Acta Physiologica最新文献_第6页

Impaired suppression of fatty acid release by insulin is a strong predictor of reduced whole-body insulin-mediated glucose uptake and skeletal muscle insulin receptor activation 胰岛素对脂肪酸释放的抑制作用受损是全身胰岛素介导的葡萄糖摄取和骨骼肌胰岛素受体活化减少的一个有力预测因素。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-11-01 DOI: 10.1111/apha.14249

Michael W. Schleh, Benjamin J. Ryan, Cheehoon Ahn, Alison C. Ludzki, Douglas W. Van Pelt, Lisa M. Pitchford, Olivia K. Chugh, Austin T. Luker, Kathryn E. Luker, Dmitri Samovski, Nada A. Abumrad, Charles F. Burant, Jeffrey F. Horowitz

Aim

To examine factors underlying why most, but not all, adults with obesity exhibit impaired insulin-mediated glucose uptake, we compared: (1) adipose tissue fatty acid (FA) release, (2) skeletal muscle lipid droplet (LD) characteristics, and (3) insulin signalling events, in skeletal muscle of adults with obesity with relatively high versus low insulin-mediated glucose uptake.

Methods

Seventeen adults with obesity (BMI: 36 ± 3 kg/m²) completed a 2 h hyperinsulinemic–euglycemic clamp with stable isotope tracer infusions to measure glucose rate of disappearance (glucose Rd) and FA rate of appearance (FA Ra). Skeletal muscle biopsies were collected at baseline and 30 min into the insulin infusion. Participants were stratified into HIGH (n = 7) and LOW (n = 10) insulin sensitivity cohorts by their glucose Rd during the hyperinsulinemic clamp (LOW< 400; HIGH >550 nmol/kgFFM/min/[μU/mL]).

Results

Insulin-mediated suppression of FA Ra was lower in LOW compared with HIGH (p < 0.01). In skeletal muscle, total intramyocellular lipid content did not differ between cohorts. However, the size of LDs in the subsarcolemmal region (SS) of type II muscle fibres was larger in LOW compared with HIGH (p = 0.01). Additionally, insulin receptor-β (IRβ) interactions with regulatory proteins CD36 and Fyn were lower in LOW versus HIGH (p < 0.01), which aligned with attenuated insulin-mediated Tyr phosphorylation of IRβ and downstream insulin-signalling proteins in LOW.

Conclusion

Collectively, reduced ability for insulin to suppress FA mobilization, with accompanying modifications in intramyocellular LD size and distribution, and diminished IRβ interaction with key regulatory proteins may be key contributors to impaired insulin-mediated glucose uptake commonly found in adults with obesity.

目的：为了研究为什么大多数肥胖症成人（而不是所有肥胖症成人）表现出胰岛素介导的葡萄糖摄取受损，我们比较了：(1) 脂肪组织脂肪酸（FA）释放；(2) 骨骼肌脂滴（LD）特征；(3) 在胰岛素介导的葡萄糖摄取相对较高和较低的肥胖症成人骨骼肌中的胰岛素信号事件：方法：17 名成人肥胖症患者（体重指数：36 ± 3 kg/m2）完成了 2 小时高胰岛素血糖钳夹，并输注稳定同位素示踪剂以测量葡萄糖消失率（glucose Rd）和 FA 出现率（FA Ra）。在基线和输注胰岛素 30 分钟时采集骨骼肌活检组织。根据参与者在高胰岛素血症钳夹（LOW550 nmol/kgFFM/min/[μU/mL]）期间的葡萄糖路分为高胰岛素敏感性组群（n = 7）和低胰岛素敏感性组群（n = 10）：结果：胰岛素介导的 FA Ra 抑制率在低胰岛素血症钳夹下低于高胰岛素血症钳夹下（p）：总之，胰岛素抑制FA动员的能力降低，伴随着细胞内LD大小和分布的改变，以及IRβ与关键调节蛋白相互作用的减弱，可能是肥胖成人中常见的胰岛素介导的葡萄糖摄取受损的主要原因。

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引用次数: 0

Differential production of mitochondrial reactive oxygen species between mouse (Mus musculus) and crucian carp (Carassius carassius) 小鼠（Mus musculus）和鲫鱼（Carassius carassius）线粒体活性氧产生的差异。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-10-28 DOI: 10.1111/apha.14244

