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Mannan A, Mohan M, Gulati A, Dhiman S, Singh TG. Aquaporin proteins: A promising frontier for therapeutic intervention in cerebral ischemic injury. Cell Signal 2024; 124:111452. [PMID: 39369758 DOI: 10.1016/j.cellsig.2024.111452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 09/25/2024] [Accepted: 10/01/2024] [Indexed: 10/08/2024]
Abstract
Cerebral ischemic injury is characterized by reduced blood flow to the brain, remains a significant cause of morbidity and mortality worldwide. Despite improvements in therapeutic approaches, there is an urgent need to identify new targets to lessen the effects of ischemic stroke. Aquaporins, a family of water channel proteins, have recently come to light as promising candidates for therapeutic intervention in cerebral ischemic injury. There are 13 aquaporins identified, and AQP4 has been thoroughly involved with cerebral ischemia as it has been reported that modulation of AQP4 activity can offers a possible pathway for therapeutic intervention along with their role in pH, osmosis, ions, and the blood-brain barrier (BBB) as possible therapeutic targets for cerebral ischemia injury. The molecular pathways which can interacts with particular cellular pathways, participation in neuroinflammation, and possible interaction with additional proteins thought to be involved in the etiology of a stroke. Understanding these pathways offers crucial information on the diverse role of AQPs in cerebral ischemia, paving the door for the development of focused/targeted therapeutics.
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Affiliation(s)
- Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Maneesh Mohan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Anshika Gulati
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Sonia Dhiman
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India; School of Public Health, Faculty of Health, University of Technology Sydney, PO Box 123, Broadway, NSW 2007, Australia.
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Mao P, Zhang X, Qian M, Wang Q, Yang Y, Gao Y, Liu H, Wang L. Transcriptomics-based analysis reveals hexafluoropropylene oxide trimer acid (HFPO-TA) induced kidney damage and lipid metabolism disorders in SD rats. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 283:116951. [PMID: 39213752 DOI: 10.1016/j.ecoenv.2024.116951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/18/2024] [Accepted: 08/25/2024] [Indexed: 09/04/2024]
Abstract
Hexafluoropropylene oxide trimer acid (HFPO-TA) is an emerging environmental pollutant that can accumulate in air and surface water. Currently, it has been widely used in fluoropolymer industry, which could cause serious environmental pollution. Due to the high bioaccumulation, the accumulation of pollutants may have an adverse effect on the normal physiological function of the kidneys. However, the toxic effects of HFPO-TA on the kidney are unknown. In this study, we investigated the toxic effects of HFPO-TA exposure on the rat kidney and its mechanism of action. Male SD rats were divided into 4 groups: control group (Ctrl group), L group (0.125 mg/kg/d), M group (0.5 mg/kg/d) and H group (2 mg/kg/d). After 14 consecutive days of gavage, periodic acid‑silver methenamine (PASM) and hematoxylin-eosin (HE) staining were used to examine the structure of the kidneys. We also used transcriptome sequencing (RNA-seq) to identify differentially expressed genes (DEGs) in the testes of rats in both the control and high dose groups. Besides, expression of key proteins was analyzed by immunohistochemistry. The results indicated that HFPO-TA can lead to injured renal capsule, change glomerular shape and have a significant impact on the protein expression levels of AQP2, p-AQP2 and PPARα. Additionally, the level of total cholesterol (TC) was obviously decreased after HFPO-TA exposure. RNA-seq analysis showed that HFPO-TA primarily affected peroxisome proliferator-activated receptor (PPAR) signaling pathway that is associated with lipid metabolism and cyclic adenosine monophosphate (cAMP) signaling pathway. In summary, exposure to HFPO-TA can lead to kidney damage and lipid metabolism disorders.
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Affiliation(s)
- Penghui Mao
- School of Public Health, Bengbu Medical University, Bengbu 233030, PR China
| | - Xuemin Zhang
- Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical University, Bengbu 233030, PR China; Bengbu Medical College Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, PR China
| | - Mingqing Qian
- School of Public Health, Bengbu Medical University, Bengbu 233030, PR China
| | - Qi Wang
- School of Fundamental Sciences, Bengbu Medical University, Bengbu, Anhui Province 233030, PR China
| | - Ying Yang
- Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical University, Bengbu 233030, PR China; Bengbu Medical College Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, PR China
| | - Yangli Gao
- School of Public Health, Bengbu Medical University, Bengbu 233030, PR China
| | - Hui Liu
- Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical University, Bengbu 233030, PR China; Bengbu Medical College Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, PR China.
| | - Li Wang
- School of Public Health, Bengbu Medical University, Bengbu 233030, PR China.
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Wang L, Sun W, Ma X, Griffin N, Liu H. Perfluorooctanoic acid (PFOA) exposure induces renal filtration and reabsorption disorders via down-regulation of aquaporins. Toxicol Lett 2024; 392:22-35. [PMID: 38123106 DOI: 10.1016/j.toxlet.2023.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 10/18/2023] [Accepted: 12/04/2023] [Indexed: 12/23/2023]
Abstract
Perfluorooctanoic acid (PFOA) exposure is associated with kidney dysfunction, however the exact mechanisms by which PFOA induces nephrotoxicity and the specific involvement of aquaporins (AQPs) in kidney tissue remains unclear. In this study, adult male Sprague-Dawley (SD) rats were exposed to PFOA by oral gavage for 28 days and compared with controls. Body weight, water intake and urine volume were recorded daily. At the end of the experiment, blood and kidney samples were collected, and serum urea, creatine and uric acid levels were assessed. The renal expression levels of water channel proteins AQP1, AQP3, AQP2 and p-AQP2 (Ser256) were observed by immunohistochemical staining, and the corresponding transcription levels were detected by Western blot and qRT-PCR. The results showed that PFOA exposure inhibited weight gain and increased water intake, urine volume, kidney weight and renal visceral index. PASM staining and transmission electron microscopy revealed pathological thickening of the glomerular capsule and basement membrane. Serum urea levels were increased, while serum creatine levels were decreased compared to controls. Additionally, the expression levels of AQP1, AQP3, AQP2 and p-AQP2 in kidney tissues were decreased, and the phosphorylation of AQP2 at Ser256 was inhibited. In conclusion, we demonstrate that PFOA exposure can damage the renal filtration barrier and reduce the expression level of AQPs in renal tissues, leading to renal filtration and reabsorption disorders.
