完全清楚。自噬和表观遗传修饰之间的相互作用增加了骨细胞调控的复杂性。本文深入探讨了这两种调控模式之间错综复杂的相互作用,重点是自噬在骨代谢中的表观遗传调控。这种认识增强了我们对骨代谢相关疾病的了解,并为开发有针对性的治疗策略提供了启示。
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引用次数: 0
Plasma of COVID-19 Patients Does Not Alter Electrical Resistance of Human Endothelial Blood-Brain Barrier In Vitro. COVID-19 患者的血浆不会改变体外人类内皮血脑屏障的抗电性
Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-09 eCollection Date: 2024-01-01 DOI: 10.1093/function/zqae002
Agnė Pociūtė, Karolina Kriaučiūnaitė, Aida Kaušylė, Birutė Zablockienė, Tadas Alčauskas, Augustė Jelinskaitė, Akvilė Rudėnaitė, Ligita Jančorienė, Saulius Ročka, Alexei Verkhratsky, Augustas Pivoriūnas

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 instigated the most serious global health crisis. Clinical presentation of COVID-19 frequently includes severe neurological and neuropsychiatric symptoms. However, it is presently unknown whether and to which extent pathological impairment of blood-brain barrier (BBB) contributes to the development of neuropathology during COVID-19 progression. In the present study, we used human induced pluripotent stem cells-derived brain endothelial cells (iBECs) to study the effects of blood plasma derived from COVID-19 patients on the BBB integrity in vitro. We also performed a comprehensive analysis of the cytokine and chemokine profiles in the plasma of COVID-19 patients, healthy and recovered individuals. We found significantly increased levels of interferon γ-induced protein 10 kDa, hepatocyte growth factor, and interleukin-18 in the plasma of COVID-19 patients. However, blood plasma from COVID-19 patients did not affect transendothelial electrical resistance in iBEC monolayers. Our results demonstrate that COVID-19-associated blood plasma inflammatory factors do not affect BBB paracellular pathway directly and suggest that pathological remodeling (if any) of BBB during COVID-19 may occur through indirect or yet unknown mechanisms.

由严重急性呼吸系统综合征冠状病毒 2 引起的 2019 年冠状病毒病(COVID-19)大流行引发了最严重的全球健康危机。COVID-19 的临床表现通常包括严重的神经和神经精神症状。然而,目前尚不清楚血脑屏障(BBB)的病理损伤是否以及在多大程度上导致了 COVID-19 进展过程中神经病理学的发展。在本研究中,我们使用诱导多能干细胞衍生的脑内皮细胞(iBECs)研究了 COVID-19 患者血浆对体外 BBB 完整性的影响。我们还对 COVID-19 患者、健康人和康复者血浆中的细胞因子和趋化因子谱进行了全面分析。我们发现 COVID-19 患者血浆中干扰素 γ 诱导的 10 kDa 蛋白、肝细胞生长因子和白细胞介素-18 的水平明显升高。然而,COVID-19 患者的血浆并不影响 iBEC 单层的跨内皮电阻。我们的研究结果表明,COVID-19 患者血浆中的炎症因子不会直接影响 BBB 旁通路,这表明 COVID-19 期间 BBB 的病理重塑(如果有的话)可能是通过间接或未知的机制发生的。
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引用次数: 0
Neuromuscular Dysfunction Precedes Cognitive Impairment in a Mouse Model of Alzheimer's Disease. 阿尔茨海默氏症小鼠模型的神经肌肉功能障碍先于认知功能受损
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2023-12-04 eCollection Date: 2024-01-01 DOI: 10.1093/function/zqad066
Matthew H Brisendine, Anna S Nichenko, Aloka B Bandara, Orion S Willoughby, Niloufar Amiri, Zach Weingrad, Kalyn S Specht, Jacob M Bond, Adele Addington, Ronald G Jones, Kevin A Murach, Steven Poelzing, Siobhan M Craige, Robert W Grange, Joshua C Drake

Alzheimer's disease (AD) develops along a continuum that spans years prior to diagnosis. Decreased muscle function and mitochondrial respiration occur years earlier in those that develop AD; however, it is unknown what causes these peripheral phenotypes in a disease of the brain. Exercise promotes muscle, mitochondria, and cognitive health and is proposed to be a potential therapeutic for AD, but no study has investigated how skeletal muscle adapts to exercise training in an AD-like context. Utilizing 5xFAD mice, an AD model that develops ad-like pathology and cognitive impairments around 6 mo of age, we examined in vivo neuromuscular function and exercise adapations (mitochondrial respiration and RNA sequencing) before the manifestation of overt cognitive impairment. We found 5xFAD mice develop neuromuscular dysfunction beginning as early as 4 mo of age, characterized by impaired nerve-stimulated muscle torque production and compound nerve action potential of the sciatic nerve. Furthermore, skeletal muscle in 5xFAD mice had altered, sex-dependent, adaptive responses (mitochondrial respiration and gene expression) to exercise training in the absence of overt cognitive impairment. Changes in peripheral systems, specifically neural communication to skeletal muscle, may be harbingers for AD and have implications for lifestyle interventions, like exercise, in AD.

阿尔茨海默病(AD)的发病过程是一个连续的过程,在确诊前数年就会出现。肌肉功能和线粒体呼吸功能的减退早在几年前就出现在阿兹海默症患者身上;然而,人们还不知道是什么原因导致这些外周表型出现在脑部疾病中。运动能促进肌肉、线粒体和认知健康,被认为是一种潜在的AD治疗方法,但还没有研究调查过骨骼肌在类似AD的情况下是如何适应运动训练的。我们利用 5xFAD 小鼠(一种在 6 个月左右出现类似 AD 病理和认知障碍的 AD 模型),在明显的认知障碍出现之前检查了体内神经肌肉功能和运动适应性(线粒体呼吸和 RNA 测序)。我们发现 5xFAD 小鼠早在 4 月龄时就出现了神经肌肉功能障碍,其特征是神经刺激肌肉产生的扭矩和坐骨神经的复合神经动作电位受损。此外,在没有明显认知障碍的情况下,5xFAD 小鼠的骨骼肌对运动训练的适应性反应(线粒体呼吸和基因表达)发生了改变,且这种改变与性别有关。外周系统的变化,特别是神经与骨骼肌之间的交流,可能是注意力缺失症的先兆,并对注意力缺失症患者的生活方式干预(如运动)产生影响。
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引用次数: 0
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Function (Oxford, England)
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