Lucie Gerber, May-Kristin Torp, Göran E. Nilsson, Sjannie Lefevre, Kåre-Olav Stensløkken

Aim

In most vertebrates, oxygen deprivation and subsequent re-oxygenation are associated with mitochondrial impairment and excess production of reactive oxygen species (ROS) like hydrogen peroxide (H₂O₂). This in turn triggers a cascade of cell-damaging events in a temperature-dependent manner. The crucian carp (Carassius carassius) is one of few vertebrates that survives months without oxygen at cold temperatures and overcomes oxidative damage during re-oxygenation periods. Mitochondria of this anoxia-tolerant species therefore serve as an excellent model in translational research to study adaptation and resilience to low oxygen conditions and thermal variability.

Methods

Here, we used high-resolution respirometry on isolated mitochondria from hearts of crucian carp and the anoxia-intolerant mouse (Mus musculus), at 37 and 8°C; two temperatures relevant for transplantation medicine (i.e., graft preservation and subsequent rewarming).

Results

We find: (1) a striking difference in H₂O₂ release between the two species at 37°C despite comparable mitochondrial efficiency and capacity, (2) a massive H₂O₂ release after inhibition of complex V in mouse at 37°C that is absent in crucian carp, and prevented in mouse by incubation at 8°C or uncoupling with a protonophore at 37°C, and (3) indications that differences in mitochondrial complex I and II capacity and thermal sensitivity influence the release of mitochondrial H₂O₂ relative to respiration.

Conclusion

Our findings provide comparative insights into a spectrum of mitochondrial adaptations in vertebrates and the importance of thermal variability. Furthermore, the species- and temperature-related changes associated with mitochondria highlighted in this study may help identify mitochondria-based targets for translational medicine.

目的：在大多数脊椎动物中，缺氧和随后的复氧与线粒体损伤和过氧化氢（H2O2）等活性氧（ROS）的过量产生有关。这反过来又以依赖温度的方式引发一连串的细胞损伤事件。鲫鱼（Carassius carassius）是少数几种能在低温缺氧的情况下存活数月，并在复氧期间克服氧化损伤的脊椎动物之一。因此，这种耐缺氧物种的线粒体在转化研究中是研究对低氧条件和热变异的适应性和恢复力的极佳模型。方法：在这里，我们使用高分辨率呼吸测定法测定了鲫鱼和耐缺氧小鼠（Mus musculus）心脏的分离线粒体，测定温度分别为 37 和 8°C；这两个温度与移植医学（即移植物保存和随后的复温）相关：结果：我们发现结果：我们发现：(1) 尽管线粒体的效率和容量相当，但在 37 摄氏度时，两种鱼类的 H2O2 释放量存在显著差异；(2) 在 37 摄氏度时，小鼠的复合体 V 受到抑制后会释放大量 H2O2，而鲫鱼则没有这种现象，在 8 摄氏度下孵育或在 37 摄氏度时用质子诱导剂解偶联可防止小鼠释放大量 H2O2；(3) 有迹象表明，线粒体复合体 I 和 II 容量以及热敏感性的差异会影响线粒体 H2O2 相对于呼吸作用的释放量：我们的研究结果提供了脊椎动物线粒体适应性谱系和热变异重要性的比较见解。此外，本研究强调的与线粒体相关的物种和温度变化可能有助于确定基于线粒体的转化医学目标。

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引用次数: 0

A quantitative analysis of bestrophin 1 cellular localization in mouse cerebral cortex 小鼠大脑皮层中 bestrophin 1 细胞定位的定量分析

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-10-28 DOI: 10.1111/apha.14245

Michael Di Palma, Wuhyun Koh, C. Justin Lee, Fiorenzo Conti

Aim

Calcium-activated ligand-gated chloride channels, beyond their role in maintaining anion homeostasis, modulate neuronal excitability by facilitating nonvesicular neurotransmitter release. BEST1, a key member of this family, is permeable to γ-aminobutyric acid (GABA) and glutamate. While astrocytic BEST1 is well-studied and known to regulate neurotransmitter levels, its distribution and role in other brain cell types remain unclear. This study aimed to reassess the localization of BEST1 in the mouse cerebral cortex.

