Function Pub Date : 2024-06-13 DOI: 10.1093/function/zqae031

Ana M. Hernández-Vega, Itzel Llorente, Raúl Sánchez-Hernández, Yayoi Segura, Teresa Tusié-Luna, Luis E Morales-Buenrostro, R. García-Villegas, León D Islas, Tamara Rosenbaum

{"title":"Identification and properties of TRPV4 mutant channels present in polycystic kidney disease patients","authors":"Ana M. Hernández-Vega, Itzel Llorente, Raúl Sánchez-Hernández, Yayoi Segura, Teresa Tusié-Luna, Luis E Morales-Buenrostro, R. García-Villegas, León D Islas, Tamara Rosenbaum","doi":"10.1093/function/zqae031","DOIUrl":"https://doi.org/10.1093/function/zqae031","url":null,"abstract":"\u0000 Polycystic kidney disease (PKD), a disease characterized by enlargement of the kidney through cystic growth is the fourth leading cause of end-stage kidney disease world-wide. TRPV4, a calcium-permeable TRP, channel participates in kidney cell physiology and since TRPV4 forms complexes with another channel whose malfunction is associated to PKD, TRPP2 (or PKD2), we sought to determine whether patients with PKD, exhibit previously unknown mutations in TRPV4. Here, we report the presence of mutations in the TRPV4 gene in patients diagnosed with PKD and determine that they produce gain-of-function (GOF). Mutations in the sequence of the TRPV4 gene have been associated to a broad spectrum of neuropathies and skeletal dysplasias but not PKD, and their biophysical effects on channel function have not been elucidated. We identified and examined the functional behavior of a novel E6K mutant and of the previously known S94L and A217S mutant TRVP4 channels. The A217S mutation has been associated to mixed neuropathy and/or skeletal dysplasia phenotypes, however, the PKD carriers of these variants had not been diagnosed with these reported clinical manifestations. The presence of certain mutations in TRPV4 may influence the progression and severity of PKD through GOF mechanisms. PKD patients carrying TRVP4 mutations are putatively more likely to require dialysis or renal transplant as compared to those without these mutations.","PeriodicalId":503843,"journal":{"name":"Function","volume":"61 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141349491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PAR1-mediated Non-periodical Synchronized Calcium Oscillations in human Mesangial Cells 人间质细胞中 PAR1 介导的非周期性同步钙振荡

Function Pub Date : 2024-06-10 DOI: 10.1093/function/zqae030

Mariia Stefanenko, M. Fedoriuk, M. Mamenko, M. Semenikhina, Tamara K Nowling, Joshua H Lipschutz, Oleksandr Maximyuk, Alexander Staruschenko, Oleg Palygin

{"title":"PAR1-mediated Non-periodical Synchronized Calcium Oscillations in human Mesangial Cells","authors":"Mariia Stefanenko, M. Fedoriuk, M. Mamenko, M. Semenikhina, Tamara K Nowling, Joshua H Lipschutz, Oleksandr Maximyuk, Alexander Staruschenko, Oleg Palygin","doi":"10.1093/function/zqae030","DOIUrl":"https://doi.org/10.1093/function/zqae030","url":null,"abstract":"\u0000 Mesangial cells offer structural support to the glomerular tuft and regulate glomerular capillary flow through their contractile capabilities. These cells undergo phenotypic changes, such as proliferation and mesangial expansion, resulting in abnormal glomerular tuft formation and reduced capillary loops. Such adaptation to the changing environment is commonly associated with various glomerular diseases, including diabetic nephropathy and glomerulonephritis. Thrombin-induced mesangial remodeling was found in diabetic patients, and expression of the corresponding protease-activated receptors (PARs) in the renal mesangium was reported. However, the functional PAR-mediated signaling in mesangial cells was not examined. This study investigated protease-activated mechanisms regulating mesangial cell calcium waves that may play an essential role in the mesangial proliferation or constriction of the arteriolar cells. Our results indicate that coagulation proteases like thrombin induce synchronized oscillations in cytoplasmic Ca2+ concentration of mesangial cells. The oscillations required PAR1 GPCRs-related activation, but not a PAR4, and were further mediated presumably through store-operated calcium entry and TRPC3 channel activity. Understanding thrombin signaling pathways and their relation to mesangial cells' contractile or synthetic (proliferative) phenotype may play a role in the development of chronic kidney disease and requires further investigation.","PeriodicalId":503843,"journal":{"name":"Function","volume":"101 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141362759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dmxl1 is an Essential Mammalian Gene that is Required for V-ATPase Assembly and Function In Vivo Dmxl1 是哺乳动物体内 V-ATP 酶组装和功能所必需的基因