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Affiliation(s)
- Li Wang
- School of Public Health, Bengbu Medical College, Bengbu 233030, PR China
| | - Weiqiang Sun
- Bengbu Medical College, Bengbu 233030, PR China; Bengbu Medical College Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu 233030, PR China; Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu 233030, PR China; Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu 233030, PR China
| | - Xinzhuang Ma
- School of Public Health, Bengbu Medical College, Bengbu 233030, PR China
| | - Nathan Griffin
- Department of Cell and Tissue Biology, University of California, San Francisco, CA, USA
| | - Hui Liu
- Bengbu Medical College, Bengbu 233030, PR China; Bengbu Medical College Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu 233030, PR China; Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu 233030, PR China; Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu 233030, PR China.
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Markou A, Kitchen P, Aldabbagh A, Repici M, Salman MM, Bill RM, Balklava Z. Mechanisms of aquaporin-4 vesicular trafficking in mammalian cells. J Neurochem 2024; 168:100-114. [PMID: 38102893 PMCID: PMC10953025 DOI: 10.1111/jnc.16029] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 11/24/2023] [Accepted: 12/02/2023] [Indexed: 12/17/2023]
Abstract
The aquaporin-4 (AQP4) water channel is abundantly expressed in the glial cells of the central nervous system and facilitates brain swelling following diverse insults, such as traumatic injury or stroke. Lack of specific and therapeutic AQP4 inhibitors highlights the need to explore alternative routes to control the water permeability of glial cell membranes. The cell surface abundance of AQP4 in mammalian cells fluctuates rapidly in response to changes in oxygen levels and tonicity, suggesting a role for vesicular trafficking in its translocation to and from the cell surface. However, the molecular mechanisms of AQP4 trafficking are not fully elucidated. In this work, early and recycling endosomes were investigated as likely candidates of rapid AQP4 translocation together with changes in cytoskeletal dynamics. In transiently transfected HEK293 cells a significant amount of AQP-eGFP colocalised with mCherry-Rab5-positive early endosomes and mCherry-Rab11-positive recycling endosomes. When exposed to hypotonic conditions, AQP4-eGFP rapidly translocated from intracellular vesicles to the cell surface. Co-expression of dominant negative forms of the mCherry-Rab5 and -Rab11 with AQP4-eGFP prevented hypotonicity-induced AQP4-eGFP trafficking and led to concentration at the cell surface or intracellular vesicles respectively. Use of endocytosis inhibiting drugs indicated that AQP4 internalisation was dynamin-dependent. Cytoskeleton dynamics-modifying drugs also affected AQP4 translocation to and from the cell surface. AQP4 trafficking mechanisms were validated in primary human astrocytes, which express high levels of endogenous AQP4. The results highlight the role of early and recycling endosomes and cytoskeletal dynamics in AQP4 translocation in response to hypotonic and hypoxic stress and suggest continuous cycling of AQP4 between intracellular vesicles and the cell surface under physiological conditions.
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Affiliation(s)
- Andrea Markou
- College of Health and Life SciencesAston UniversityBirminghamUK
- School of Biosciences, Faculty of Health and Medical SciencesUniversity of SurreyGuildfordUK
| | - Philip Kitchen
- College of Health and Life SciencesAston UniversityBirminghamUK
| | - Ahmed Aldabbagh
- College of Health and Life SciencesAston UniversityBirminghamUK
| | | | - Mootaz M. Salman
- Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
- Kavli Institute for NanoScience DiscoveryUniversity of OxfordOxfordUK
| | - Roslyn M. Bill
- College of Health and Life SciencesAston UniversityBirminghamUK
| | - Zita Balklava
- College of Health and Life SciencesAston UniversityBirminghamUK
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Qian M, Ren X, Mao P, Li Z, Qian T, Wang L, Liu H. Transcriptomics-based analysis reveals the nephrotoxic effects of triphenyltin (TPT) on SD rats by affecting RAS, AQPs and lipid metabolism. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2024; 199:105792. [PMID: 38458666 DOI: 10.1016/j.pestbp.2024.105792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 01/06/2024] [Accepted: 01/14/2024] [Indexed: 03/10/2024]
Abstract
Triphenyltin (TPT) is a class of organotin compounds that are extensively used in industry and agriculture. They have endocrine-disrupting effects and cause severe environmental contamination. Pollutants may accumulate in the kidneys and cause pathological complications. However, the mechanism of TPT's toxicological effects on the kidney remains unclear. This study aimed to investigate the toxic effects and mechanism of action of TPT exposure on renal impairment in rats. Male SD rats were divided into four groups: the Ctrl group (control group), TPT-L group (0.5 mg/kg/d), TPT-M group (1 mg/kg/d), and TPT-H group (2 mg/kg/d). After 28 days of exposure to TPT, we observed the morphology and structure of kidney tissue using HE, PASM, and Masson staining. We also detected serum biochemical indexes, performed transcriptome sequencing of rat kidney tissue using RNA-seq. Furthermore, protein expression levels were measured through immunohistochemistry and gene expression levels were determined using RT-qPCR. The study results indicated a decrease in kidney weight and relative kidney weight after 28 days of exposure to TPT. Additionally, TPT caused damage to kidney structure and function, as evidenced by HE staining, PASM staining, and serum biochemical tests. Transcriptomics identified 352 DEGs, and enrichment analyses revealed that TPT exposure primarily impacted the renin-angiotensin system (RAS). The expression levels of water channel proteins were reduced, and the expression levels of RAS and lipid metabolism-related genes (Mme, Ace, Fasn, Cyp4a8, Cpt1b and Ppard) were significantly decreased in the TPT-treated group. In summary, exposure to TPT may impair renal structure and function in rats by affecting RAS, AQPs, and lipid metabolism.
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Affiliation(s)
- Mingqing Qian
- School of Public Health, Bengbu Medical University, Bengbu 233030, PR China
| | - Xijuan Ren
- School of Public Health, Bengbu Medical University, Bengbu 233030, PR China
| | - Penghui Mao
- School of Public Health, Bengbu Medical University, Bengbu 233030, PR China
| | - Zhi Li
- School of Public Health, Bengbu Medical University, Bengbu 233030, PR China
| | - Tingting Qian
- Bengbu Medical University Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical University, Bengbu 233030, PR China
| | - Li Wang
- School of Public Health, Bengbu Medical University, Bengbu 233030, PR China.
| | - Hui Liu
- Bengbu Medical University Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical University, Bengbu 233030, PR China.