Methods

We examined the localization and distribution of BEST1 in the mouse parietal cortex using light microscopy, confocal double-labeling with markers for astrocytes, neurons, microglia, and oligodendrocyte precursor cells, and 3D reconstruction techniques.

Results

In the cerebral cortex, BEST1 is more broadly distributed than previously thought. Neurons are the second most abundant BEST1⁺ cell type in the cerebral cortex, following astrocytes. BEST1 is diffusely expressed in neuronal somatic and neuropilar domains and is present at glutamatergic and GABAergic terminals, with a prevalence at GABAergic terminals. We also confirmed that BEST1 is expressed in cortical microglia and identified it in oligodendrocyte precursor cells, albeit to a lesser extent.

Conclusions

Together, these findings suggest that BEST1's role in controlling neurotransmission may extend beyond astrocytes to include other brain cells. Understanding BEST1's function in these cells could offer new insights into the molecular mechanisms shaping cortical circuitry. Further research is needed to clarify the diverse roles of BEST1 in both normal and pathophysiological conditions.

目的：钙激活配体门控氯离子通道除了维持阴离子平衡的作用外，还通过促进非膀胱神经递质的释放来调节神经元的兴奋性。BEST1 是这一家族的重要成员，对γ-氨基丁酸（GABA）和谷氨酸具有通透性。虽然对星形胶质细胞 BEST1 进行了深入研究，并知道它能调节神经递质水平，但它在其他脑细胞类型中的分布和作用仍不清楚。本研究旨在重新评估 BEST1 在小鼠大脑皮层中的定位：方法：我们使用光学显微镜、共焦双标记星形胶质细胞、神经元、小胶质细胞和少突胶质细胞前体细胞以及三维重建技术研究了 BEST1 在小鼠顶叶皮层中的定位和分布：结果：在大脑皮层中，BEST1的分布比之前认为的更为广泛。神经元是继星形胶质细胞之后大脑皮层中第二大 BEST1+ 细胞类型。BEST1 在神经元体细胞和神经细胞域弥漫表达，存在于谷氨酸能和 GABAergic 末端，其中 GABAergic 末端最多。我们还证实 BEST1 在大脑皮层小胶质细胞中表达，并在少突胶质细胞前体细胞中发现了它，尽管程度较低：这些发现共同表明，BEST1 在控制神经传递方面的作用可能超出了星形胶质细胞的范围，还包括其他脑细胞。了解 BEST1 在这些细胞中的功能可为我们提供有关塑造大脑皮层回路的分子机制的新见解。要弄清 BEST1 在正常和病理生理条件下的各种作用，还需要进一步的研究。

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引用次数: 0

Calcineurin inhibitors and the renin–angiotensin–aldosterone system 降钙素抑制剂和肾素-血管紧张素-醛固酮系统。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-10-25 DOI: 10.1111/apha.14248

Mesut Berber, David Penton

Calcineurin inhibitors (CnIs) are effective immunosuppressants with decades of accumulated experience in treating immune disorders and, most notably, solid organ transplantation. While CnIs have significantly increased graft survival and transformed the patient standard of care, their use has been overshadowed by a number of undesired side effects. For instance, CnI-associated nephrotoxicity has been reported since early studies and remains a major therapeutic concern. The occurrence of several ion imbalances alongside hypertension was also noted early on, indicating the involvement of the renin–angiotensin–aldosterone system (RAAS) in CnI-mediated toxicity. However, the literature in this field is crowded with conflicting reports from clinical trials as well as studies using animal and invitro models. With this review, we aim to provide a structured and updated overview of the physiological and pathophysiological evidence supporting the involvement of the classical RAAS in CnI-associated toxicity.