Function Pub Date : 2024-05-16 DOI: 10.1093/function/zqae025

Amity F. Eaton, Elizabeth C Danielson, Diane Capen, M. Merkulova, Dennis Brown

{"title":"Dmxl1 is an Essential Mammalian Gene that is Required for V-ATPase Assembly and Function In Vivo","authors":"Amity F. Eaton, Elizabeth C Danielson, Diane Capen, M. Merkulova, Dennis Brown","doi":"10.1093/function/zqae025","DOIUrl":"https://doi.org/10.1093/function/zqae025","url":null,"abstract":"\u0000 The proton pumping V-ATPase drives essential biological processes, such as acidification of intracellular organelles. Critically, the V-ATPase domains, V1 and VO, must assemble to produce a functional holoenzyme. V-ATPase dysfunction results in cancer, neurodegeneration, and diabetes, as well as systemic acidosis caused by reduced activity of proton-secreting kidney intercalated cells (ICs). However, little is known about the molecular regulation of V-ATPase in mammals. We identified a novel interactor of the mammalian V-ATPase, Drosophila melanogaster X chromosomal gene-like 1 (Dmxl1), aka Rabconnectin-3A. The yeast homologue of Dmxl1, Rav1p, is part of a complex that catalyzes the reversible assembly of the domains. We, therefore, hypothesized that Dmxl1 is a mammalian V-ATPase assembly factor. Here, we generated kidney IC-specific Dmxl1 knockout (KO) mice, which had high urine pH, like B1 V-ATPase KO mice, suggesting impaired V-ATPase function. Western blotting showed decreased B1 expression and B1 (V1) and a4 (VO) subunits were more intracellular and less colocalized in Dmxl1 KO ICs. In parallel, subcellular fractionation revealed less V1 associated B1 in the membrane fraction of KO cells relative to the cytosol. Furthermore, a Proximity Ligation Assay (PLA) performed using probes against B1 and a4 V-ATPase subunits also revealed decreased association. We propose that loss of Dmxl1 reduces V-ATPase holoenzyme assembly, thereby inhibiting proton pumping function. Dmxl1 may recruit the V1 domain to the membrane and facilitate assembly with the VO domain and in its absence V1 may be targeted for degradation. We conclude that Dmxl1 is a bona-fide mammalian V-ATPase assembly factor.","PeriodicalId":503843,"journal":{"name":"Function","volume":"27 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140970978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Physiology Brings Relevance to Biological Research: A Vision for Function 生理学为生物研究带来现实意义：功能展望

Function Pub Date : 2024-05-06 DOI: 10.1093/function/zqae023

David M Pollock

引用次数: 0

Brain Ballet: The Choreography of Left-Right Neuroendocrine Signals in Injury. A Perspective on “The Left-Right Side-Specific Neuroendocrine Signaling from Injured Brain: An Organizational Principle” 大脑芭蕾：损伤中左右神经内分泌信号的编排。透视 "来自损伤大脑的左右侧特异性神经内分泌信号：组织原则 "的视角

Function Pub Date : 2024-05-03 DOI: 10.1093/function/zqae022

M.T. Holland, Bryan Becker

引用次数: 0

It's all about the CREY! 这一切都与 CREY 有关！

Function Pub Date : 2024-04-22 DOI: 10.1093/function/zqae021

Stephanie Franzén

引用次数: 0

Exit, O Sodium! 出口，钠啊！

Function Pub Date : 2024-04-08 DOI: 10.1093/function/zqae018

S. Pirkmajer, A. Chibalin

引用次数: 0

Combination of The CRAC Channel Inhibitor CM4620 And Galactose as A Potential Therapy for Acute Pancreatitis CRAC通道抑制剂CM4620与半乳糖的联合疗法有望治疗急性胰腺炎