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Sun Z, Shao X, Wu H, Zhao Y, Cao Y, Li D, Sun Y, Wang Q. Loss of Pten in Renal Tubular Cells Leads to Water Retention by Upregulating AQP2. KIDNEY DISEASES (BASEL, SWITZERLAND) 2022; 9:58-71. [PMID: 36756085 PMCID: PMC9900467 DOI: 10.1159/000528010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 10/26/2022] [Indexed: 12/02/2022]
Abstract
Introduction Phosphatase and tensin (PTEN) is a multifunctional gene associated with the normal development and physiological function of various tissues including the kidney. However, its role in renal tubular reabsorption function has not been well elucidated. Methods We generated a renal tubule-specific Pten knockout mouse model by crossing Ptenfl/fl mice with Ksp-Cre transgenic mice, evaluated the effect of Pten loss on renal tubular function, and investigated the underlying mechanisms. Results Pten loss resulted in abnormal renal structure and function and water retention in multiple organs. Our results also demonstrated that aquaporin-2 (AQP2), an important water channel protein, was upregulated and concentrated on the apical plasma membrane of collecting duct cells, which could be responsible for the impaired water balance in Pten loss mice. The regulation of Pten loss on AQP2 was mediated by protein kinase B (AKT) activation. Conclusions Our results reveal a connection between PTEN gene inactivation and water retention, suggesting the importance of PTEN in normal kidney development and function.
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Affiliation(s)
- Zhuo Sun
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, China
| | - Xiaotong Shao
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, China
| | - Haotian Wu
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, China
| | - Yaxian Zhao
- Department of Pathology, Xuzhou Maternity and Child Health Care Hospital, Xuzhou, China
| | - Yidan Cao
- Department of Pathology, Wuxi No.2 People's Hospital, Wuxi, China
| | - Danhua Li
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, China
| | - Ying Sun
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Qingling Wang
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, China,*Qingling Wang,
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Altered Expression of AQP1 and AQP4 in Brain Barriers and Cerebrospinal Fluid May Affect Cerebral Water Balance during Chronic Hypertension. Int J Mol Sci 2022; 23:ijms232012277. [PMID: 36293145 PMCID: PMC9603298 DOI: 10.3390/ijms232012277] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 10/03/2022] [Accepted: 10/11/2022] [Indexed: 11/07/2022] Open
Abstract
Hypertension is the leading cause of cardiovascular affection and premature death worldwide. The spontaneously hypertensive rat (SHR) is the most common animal model of hypertension, which is characterized by secondary ventricular dilation and hydrocephalus. Aquaporin (AQP) 1 and 4 are the main water channels responsible for the brain’s water balance. The present study focuses on defining the expression of AQPs through the time course of the development of spontaneous chronic hypertension. We performed immunofluorescence and ELISA to examine brain AQPs from 10 SHR, and 10 Wistar−Kyoto (WKY) rats studied at 6 and 12 months old. There was a significant decrease in AQP1 in the choroid plexus of the SHR-12-months group compared with the age-matched control (p < 0.05). In the ependyma, AQP4 was significantly decreased only in the SHR-12-months group compared with the control or SHR-6-months groups (p < 0.05). Per contra, AQP4 increased in astrocytes end-feet of 6 months and 12 months SHR rats (p < 0.05). CSF AQP detection was higher in the SHR-12-months group than in the age-matched control group. CSF findings were confirmed by Western blot. In SHR, ependymal and choroidal AQPs decreased over time, while CSF AQPs levels increased. In turn, astrocytes AQP4 increased in SHR rats. These AQP alterations may underlie hypertensive-dependent ventriculomegaly.
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Kandel Y, Pinch M, Lamsal M, Martinez N, Hansen IA. Exploratory phosphoproteomics profiling of Aedes aegypti Malpighian tubules during blood meal processing reveals dramatic transition in function. PLoS One 2022; 17:e0271248. [PMID: 35802606 PMCID: PMC9269769 DOI: 10.1371/journal.pone.0271248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/24/2022] [Indexed: 11/20/2022] Open
Abstract
Malpighian tubules, the renal organs of mosquitoes, facilitate the rapid dehydration of blood meals through aquaporin-mediated osmosis. We performed phosphoproteomics analysis of three Malpighian tubule protein-libraries (1000 tubules/sample) from unfed female mosquitoes as well as one and 24 hours after a blood meal. We identified 4663 putative phosphorylation sites in 1955 different proteins. Our exploratory dataset reveals blood meal-induced changes in phosphorylation patterns in many subunits of V-ATPase, proteins of the target of rapamycin signaling pathway, vesicle-mediated protein transport proteins, proteins involved in monocarboxylate transport, and aquaporins. Our phosphoproteomics data suggest the involvement of a variety of new pathways including nutrient-signaling, membrane protein shuttling, and paracellular water flow in the regulation of urine excretion. Our results support a model in which aquaporin channels translocate from intracellular vesicles to the cell membrane of stellate cells and the brush border membrane of principal cells upon blood feeding.
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Affiliation(s)
- Yashoda Kandel
- Department of Biology, New Mexico State University, Las Cruces, New Mexico, United States of America
| | - Matthew Pinch
- Department of Biology, New Mexico State University, Las Cruces, New Mexico, United States of America
| | - Mahesh Lamsal
- Department of Biology, New Mexico State University, Las Cruces, New Mexico, United States of America
| | - Nathan Martinez
- Department of Biology, New Mexico State University, Las Cruces, New Mexico, United States of America
| | - Immo A. Hansen
- Department of Biology, New Mexico State University, Las Cruces, New Mexico, United States of America
- Institute of Applied Biosciences, New Mexico State University, Las Cruces, New Mexico, United States of America
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Yang L, Huang S, Zhang Z, Liu Z, Zhang L. Roles and Applications of Red Blood Cell-Derived Extracellular Vesicles in Health and Diseases. Int J Mol Sci 2022; 23:ijms23115927. [PMID: 35682606 PMCID: PMC9180222 DOI: 10.3390/ijms23115927] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/19/2022] [Accepted: 05/23/2022] [Indexed: 12/10/2022] Open
Abstract
Red blood cell-derived extracellular vesicles (RBCEVs) are vesicles naturally produced by red blood cells and play multiple roles such as acting as cell-to-cell communication messengers in both normal physiological and diseased states. RBCEVs are highly promising delivery vehicles for therapeutic agents such as biomolecules and nucleic acids as they are easy to source, safe, and versatile. RBCEVs autonomously target the liver and pass the blood-brain barrier into the brain, which is highly valuable for the treatment of liver and brain diseases. RBCEVs can be modified by various functional units, including various functional molecules and nanoparticles, to improve their active targeting capabilities for tumors or other sites. Moreover, the RBCEV level is significantly shifted in many diseased states; hence, they can also serve as important biomarkers for disease diagnoses. It is clear that RBCEVs have considerable potential in multiple medical applications. In this review, we briefly introduce the biological roles of RBCEVs, presented interesting advances in RBCEV applications, and discuss several challenges that need to be addressed for their clinical translation.