降钙素抑制剂（CnIs）是一种有效的免疫抑制剂，在治疗免疫性疾病，尤其是实体器官移植方面积累了数十年的经验。虽然 CnIs 显著提高了移植存活率，并改变了患者的治疗标准，但其使用也因一些不良副作用而蒙上了阴影。例如，与 CnI 相关的肾毒性从早期研究就有报道，目前仍是治疗方面的一个主要问题。人们很早就注意到在高血压的同时还出现了多种离子失衡，这表明肾素-血管紧张素-醛固酮系统（RAAS）参与了 CnI 介导的毒性。然而，在这一领域的文献中，来自临床试验以及动物和无创模型研究的报告相互矛盾。本综述旨在对支持经典 RAAS 参与 CnI 相关毒性的生理和病理生理学证据进行结构化的最新概述。

引用次数: 0

High chloride induces aldosterone resistance in the distal nephron 高氯化物诱导远端肾小球的醛固酮抵抗。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-10-24 DOI: 10.1111/apha.14246

Helga Vitzthum, Nina Hauswald, Helena Pham, Leya Eckermann-Reimer, Catherine Meyer-Schwesinger, Heimo Ehmke

Aim

Increasing the dietary intake of K⁺ in the setting of a high salt intake promotes renal Na⁺ excretion even though K⁺ concurrently enhances the secretion of aldosterone, the most effective stimulus for renal Na⁺ reabsorption. Here, we questioned whether in the high salt state a mechanism exists, which attenuates the aldosterone response to prevent renal Na⁺ reabsorption after high K⁺ intake.

Methods

Mice were fed diets containing varying amounts of Na⁺ combined with KCl or KCitrate. Murine cortical connecting duct (mCCDcl1) cells were cultured in media containing normal or high [Cl⁻]. The response to aldosterone was analyzed by high-resolution imaging and by biochemical approaches.

Results

The canonical cellular response to aldosterone, encompassing translocation of the mineralocorticoid receptor (MR) and activation of the epithelial Na⁺ channel ENaC was repressed in Na⁺-replete mice fed a high KCl diet, even though plasma aldosterone concentrations were increased. The response to aldosterone was restored in Na⁺-replete mice when the extracellular [Cl⁻] increase was prevented by feeding a high KCitrate diet. In mCCDcl1 cells, an elevated extracellular [Cl⁻] was sufficient to disrupt the aldosterone-induced MR translocation.

Conclusion

These findings indicate a pivotal role for extracellular [Cl⁻] in modulating renal aldosterone signaling to adapt MR activation by a high K⁺ intake to the NaCl balance. An impairment of [Cl⁻]-mediated aldosterone resistance may contribute to excessive MR activation by aldosterone in the presence of a high salt intake characteristic of the Western diet, resulting in an inappropriate salt reabsorption and its downstream detrimental effects.

目的：在高盐摄入的情况下，增加膳食中 K+ 的摄入量会促进肾脏 Na+ 的排泄，尽管 K+ 同时会增强醛固酮的分泌，而醛固酮是肾脏 Na+ 重吸收的最有效刺激物。在此，我们想知道在高盐状态下是否存在一种机制，可以减弱醛固酮的反应，从而在摄入大量 K+ 后防止肾脏 Na+ 重吸收：方法：给小鼠喂食含有不同量 Na+ 和 KCl 或柠檬酸盐的食物。在含有正常或高[Cl-]的培养基中培养小鼠皮质连接管（mCCDcl1）细胞。通过高分辨率成像和生化方法分析了细胞对醛固酮的反应：结果：尽管血浆醛固酮浓度升高，但在以高氯化钾饮食喂养的 Na+ 充足的小鼠中，细胞对醛固酮的典型反应（包括矿质皮质激素受体（MR）的转位和上皮 Na+ 通道 ENaC 的激活）受到抑制。当通过喂食高柠檬酸盐饮食防止细胞外[Cl-]增加时，Na+完全的小鼠对醛固酮的反应就会恢复。在 mCCDcl1 细胞中，细胞外 [Cl-] 的升高足以破坏醛固酮诱导的 MR 转位：这些研究结果表明，细胞外[Cl-]在调节肾醛固酮信号，使高K+摄入的MR激活适应NaCl平衡方面起着关键作用。[Cl-]介导的醛固酮抗性受损可能会导致醛固酮过度激活醛固酮，从而导致不适当的盐重吸收及其下游有害影响。

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引用次数: 0

The effects of cannabinoids on the kidney 大麻素对肾脏的影响。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-10-24 DOI: 10.1111/apha.14247