Function Pub Date : 2024-04-05 DOI: 10.1093/function/zqae017

S. Lewis, D. Evans, T. Tsugorka, S. Peng, K. Stauderman, O. Gerasimenko, J. Gerasimenko

{"title":"Combination of The CRAC Channel Inhibitor CM4620 And Galactose as A Potential Therapy for Acute Pancreatitis","authors":"S. Lewis, D. Evans, T. Tsugorka, S. Peng, K. Stauderman, O. Gerasimenko, J. Gerasimenko","doi":"10.1093/function/zqae017","DOIUrl":"https://doi.org/10.1093/function/zqae017","url":null,"abstract":"\u0000 Acute pancreatitis (AP) is a life-threatening inflammatory disease with no specific therapy. Excessive cytoplasmic Ca2+ elevation and intracellular ATP depletion are responsible for the initiation of AP. Inhibition of CRAC channels has been proposed as a potential treatment and currently, a novel selective CRAC channel inhibitor CM4620 (AuxoraTM, CalciMedica), is in Phase 2b human trials. While CM4620 is on track to become the first effective treatment for AP, it does not produce complete protection in animal models. Recently, an alternative approach has suggested reducing ATP depletion with a natural carbohydrate galactose. Here we have investigated the possibility of using the smallest effective concentration of CM4620 in combination with galactose.\u0000 Protective effects of CM4620, in the range of 1-100 nM, have been studied against necrosis induced by either bile acids, palmitoleic acid or L-asparaginase. CM4620 markedly protected against necrosis induced by bile acids or asparaginase starting from 50 nM, and palmitoleic acid starting from 1 nM. Combining CM4620 and galactose (1 mM) significantly reduced the extent of necrosis to near-control levels. In the palmitoleic acids-alcohol-induced experimental mouse model of AP, CM4620 at a concentration of 0.1 mg/kg alone significantly reduced oedema, necrosis, inflammation, and the total histopathological score. A combination of 0.1 mg/kg CM4620 with galactose (100 mM) significantly reduced further necrosis, inflammation, and histopathological score.\u0000 Our data show that CM4620 can be used at much lower concentrations than reported previously, reducing potential side effects. The novel combination of CM4620 with galactose synergistically targets complementary pathological mechanisms of AP.","PeriodicalId":503843,"journal":{"name":"Function","volume":"3 11‐12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140739846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lipidomic Profiling of Kidney Cortical Tubule Segments Identifies Lipotypes with Physiological Implications 肾皮质小管部分的脂质组图谱鉴定出具有生理意义的脂型

Function Pub Date : 2024-03-30 DOI: 10.1093/function/zqae016

L. Cheval, Virginie Poindessous, Julio L Sampaio, Gilles Crambert, Nicolas Pallet

{"title":"Lipidomic Profiling of Kidney Cortical Tubule Segments Identifies Lipotypes with Physiological Implications","authors":"L. Cheval, Virginie Poindessous, Julio L Sampaio, Gilles Crambert, Nicolas Pallet","doi":"10.1093/function/zqae016","DOIUrl":"https://doi.org/10.1093/function/zqae016","url":null,"abstract":"\u0000 A detailed knowledge of the lipid composition of components of nephrons is crucial for understanding physiological processes and the development of kidney diseases. However, the lipidomic composition of kidney tubular segments is unknown. We manually isolated the proximal convoluted tubule (PCT), the cortical thick ascending limb of Henle's loop (cTAL) and the cortical collecting duct (CCD) from five lean and obese mice and subjected the samples to shotgun lipidomics analysis by high resolution mass spectrometry acquisition. Across all samples, more than five hundred lipid species were identified, quantified and compared. We observed significant compositional differences among the three tubular segments, which serve as true signatures. These intrinsic lipidomic features are associated with a distinct proteomic program that regulates highly specific physiological functions. The distinctive lipidomic features of each of the three segments are mostly based on the relative composition of neutral lipids, long-chain polyunsaturated fatty acids, sphingolipids, and ether phospholipids. These features support the hypothesis of a lipotype assigned to specific tubular segments. Obesity profoundly impacts the lipotype of proximal convoluted tubules. In conclusion, we present a comprehensive lipidomic analysis of three cortical segments of mouse kidney tubules. This valuable resource provides unparalleled detail that enhances our understanding of tubular physiology and the potential impact of pathological conditions.","PeriodicalId":503843,"journal":{"name":"Function","volume":"8 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140362549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Systems Approaches to Cell Culture-Derived Extracellular Vesicles for Acute Kidney Injury Therapy: Prospects And Challenges 细胞培养产生的细胞外囊泡用于急性肾损伤治疗的系统方法：前景与挑战

Function Pub Date : 2024-03-28 DOI: 10.1093/function/zqae012

David J. Lundy, Barbara Szomolay, Chia-Te Liao

{"title":"Systems Approaches to Cell Culture-Derived Extracellular Vesicles for Acute Kidney Injury Therapy: Prospects And Challenges","authors":"David J. Lundy, Barbara Szomolay, Chia-Te Liao","doi":"10.1093/function/zqae012","DOIUrl":"https://doi.org/10.1093/function/zqae012","url":null,"abstract":"\u0000 Acute kidney injury (AKI) is a heterogeneous syndrome, comprising diverse aetiologies of kidney insults which result in high mortality and morbidity if not well-managed. Although great efforts have been made to investigate underlying pathogenic mechanisms of AKI, there are limited therapeutic strategies available. Extracellular vesicles (EV) are membrane-bound vesicles secreted by various cell types which can serve as cell-free therapy through transfer of bioactive molecules. In this review, we first overview the AKI syndrome and EV biology, with a particular focus on the technical aspects and therapeutic application of cell culture-derived EVs. Secondly, we illustrate how multi-omic approaches to EV miRNA, protein and genomic cargo analysis can yield new insights into their mechanisms of action and address unresolved questions in the field. We then summarise major experimental evidence regarding the therapeutic potential of EVs in AKI, which we subdivide into stem cell and non-stem cell-derived EVs. Finally, we highlight the challenges and opportunities related to clinical translation of animal studies into human patients.","PeriodicalId":503843,"journal":{"name":"Function","volume":"105 17","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140370705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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