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Affiliation(s)
- Lan Yang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; (L.Y.); (S.H.); (Z.Z.)
| | - Shiqi Huang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; (L.Y.); (S.H.); (Z.Z.)
| | - Zhirong Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; (L.Y.); (S.H.); (Z.Z.)
| | - Zhenmi Liu
- Med-X Center for Materials, West China School of Public Health, Sichuan University, Chengdu 610041, China;
| | - Ling Zhang
- Med-X Center for Materials, College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, China
- Correspondence:
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Kobayashi A, Hamada M, Yoshida MA, Kobayashi Y, Tsutsui N, Sekiguchi T, Matsukawa Y, Maejima S, Gingell JJ, Sekiguchi S, Hamamoto A, Hay DL, Morris JF, Sakamoto T, Sakamoto H. Vasopressin-oxytocin-type signaling is ancient and has a conserved water homeostasis role in euryhaline marine planarians. SCIENCE ADVANCES 2022; 8:eabk0331. [PMID: 35245108 PMCID: PMC8896804 DOI: 10.1126/sciadv.abk0331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
Vasopressin/oxytocin (VP/OT)-related peptides are essential for mammalian antidiuresis, sociosexual behavior, and reproduction. However, the evolutionary origin of this peptide system is still uncertain. Here, we identify orthologous genes to those for VP/OT in Platyhelminthes, intertidal planarians that have a simple bilaterian body structure but lack a coelom and body-fluid circulatory system. We report a comprehensive characterization of the neuropeptide derived from this VP/OT-type gene, identifying its functional receptor, and name it the "platytocin" system. Our experiments with these euryhaline planarians, living where environmental salinities fluctuate due to evaporation and rainfall, suggest that platytocin functions as an "antidiuretic hormone" and also organizes diverse actions including reproduction and chemosensory-associated behavior. We propose that bilaterians acquired physiological adaptations to amphibious lives by such regulation of the body fluids. This neuropeptide-secreting system clearly became indispensable for life even without the development of a vascular circulatory system or relevant synapses.
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Affiliation(s)
- Aoshi Kobayashi
- Ushimado Marine Institute (UMI), Graduate School of Natural Science and Technology, Okayama University, Ushimado, Setouchi, Okayama 701-4303, Japan
| | - Mayuko Hamada
- Ushimado Marine Institute (UMI), Graduate School of Natural Science and Technology, Okayama University, Ushimado, Setouchi, Okayama 701-4303, Japan
| | - Masa-aki Yoshida
- Oki Marine Biological Station, Shimane University, 194 Kamo, Okinoshima, Oki, Shimane 685-0024, Japan
| | - Yasuhisa Kobayashi
- Ushimado Marine Institute (UMI), Graduate School of Natural Science and Technology, Okayama University, Ushimado, Setouchi, Okayama 701-4303, Japan
- Laboratory for Aquatic Biology, Department of Fisheries, Faculty of Agriculture, Kindai University, Nakamachi, Nara, Japan
| | - Naoaki Tsutsui
- Ushimado Marine Institute (UMI), Graduate School of Natural Science and Technology, Okayama University, Ushimado, Setouchi, Okayama 701-4303, Japan
- Department of Marine Bioresources, Faculty of Bioresources, Mie University, Tsu, Mie 514-8507, Japan
| | - Toshio Sekiguchi
- Noto Marine Laboratory, Institute of Nature and Environmental Technology, Division of Marine Environmental Studies, Kanazawa University, Ogi, Noto-cho, Ishikawa 927-0553, Japan
- School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
| | - Yuta Matsukawa
- Ushimado Marine Institute (UMI), Graduate School of Natural Science and Technology, Okayama University, Ushimado, Setouchi, Okayama 701-4303, Japan
| | - Sho Maejima
- Ushimado Marine Institute (UMI), Graduate School of Natural Science and Technology, Okayama University, Ushimado, Setouchi, Okayama 701-4303, Japan
| | - Joseph J. Gingell
- Vertex Pharmaceuticals (Europe) Ltd., Milton Park, Abingdon OX11 4RW, UK
| | - Shoko Sekiguchi
- Ushimado Marine Institute (UMI), Graduate School of Natural Science and Technology, Okayama University, Ushimado, Setouchi, Okayama 701-4303, Japan
| | - Ayumu Hamamoto
- Ushimado Marine Institute (UMI), Graduate School of Natural Science and Technology, Okayama University, Ushimado, Setouchi, Okayama 701-4303, Japan
- Department of Biology, Faculty of Science, Okayama University, 3-1-1 Kita-ku, Tsushimanaka, Okayama 700-8530, Japan
| | - Debbie L. Hay
- School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
- Department of Pharmacology and Toxicology, University of Otago, Otago, New Zealand
| | - John F. Morris
- Department of Physiology, Anatomy, and Genetic, Le Gros Clark Building, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
| | - Tatsuya Sakamoto
- Ushimado Marine Institute (UMI), Graduate School of Natural Science and Technology, Okayama University, Ushimado, Setouchi, Okayama 701-4303, Japan
| | - Hirotaka Sakamoto
- Ushimado Marine Institute (UMI), Graduate School of Natural Science and Technology, Okayama University, Ushimado, Setouchi, Okayama 701-4303, Japan
- Department of Physiology, Anatomy, and Genetic, Le Gros Clark Building, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
- Corresponding author.
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Wagner K, Unger L, Salman MM, Kitchen P, Bill RM, Yool AJ. Signaling Mechanisms and Pharmacological Modulators Governing Diverse Aquaporin Functions in Human Health and Disease. Int J Mol Sci 2022; 23:1388. [PMID: 35163313 PMCID: PMC8836214 DOI: 10.3390/ijms23031388] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023] Open
Abstract
The aquaporins (AQPs) are a family of small integral membrane proteins that facilitate the bidirectional transport of water across biological membranes in response to osmotic pressure gradients as well as enable the transmembrane diffusion of small neutral solutes (such as urea, glycerol, and hydrogen peroxide) and ions. AQPs are expressed throughout the human body. Here, we review their key roles in fluid homeostasis, glandular secretions, signal transduction and sensation, barrier function, immunity and inflammation, cell migration, and angiogenesis. Evidence from a wide variety of studies now supports a view of the functions of AQPs being much more complex than simply mediating the passive flow of water across biological membranes. The discovery and development of small-molecule AQP inhibitors for research use and therapeutic development will lead to new insights into the basic biology of and novel treatments for the wide range of AQP-associated disorders.