Steven Didik, Oleg Palygin, Mark Chandy, Alexander Staruschenko

Cannabinoids are a class of drugs derived from the Cannabis plant that are widely used for the treatment of various medical conditions and recreational use. Common examples include Δ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD), spice, and 2-arachidonoylglycerol (2-AG). With more than 100 cannabinoids identified, their influence on the nervous system, role in pain management, and effects due to illicit use have been extensively studied. However, their effects on peripheral organs, such as the kidneys, require further examination. With dramatic rises in use, production, and legalization, it is essential to understand the impact and mechanistic properties of these drugs as they pertain to renal and cardiovascular physiology. The goal of this review is to summarize prior literature on the expression of cannabinoid receptors and how cannabinoids influence renal function. This review first discusses the interaction of the endocannabinoid system (ECS) and renal physiology and pathophysiology. Following, we briefly discuss the role of the ECS in various kidney diseases and the potential therapeutic applications of drugs targeting the cannabinoid system. Lastly, recent studies have identified several detrimental effects of cannabinoids, not only on the kidney but also in contributing to adverse cardiovascular outcomes. Thus, the negative impact of cannabinoids on renal function and the development of various cardiovascular diseases is also discussed.

大麻素是一类从大麻植物中提取的药物，被广泛用于治疗各种病症和娱乐用途。常见的例子包括Δ9-四氢大麻酚（THC）、大麻二酚（CBD）、香料和 2-阿拉西酮酰甘油（2-AG）。目前已确认的大麻素有 100 多种，人们已广泛研究了它们对神经系统的影响、在止痛方面的作用以及非法使用所产生的影响。不过，它们对肾脏等外周器官的影响还需要进一步研究。随着使用、生产和合法化的急剧增加，了解这些药物对肾脏和心血管生理学的影响和机理特性至关重要。本综述旨在总结有关大麻素受体表达以及大麻素如何影响肾功能的以往文献。本综述首先讨论了内源性大麻素系统（ECS）与肾脏生理和病理生理学之间的相互作用。随后，我们简要讨论了 ECS 在各种肾脏疾病中的作用以及针对大麻素系统的药物的潜在治疗应用。最后，最近的研究发现了大麻素的几种有害影响，不仅对肾脏有害，而且还会导致不良的心血管后果。因此，本文还讨论了大麻素对肾功能和各种心血管疾病发展的负面影响。

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引用次数: 0

Histone deacetylase 6 inhibition promotes microtubule acetylation and facilitates autophagosome–lysosome fusion in dystrophin-deficient mdx mice 抑制组蛋白去乙酰化酶 6 可促进微管乙酰化，并有助于肌营养不良 mdx 小鼠的自噬体-溶酶体融合。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-10-18 DOI: 10.1111/apha.14243

Akanksha Agrawal, Erin L. Clayton, Courtney L. Cavazos, Benjamin A. Clayton, George G. Rodney

Aim

Duchenne muscular dystrophy is a progressive muscle-wasting disease caused by mutations in the dystrophin gene. Despite progress in dystrophin-targeted gene therapies, it is still a fatal disease requiring novel therapeutics that can be used synergistically or alternatively to emerging gene therapy. Defective autophagy and disorganized microtubule networks contribute to dystrophic pathogenesis, yet the mechanisms by which microtubule alterations regulate autophagy remain elusive. The present study was designed to uncover possible mechanisms underpinning the role of microtubules in regulating autophagy in dystrophic mice.

Methods

Mdx mice were also supplemented with Tubastatin A, a pharmacological inhibitor of histone deacetylase 6, and pathophysiology was assessed. Mdx mice with a genetic deletion of the Nox-2 scaffolding subunit p47^phox were used to assess redox dependence on tubulin acetylation.

Results

Our data show decreased acetylation of α-tubulin with enhanced histone deacetylase 6 expression. Tubastatin A increases tubulin acetylation and Q-SNARE complex formation but does not alter microtubule organization or density, indicating improved autophagosome–lysosome fusion. Tubastatin A increases the acetylation of peroxiredoxin and protects it from hyper-oxidation, hence modulating intracellular redox status in mdx mice. Tubastatin A reduces muscle damage and enhances force production. Genetic down regulation of Nox2 activity in the mdx mice promotes autophagosome maturation but not autolysosome formation.

Conclusion

Our data highlight that autophagy is differentially regulated by redox and acetylation in mdx mice. By improving autophagy through promoting tubulin acetylation, Tubastatin A decreases the dystrophic phenotype and improves muscle function, suggesting a great potential for clinical translation and treating dystrophic patients.

目的：杜氏肌营养不良症是一种进行性肌肉萎缩疾病，由肌营养不良蛋白基因突变引起。尽管肌营养不良症靶向基因疗法取得了进展，但它仍然是一种致命的疾病，需要新型疗法与新出现的基因疗法协同或交替使用。自噬功能缺陷和微管网络紊乱是肌营养不良症发病的原因之一，但微管改变调控自噬功能的机制仍然难以捉摸。本研究旨在揭示微管在肌营养不良小鼠中调节自噬作用的可能机制：Mdx小鼠也补充了组蛋白去乙酰化酶6的药理抑制剂Tubastatin A，并对病理生理学进行了评估。用遗传性缺失 Nox-2 支架亚基 p47phox 的 Mdx 小鼠来评估氧化还原对小管蛋白乙酰化的依赖性：结果：我们的数据显示，α-微管蛋白乙酰化减少，组蛋白去乙酰化酶6表达增强。他巴司汀 A 增加了小管蛋白乙酰化和 Q-SNARE 复合物的形成，但并没有改变微管的组织或密度，这表明自噬体与溶酶体的融合得到了改善。胖司他丁 A 可增加过氧化还蛋白的乙酰化，保护其免受过度氧化，从而调节 mdx 小鼠细胞内的氧化还原状态。管司他丁 A 可减少肌肉损伤，增强肌肉力量。在 mdx 小鼠中通过基因下调 Nox2 的活性可促进自噬体的成熟，但不能促进自噬体的形成：我们的数据突出表明，在 mdx 小鼠体内，自噬受氧化还原和乙酰化的不同调节。通过促进小管蛋白乙酰化来改善自噬，Tubastatin A能减少肌营养不良表型并改善肌肉功能，这表明它在临床转化和治疗肌营养不良患者方面具有巨大潜力。

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引用次数: 0

Beyond hemoglobin: Critical role of 2,3-bisphosphoglycerate mutase in kidney function and injury 超越血红蛋白：2,3-二磷酸甘油酯突变酶在肾功能和肾损伤中的关键作用。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-10-18 DOI: 10.1111/apha.14242

Vera A. Kulow, Kameliya Roegner, Robert Labes, Mumtaz Kasim, Susanne Mathia, Claudia S. Czopek, Nikolaus Berndt, Philipp N. Becker, Gohar Ter-Avetisyan, Friedrich C. Luft, Philipp Enghard, Christian Hinze, Jan Klocke, Kai-Uwe Eckardt, Kai M. Schmidt-Ott, Pontus B. Persson, Christian Rosenberger, Michael Fähling

Aim

2,3-bisphosphoglycerate mutase (BPGM) is traditionally recognized for its role in modulating oxygen affinity to hemoglobin in erythrocytes. Recent transcriptomic analyses, however, have indicated a significant upregulation of BPGM in acutely injured murine and human kidneys, suggesting a potential renal function for this enzyme. Here we aim to explore the physiological role of BPGM in the kidney.

Methods

A tubular-specific, doxycycline-inducible Bpgm-knockout mouse model was generated. Histological, immunofluorescence, and proteomic analyses were conducted to examine the localization of BPGM expression and the impact of its knockout on kidney structure and function. In vitro studies were performed to investigate the metabolic consequences of Bpgm knockdown under osmotic stress.

Results

BPGM expression was localized to the distal nephron and was absent in proximal tubules. Inducible knockout of Bpgm resulted in rapid kidney injury within 4 days, characterized by proximal tubular damage and tubulointerstitial fibrosis. Proteomic analyses revealed involvement of BPGM in key metabolic pathways, including glycolysis, oxidative stress response, and inflammation. In vitro, Bpgm knockdown led to enhanced glycolysis, decreased reactive oxygen species elimination capacity under osmotic stress, and increased apoptosis. Furthermore, interactions between nephron segments and immune cells in the kidney suggested a mechanism for propagating stress signals from distal to proximal tubules.