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Affiliation(s)
- Kim Wagner
- School of Biomedicine, University of Adelaide, Adelaide, SA 5005, Australia;
| | - Lucas Unger
- College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (L.U.); (P.K.)
| | - Mootaz M. Salman
- Department of Physiology Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK;
- Oxford Parkinson’s Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
| | - Philip Kitchen
- College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (L.U.); (P.K.)
| | - Roslyn M. Bill
- College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (L.U.); (P.K.)
| | - Andrea J. Yool
- School of Biomedicine, University of Adelaide, Adelaide, SA 5005, Australia;
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12
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Immunohistochemical Expression of AQP2 and HSP70 in Broiler Kidney Tissue Treated with Salix tetrasperma Roxb. Extract under Heat Exposure. ScientificWorldJournal 2021; 2021:8711286. [PMID: 34707467 PMCID: PMC8545545 DOI: 10.1155/2021/8711286] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 09/08/2021] [Accepted: 10/05/2021] [Indexed: 11/18/2022] Open
Abstract
The administration of plant extracts to broilers may be a way to mitigate the effects of heat stress. The importance of AQP2 and HSP70 compounds in maintaining the homeostasis of the chicken body when it is subjected to heat stress is well established. This study aims to determine the effect of giving the ethanolic extract of the leaves of Salix tetrasperma Roxb. on the immunohistochemical expression of AQP2 and HSP70 in exposed and unexposed broiler kidney tissue. This study used 36 samples of 28-day-old chicken kidneys. Chickens were kept in individual cages, provided with feed and drinking water ad libitum. The design used was a completely randomized design with 6 treatments and 6 replications: (a) chickens were reared in conditions exposed to heat (HS + 0); (b) chickens were reared in conditions exposed to heat and given Salix extract at a dose of 50 mg/L drinking water (HS + 50); (c) chickens were reared under heat-exposed conditions and given Salix extract at a dose of 100 mg/L drinking water (HS + 100); (d) chickens were reared in conditions without exposure to heat (n-HS + 0); (e) chickens were reared in conditions without exposure to heat and given Salix extract at a dose of 50 mg/L drinking water (nHS + 50); and (f) chickens were reared in conditions exposed without exposure to heat and given 100 mg/L drinking water (nHS + 100) of Salix extract. Salix extract was given for 24 hours and was renewed every 6 hours. The results showed that giving Salix extract 100 mg/L in drinking water to chickens exposed to heat (HS + 100) reduced the value of the H/L ratio. Giving Salix extract 50–100 mg/L in drinking water caused an upregulated AQP2 expression; on the other hand, it downregulated HSP-70 expression, in chicken kidney tubules both exposed to heat stress and nonexposed to heat stress. In conclusion, exposure to heat stress in broiler chickens and giving Salix extract can increase the formation of aquaporin 2 compounds and suppress the formation of HSP70.
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13
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Matchimakul P, Pongkan W, Kongtung P, Mektrirat R. Comparative quantitation of aquaporin-2 and arginine vasopressin receptor-2 localizations among chronic kidney disease and healthy kidney in dogs. Vet World 2021; 14:2773-2781. [PMID: 34903939 PMCID: PMC8654747 DOI: 10.14202/vetworld.2021.2773-2781] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 09/09/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND AND AIM Aquaporin-2 (AQP2) and arginine vasopressin receptor-2 (AVPR2) are proteins that control water homeostasis in principal cells. Chronic kidney disease (CKD) is defined as the impairment and irreversible loss of kidney function and/or structure, which causes water imbalances and polyuria. The study aimed to know the expression of AQPs and AVPR2 in the kidneys of a canine with CKD. MATERIALS AND METHODS The kidneys were collected from two dog carcasses from Small Animal Teaching Hospital, Faculty of Veterinary Medicine, Chiang Mai University. The kidney tissue was prepared for immunohistochemistry and investigated the expression and localization of tissue's AQP2 and AVPR2. For statistical analysis, the Mann-Whitney U-test was applied to the data. RESULTS By immunohistochemistry, AQP2 was expressed strongly in the basolateral and apical membranes of the principal cells, whereas AVPR2 was localized in the principal cell's basolateral membrane in both renal cortex and renal medulla. In the normal kidney, the semi-quantitative immunohistochemistry for the percentage of protein expression of AQP2 and AVPR2 was 5.062±0.4587 and 4.306±0.7695, respectively. In contrast, protein expression of AQP2 and AVPR2 in CKD was found to be 1.218±0.1719 and 0.8536±0.1396, respectively. The data shows that the percentage of AQP2 and AVPR2 expression was decreased, corresponding to a 4-fold and 5-fold in CKD (p<0.001). CONCLUSION Our findings revealed that CKD was a marked decrease in AQP2 and AVPR2 expression. The central role of specific AQP2 and AVPR2 in regulating water homeostasis will provide correlations in case of CKD with polyuria.
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Affiliation(s)
- Pitchaya Matchimakul
- Department of Veterinary Bioscience and Veterinary Public Health, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai 50100, Thailand
- Integrative Research Center for Veterinary Circulatory Sciences, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai 50100, Thailand
| | - Wanpitak Pongkan
- Department of Veterinary Bioscience and Veterinary Public Health, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai 50100, Thailand
- Integrative Research Center for Veterinary Circulatory Sciences, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai 50100, Thailand
| | - Piyamat Kongtung
- Central Laboratory, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai 50100, Thailand
| | - Raktham Mektrirat
- Department of Veterinary Bioscience and Veterinary Public Health, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai 50100, Thailand
- Integrative Research Center for Veterinary Circulatory Sciences, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai 50100, Thailand
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14
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Alvira-Iraizoz F, Gillard BT, Lin P, Paterson A, Pauža AG, Ali MA, Alabsi AH, Burger PA, Hamadi N, Adem A, Murphy D, Greenwood MP. Multiomic analysis of the Arabian camel (Camelus dromedarius) kidney reveals a role for cholesterol in water conservation. Commun Biol 2021; 4:779. [PMID: 34163009 PMCID: PMC8222267 DOI: 10.1038/s42003-021-02327-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 06/06/2021] [Indexed: 02/05/2023] Open
Abstract
The Arabian camel (Camelus dromedarius) is the most important livestock animal in arid and semi-arid regions and provides basic necessities to millions of people. In the current context of climate change, there is renewed interest in the mechanisms that enable camelids to survive in arid conditions. Recent investigations described genomic signatures revealing evolutionary adaptations to desert environments. We now present a comprehensive catalogue of the transcriptomes and proteomes of the dromedary kidney and describe how gene expression is modulated as a consequence of chronic dehydration and acute rehydration. Our analyses suggested an enrichment of the cholesterol biosynthetic process and an overrepresentation of categories related to ion transport. Thus, we further validated differentially expressed genes with known roles in water conservation which are affected by changes in cholesterol levels. Our datasets suggest that suppression of cholesterol biosynthesis may facilitate water retention in the kidney by indirectly facilitating the AQP2-mediated water reabsorption.