Conclusion

BPGM fulfills critical functions beyond the erythrocyte in maintaining glucose metabolism in the distal nephron. Its absence leads to metabolic imbalances, increased oxidative stress, inflammation, and ultimately kidney injury.

目的：2,3-二磷酸甘油酯突变酶（BPGM）传统上被认为在调节红细胞中血红蛋白的氧亲和力方面发挥作用。然而，最近的转录组分析表明，BPGM 在急性损伤的小鼠和人类肾脏中显著上调，表明这种酶具有潜在的肾脏功能。在此，我们旨在探索 BPGM 在肾脏中的生理作用：方法：建立了一个肾小管特异性、强力霉素诱导的 BPGM 基因剔除小鼠模型。通过组织学、免疫荧光和蛋白质组学分析，研究 BPGM 的表达定位以及基因敲除对肾脏结构和功能的影响。还进行了体外研究，以探讨在渗透压胁迫下敲除 BPGM 对新陈代谢的影响：结果：BPGM的表达定位于远端肾小球，在近端肾小管中缺失。诱导性敲除 Bpgm 会在 4 天内导致肾脏快速损伤，其特征是近端肾小管损伤和肾小管间质纤维化。蛋白质组分析显示，BPGM 参与了关键的代谢途径，包括糖酵解、氧化应激反应和炎症。在体外，BPGM 基因敲除导致糖酵解增强、渗透压下活性氧消除能力下降以及细胞凋亡增加。此外，肾小管节段与肾脏中免疫细胞之间的相互作用表明，压力信号是从远端肾小管向近端肾小管传播的一种机制：结论：BPGM 在维持远端肾小管葡萄糖代谢方面发挥着超越红细胞的重要功能。它的缺失会导致代谢失衡、氧化应激增加、炎症以及最终的肾损伤。

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引用次数: 0

SUMO: A new perspective to decipher fibrosis SUMO：解读纤维化的新视角

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-10-15 DOI: 10.1111/apha.14240

Ling Li, Ping-Ping Gao, Ting-Ting Chen, Nan Li, Hui-Juan Zhang, Meng-Qi Li, Ya-Ning Chen, Wei Wei, Hua Wang, Wu-Yi Sun

Fibrosis is characterized by excessive extracellular matrix (ECM) deposition resulting from dysregulated wound healing and connective tissue repair mechanisms. Excessive accumulation of ECM leads to fibrous tissue formation, impairing organ function and driving the progression of various fibrotic diseases. Recently, the role of small ubiquitin-like modifiers (SUMO) in fibrotic diseases has attracted significant attention. SUMO-mediated SUMOylation, a highly conserved posttranslational modification, participates in a variety of biological processes, including nuclear-cytosolic transport, cell cycle progression, DNA damage repair, and cellular metabolism. Conversely, SUMO-specific proteases cleave the isopeptide bond of SUMO conjugates, thereby regulating the deSUMOylation process. Mounting evidence indicates that SUMOylation and deSUMOylation regulate the functions of several proteins, such as Smad3, NF-κB, and promyelocytic leukemia protein, which are implicated in fibrotic diseases like liver fibrosis, myocardial fibrosis, and pulmonary fibrosis. This review summarizes the role of SUMO in fibrosis-related pathways and explores its pathological relevance in various fibrotic diseases. All evidence suggest that the SUMO pathway is important targets for the development of treatments for fibrotic diseases.

纤维化的特点是伤口愈合和结缔组织修复机制失调导致细胞外基质（ECM）过度沉积。ECM 的过度积累会导致纤维组织的形成，损害器官功能并推动各种纤维化疾病的发展。最近，小泛素样修饰物（SUMO）在纤维化疾病中的作用引起了人们的极大关注。SUMO介导的SUMOylation是一种高度保守的翻译后修饰，参与多种生物过程，包括核-胞浆转运、细胞周期进展、DNA损伤修复和细胞代谢。相反，SUMO 特异性蛋白酶会裂解 SUMO 共轭物的异肽键，从而调节去 SUMO 化过程。越来越多的证据表明，SUMOylation 和 deSUMOylation 可调节 Smad3、NF-κB 和早幼粒细胞白血病蛋白等多种蛋白质的功能，而这些蛋白质与肝纤维化、心肌纤维化和肺纤维化等纤维化疾病有关。本综述总结了 SUMO 在纤维化相关通路中的作用，并探讨了其在各种纤维化疾病中的病理相关性。所有证据都表明，SUMO通路是开发纤维化疾病治疗方法的重要靶点。