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Affiliation(s)
- Fernando Alvira-Iraizoz
- Molecular Neuroendocrinology Research Group, Bristol Medical School: Translational Health Sciences, University of Bristol, Bristol, UK.
| | - Benjamin T Gillard
- Molecular Neuroendocrinology Research Group, Bristol Medical School: Translational Health Sciences, University of Bristol, Bristol, UK
| | - Panjiao Lin
- Molecular Neuroendocrinology Research Group, Bristol Medical School: Translational Health Sciences, University of Bristol, Bristol, UK
| | - Alex Paterson
- Molecular Neuroendocrinology Research Group, Bristol Medical School: Translational Health Sciences, University of Bristol, Bristol, UK
| | - Audrys G Pauža
- Molecular Neuroendocrinology Research Group, Bristol Medical School: Translational Health Sciences, University of Bristol, Bristol, UK
| | - Mahmoud A Ali
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, AL Ain, United Arab Emirates
| | - Ammar H Alabsi
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Pamela A Burger
- Department of Interdisciplinary Life Sciences, Research Institute of Wildlife Ecology, Vetmeduni Vienna, Vienna, Austria
| | - Naserddine Hamadi
- Department of Life and Environmental Sciences, College of Natural and Health Sciences, Zayed University, Abu Dhabi, United Arab Emirates
| | - Abdu Adem
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, AL Ain, United Arab Emirates.
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates.
| | - David Murphy
- Molecular Neuroendocrinology Research Group, Bristol Medical School: Translational Health Sciences, University of Bristol, Bristol, UK
| | - Michael P Greenwood
- Molecular Neuroendocrinology Research Group, Bristol Medical School: Translational Health Sciences, University of Bristol, Bristol, UK
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15
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Manning JA, Shah SS, Nikolic A, Henshall TL, Khew-Goodall Y, Kumar S. The ubiquitin ligase NEDD4-2/NEDD4L regulates both sodium homeostasis and fibrotic signaling to prevent end-stage renal disease. Cell Death Dis 2021; 12:398. [PMID: 33854040 PMCID: PMC8046789 DOI: 10.1038/s41419-021-03688-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 02/06/2023]
Abstract
Kidney disease progression can be affected by Na+ abundance. A key regulator of Na+ homeostasis is the ubiquitin ligase NEDD4-2 and its deficiency leads to increased Na+ transport activity and salt-sensitive progressive kidney damage. However, the mechanisms responsible for high Na+ induced damage remain poorly understood. Here we show that a high Na+ diet compromised kidney function in Nedd4-2-deficient mice, indicative of progression toward end-stage renal disease. Injury was characterized by enhanced tubule dilation and extracellular matrix accumulation, together with sustained activation of both Wnt/β-catenin and TGF-β signaling. Nedd4-2 knockout in cortical collecting duct cells also activated these pathways and led to epithelial-mesenchymal transition. Furthermore, low dietary Na+ rescued kidney disease in Nedd4-2-deficient mice and silenced Wnt/β-catenin and TGF-β signaling. Our study reveals the important role of NEDD4-2-dependent ubiquitination in Na+ homeostasis and protecting against aberrant Wnt/β-catenin/TGF-β signaling in progressive kidney disease.
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Affiliation(s)
- Jantina A. Manning
- grid.1026.50000 0000 8994 5086Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, 5001 Australia
| | - Sonia S. Shah
- grid.1026.50000 0000 8994 5086Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, 5001 Australia
| | - Andrej Nikolic
- grid.1026.50000 0000 8994 5086Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, 5001 Australia
| | - Tanya L. Henshall
- grid.1026.50000 0000 8994 5086Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, 5001 Australia
| | - Yeesim Khew-Goodall
- grid.1026.50000 0000 8994 5086Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, 5001 Australia
| | - Sharad Kumar
- grid.1026.50000 0000 8994 5086Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, 5001 Australia
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16
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Giraud S, Kerforne T, Zely J, Ameteau V, Couturier P, Tauc M, Hauet T. The inhibition of eIF5A hypusination by GC7, a preconditioning protocol to prevent brain death-induced renal injuries in a preclinical porcine kidney transplantation model. Am J Transplant 2020; 20:3326-3340. [PMID: 32400964 DOI: 10.1111/ajt.15994] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/07/2020] [Accepted: 04/29/2020] [Indexed: 01/25/2023]
Abstract
The eIF5A hypusination inhibitor GC7 (N1-guanyl-1,7-diaminoheptane) was shown to protect from ischemic injuries. We hypothesized that GC7 could be useful for preconditioning kidneys from donors before transplantation. Using a preclinical porcine brain death (BD) donation model, we carried out in vivo evaluation of GC7 pretreatment (3 mg/kg iv, 5 minutes after BD) at the beginning of the 4h-donor management, after which kidneys were collected and cold-stored (18h in University of Wisconsin solution) and 1 was allotransplanted. Groups were defined as following (n = 6 per group): healthy (CTL), untreated BD (Vehicle), and GC7-treated BD (Vehicle + GC7). At the end of 4h-management, GC7 treatment decreased BD-induced markers, as radical oxygen species markers. In addition, GC7 increased expression of mitochondrial protective peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC1α) and antioxidant proteins (superoxyde-dismutase-2, heme oxygenase-1, nuclear factor [erythroid-derived 2]-like 2 [NRF2], and sirtuins). At the end of cold storage, GC7 treatment induced an increase of NRF2 and PGC1α mRNA and a better mitochondrial integrity/homeostasis with a decrease of dynamin- related protein-1 activation and increase of mitofusin-2. Moreover, GC7 treatment significantly improved kidney outcome during 90 days follow-up after transplantation (fewer creatininemia and fibrosis). Overall, GC7 treatment was shown to be protective for kidneys against BD-induced injuries during donor management and subsequently appeared to preserve antioxidant defenses and mitochondria homeostasis; these protective effects being accompanied by a better transplantation outcome.
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Affiliation(s)
- Sebastien Giraud
- INSERM UMR-1082 IRTOMIT, Poitiers, France.,Service de Biochimie, CHU de Poitiers, Poitiers, France
| | - Thomas Kerforne
- INSERM UMR-1082 IRTOMIT, Poitiers, France.,Faculté de Médecine et de Pharmacie, Université de Poitiers, Poitiers, France.,Service d'Anesthésie-Réanimation, CHU de Poitiers, Poitiers, France
| | - Jeremy Zely
- INSERM UMR-1082 IRTOMIT, Poitiers, France.,Faculté de Médecine et de Pharmacie, Université de Poitiers, Poitiers, France.,Service d'Anesthésie-Réanimation, CHU de Poitiers, Poitiers, France
| | - Virginie Ameteau
- INSERM UMR-1082 IRTOMIT, Poitiers, France.,Faculté de Médecine et de Pharmacie, Université de Poitiers, Poitiers, France
| | - Pierre Couturier
- INSERM UMR-1082 IRTOMIT, Poitiers, France.,Service de Biochimie, CHU de Poitiers, Poitiers, France.,MOPICT 'plate-forme MOdélisation Préclinique - Innovations Chirurgicale et Technologique', Domaine Expérimental du Magneraud, Surgères, France
| | - Michel Tauc
- Université Cote d'Azur, LP2M, CNRS-7370, Nice, France
| | - Thierry Hauet
- INSERM UMR-1082 IRTOMIT, Poitiers, France.,Service de Biochimie, CHU de Poitiers, Poitiers, France.,Faculté de Médecine et de Pharmacie, Université de Poitiers, Poitiers, France.,MOPICT 'plate-forme MOdélisation Préclinique - Innovations Chirurgicale et Technologique', Domaine Expérimental du Magneraud, Surgères, France.,FHU SUPORT 'SUrvival oPtimization in ORgan Transplantation', Poitiers, France
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17
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Effect of Mesenchymal Stem Cell-Derived Exosomes on Retinal Injury: A Review of Current Findings. Stem Cells Int 2020; 2020:8883616. [PMID: 33082789 PMCID: PMC7556062 DOI: 10.1155/2020/8883616] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 09/14/2020] [Accepted: 09/21/2020] [Indexed: 02/08/2023] Open
Abstract
In recent years, various studies have followed in the literature on the therapeutic effects of mesenchymal stem cells (MSC) on damage in retinal cells. The evidence that MSCs exert their regenerative and damage reduction effect in a paracrine way, through the release of soluble factors and exosomes, is now consolidated. Exosomes are microvesicles formed by a double layer of phospholipid membrane and carry proteins and RNA, through which they play a therapeutic role on target cells. Scientific research has recently focused on the use of exosomes derived from MSC in various models of retinal damage in vitro and in vivo as they, compared to MSCs, have similar functions and at the same time have different advantages such as greater stability and handling, a lower chance of immunological rejection and no risk of malignant transformation. The purpose of this review is to summarize current knowledge on the therapeutic use of exosomes derived from MSCs in retinal damage and to stimulate new clinical perspectives regarding their use.
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18
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Wong KY, Wang WL, Su SH, Liu CF, Yu MJ. Intracellular location of aquaporin-2 serine 269 phosphorylation and dephosphorylation in kidney collecting duct cells. Am J Physiol Renal Physiol 2020; 319:F592-F602. [PMID: 32799672 DOI: 10.1152/ajprenal.00205.2020] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Aquaporin-2 (AQP2) is a vasopressin-regulated water channel protein responsible for water reabsorption by the kidney collecting ducts. Under control conditions, most AQP2 resides in the recycling endosomes of principal cells, where it answers to vasopressin with trafficking to the apical plasma membrane to increase water reabsorption. Upon vasopressin withdrawal, apical AQP2 retreats to the early endosomes before joining the recycling endosomes for the next vasopressin stimulation. Prior studies have demonstrated a role of AQP2 S269 phosphorylation in reducing AQP2 endocytosis, thereby prolonging apical AQP2 retention. Here, we studied where in the cells S269 was phosphorylated and dephosphorylated in response to vasopressin versus withdrawal. In mpkCCD collecting cells, vacuolar protein sorting 35 knockdown slowed vasopressin-induced apical AQP2 trafficking, resulting in AQP2 accumulation in the recycling endosomes where S269 was phosphorylated. Rab7 knockdown, which impaired AQP2 trafficking from the early to recycling endosomes, reduced vasopressin-induced S269 phosphorylation. Rab5 knockdown, which impaired AQP2 endocytosis, did not affect vasopressin-induced S269 phosphorylation. Upon vasopressin withdrawal, S269 was not dephosphorylated in Rab5 knockdown cells. In contrast, S269 dephosphorylation upon vasopressin withdrawal was completed in Rab7 or vacuolar protein sorting 35 knockdown cells. We conclude that S269 is dephosphorylated during Rab5-mediated AQP2 endocytosis before AQP2 joins the recycling endosomes upon vasopressin withdrawal. While in the recycling endosomes, AQP2 can be phosphorylated at S269 in response to vasopressin before apical trafficking.
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Affiliation(s)
- Kit Yee Wong
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wei-Ling Wang
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shih-Han Su
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chin-Fu Liu
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ming-Jiun Yu
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
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19
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Wang WL, Su SH, Wong KY, Yang CW, Liu CF, Yu MJ. Rab7 involves Vps35 to mediate AQP2 sorting and apical trafficking in collecting duct cells. Am J Physiol Renal Physiol 2020; 318:F956-F970. [PMID: 32088968 DOI: 10.1152/ajprenal.00297.2019] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Aquaporin-2 (AQP2) is a vasopressin-regulated water channel protein responsible for osmotic water reabsorption by kidney collecting ducts. In response to vasopressin, AQP2 traffics from intracellular vesicles to the apical plasma membrane of collecting duct principal cells, where it increases water permeability and, hence, water reabsorption. Despite continuing efforts, gaps remain in our knowledge of vasopressin-regulated AQP2 trafficking. Here, we studied the functions of two retromer complex proteins, small GTPase Rab7 and vacuolar protein sorting 35 (Vps35), in vasopressin-induced AQP2 trafficking in a collecting duct cell model (mpkCCD cells). We showed that upon vasopressin removal, apical AQP2 returned to Rab5-positive early endosomes before joining Rab11-positive recycling endosomes. In response to vasopressin, Rab11-associated AQP2 trafficked to the apical plasma membrane before Rab5-associated AQP2 did so. Rab7 knockdown resulted in AQP2 accumulation in early endosomes and impaired vasopressin-induced apical AQP2 trafficking. In response to vasopressin, Rab7 transiently colocalized with Rab5, indicative of a role of Rab7 in AQP2 sorting in early endosomes before trafficking to the apical membrane. Rab7-mediated apical AQP2 trafficking in response to vasopressin required GTPase activity. When Vps35 was knocked down, AQP2 accumulated in recycling endosomes under vehicle conditions and did not traffic to the apical plasma membrane in response to vasopressin. We conclude that Rab7 and Vps35 participate in AQP2 sorting in early endosomes under vehicle conditions and apical membrane trafficking in response to vasopressin.