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引用次数: 0

Adipose endothelin signaling—An unusual suspect linking obesity to insulin resistance 脂肪内皮素信号转导--将肥胖与胰岛素抵抗联系起来的不寻常嫌疑人。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-10-08 DOI: 10.1111/apha.14241

Henrik Oster

<p>Endothelins are peptide hormones best known for their function in the regulation of vessel tone. They are mainly secreted by endothelial cells, but expression has been reported for many other tissues including liver, muscle, adipose tissues, and the brain.<span><sup>1</sup></span> The main of the three endothelin isoforms, endothelin-1 (ET-1), is the most potent natural vasoconstrictor known so far and has been implicated in a broad range of cardiovascular diseases. Interestingly, increased ET-1 levels are also reported in obese and diabetic patients, and ET-1 signaling through one of its two receptors, endothelin receptor beta (ET<sub>B</sub>), has been implicated in the regulation of insulin action and glucose homeostasis.</p><p>In this issue, Rivera-Gonzalez and co-workers studied the metabolic function of ET-1/ET<sub>B</sub> signaling in a mouse model of diet-induced obesity.<span><sup>2</sup></span> Their data suggest that ET-1-induced ET<sub>B</sub> signaling in adipose tissues inhibits the expression and release of the adipokine hormone adiponectin. This, in turn, is a well-known sensitizer of insulin signaling and glucose import and metabolization in tissues, such as adipose, muscle, and liver.<span><sup>3</sup></span> The new data offer an intriguing mechanistic explanation for the metabolic function of ET-1 signaling: obesity-induced upregulation of ET-1 expression leads to ET<sub>B</sub>-mediated downregulation of adiponectin release from adipocytes. Diminished adiponectin levels in the circulation, in turn, would desensitize insulin signaling and glucose disposal in target tissues promoting hyperglycemia and the development of insulin resistance (Figure 1).</p><p>The authors of this study provide several lines of evidence supporting their conclusions. First, they studied metabolic responses to ET-1 treatment in primary adipocytes upon genetic or pharmacological inhibition of ET<sub>B</sub> signaling. They show that ET-1 downregulates expression of the master metabolic transcriptional regulator, peroxisome proliferator-activated receptor gamma (<i>Pparγ</i>), and adiponectin (<i>Adipoq</i>). Second, they generated mice that specifically carry a knockout of or overexpress ET<sub>B</sub> in adipose tissue. By adipose tissue RNA-sequencing, they show that genes associated with metabolic pathways like insulin and adipokine signaling are upregulated in ET<sub>B</sub> knockout animals under high-fat-diet conditions. These include insulin receptor 1 (<i>Irs-1</i>), the insulin-dependent glucose transporter GLUT4 (<i>Slc2a4</i>), and adiponectin (<i>Adipoq</i>). Effects on other adipokines such as leptin and adipsin were also observed suggesting a pro-obesogenic action of ET-1 in adipose tissue. These effects were more pronounced in—hormonally more active—visceral compared to subcutaneous adipose depots. Finally, knockout of ET<sub>B</sub> improved insulin sensitivity and glucose handling in obese animals, while ET<sub>B</sub> overexpressio

虽然这可能是由于饮食的特殊选择（高脂肪而不是像自助餐厅饮食那样的糖尿病饮食）或 8 周的适度干预期，但也可能意味着应考虑 ET-1 作用的其他部位，如肌肉或大脑。此外，ET-1/ETB/降脂素/胰岛素信号传导是否只发生在脂肪组织中，或者是否涉及降脂素的全身效应，也还有待证明。总之，Rivera-Gonzalez 及其合作者提供了令人信服的证据，证明 ET-1 信号可能是连接胰岛素抵抗和心血管功能障碍这两种肥胖症重要并发症的有吸引力的替代靶点。Henrik Oster：构思、验证、撰写。本社论中的工作未获得任何资助，作者声明无利益冲突。本社论中的工作无需征得患者同意。

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引用次数: 0