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Affiliation(s)
- Wei-Ling Wang
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shih-Han Su
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Kit Yee Wong
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chan-Wei Yang
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chin-Fu Liu
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ming-Jiun Yu
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
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20
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Ranjan P, Kumari R, Verma SK. Cardiac Fibroblasts and Cardiac Fibrosis: Precise Role of Exosomes. Front Cell Dev Biol 2019; 7:318. [PMID: 31867328 PMCID: PMC6904280 DOI: 10.3389/fcell.2019.00318] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 11/20/2019] [Indexed: 12/12/2022] Open
Abstract
Exosomes are a group of extracellular microvesicles that deliver biologically active RNAs, proteins, lipids and other signaling molecules to recipient cells. Classically, exosomes act as a vehicle by which cells or organs communicate with each other to maintain cellular/tissue homeostasis and to respond to pathological stress. Most multicellular systems, including the cardiovascular system, use exosomes for intercellular communication. In heart, endogenous exosomes from cardiac cells or stem cells aid in regulation of cell survival, cell proliferation and cell death; and thus tightly regulate cardiac biology and repair processes. Pathological stimulus in heart alters secretion and molecular composition of exosomes, thus influencing the above processes. The past decade has yielded increasing interest in the role of exosomes in the cardiovascular system and significant contribution of cardiac fibroblast (CF) and mediated cardiac fibrosis in heart failure, in this review we had overviewed the relevant literatures about fibroblast exosomes, its effect in the cardiovascular biology and its impact on cardiovascular disease (CVD). This review briefly describes the communication between fibroblasts and other cardiac cells via exosomes, the influence of such on myocardial fibrosis and remodeling, and the possibilities to use exosomes as biomarkers for acute and chronic heart diseases.
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Affiliation(s)
- Prabhat Ranjan
- Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL, United States
| | - Rajesh Kumari
- Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL, United States
| | - Suresh Kumar Verma
- Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL, United States.,Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, AL, United States
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21
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Kumaran GK, Hanukoglu I. Identification and classification of epithelial cells in nephron segments by actin cytoskeleton patterns. FEBS J 2019; 287:1176-1194. [PMID: 31605441 PMCID: PMC7384063 DOI: 10.1111/febs.15088] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 09/11/2019] [Accepted: 10/09/2019] [Indexed: 12/11/2022]
Abstract
The basic functional unit in a kidney is the nephron, which is a long and morphologically segmented tubule. The nephron begins with a cluster of capillaries called glomerulus through which the blood is filtered into the Bowman's space. The filtrate flows through the nephron segments. During this flow, electrolytes and solutes are reabsorbed by channels and transport systems into the capillaries wrapped around the nephron. Many questions related to renal function focus on identifying the sites of expression of these systems. In this study, we mapped whole kidney sections by confocal microscopic imaging of fluorescent phalloidin, which binds to actin filaments. In tile scans (composed of hundreds of images) of these sections, the cortex and the medullary regions (outer and inner stripes of the outer medulla, and inner medulla) could be easily identified by their cytoskeletal patterns. At a higher resolution, we identified distinct features of the actin cytoskeleton in the apical, basal, and lateral borders of the cells. These features could be used to identify segments of a nephron (the proximal tubule, thin and thick segments of Henle's loop, and distal tubule), the collecting duct system, the papillary ducts in the papilla, and the urothelium that covers the pelvis. To verify our findings, we used additional markers, including aquaporin isoforms, cytokeratin 8‐18, and WGA lectin. This study highlights the power of high‐resolution confocal microscopy for identifying specific cell types using the simple probe of F‐actin‐binding phalloidin.
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22
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Xia H, Chen L, Shao D, Liu X, Wang Q, Zhu F, Guo Z, Gao L, Chen K. Vacuolar protein sorting 4 is required for silkworm metamorphosis. INSECT MOLECULAR BIOLOGY 2019; 28:728-738. [PMID: 30955208 DOI: 10.1111/imb.12586] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Vacuolar protein sorting 4 (Vps4) not only functions with its positive regulator vacuolar protein sorting 20-associated 1 (Vta1) in the multivesicular body (MVB) pathway but also participates alone in MVB-unrelated cellular processes. However, its physiological roles at the organism level remain rarely explored. We previously identified their respective homologues Bombyx mori Vps4 (BmVps4) and BmVta1 from the silkworm, a model organism for insect research. In this study, we performed fluorescence quantitative real-time PCR and Western blot to globally characterize the transcription and protein expression profiles of BmVps4 and BmVta1 during silkworm development and in different silkworm tissues and organs. The results showed that they were significantly up-regulated in metamorphosis, adulthood and embryogenesis relative to larval stages, and displayed a roughly similar tissue-and-organ specificity for transcriptions in silkworm larvae. Importantly, BmVps4 was down-regulated during the early period of the fifth instar, reaching the lowest level of transcription on Day 6, then up-regulated from Day 7 to the wandering, spinning and pupal stages, and down-regulated again in adulthood. Moreover, knocking down BmVps4 by RNA interference significantly inhibited silk gland growth, shortened spinning time, prolonged pupation, reduced pupal size and weight, and increased moth wing defects. Together, our data demonstrate the critical and broad requirements for BmVps4 in silkworm metamorphosis.
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Affiliation(s)
- H Xia
- Institute of Life Sciences, Jiangsu University, Zhenjiang, China
| | - L Chen
- Institute of Life Sciences, Jiangsu University, Zhenjiang, China
| | - D Shao
- Institute of Life Sciences, Jiangsu University, Zhenjiang, China
| | - X Liu
- Institute of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Q Wang
- Institute of Life Sciences, Jiangsu University, Zhenjiang, China
| | - F Zhu
- Institute of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Z Guo
- Institute of Life Sciences, Jiangsu University, Zhenjiang, China
| | - L Gao
- Institute of Life Sciences, Jiangsu University, Zhenjiang, China
| | - K Chen
- Institute of Life Sciences, Jiangsu University, Zhenjiang, China
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Gilleron J, Gerdes JM, Zeigerer A. Metabolic regulation through the endosomal system. Traffic 2019; 20:552-570. [PMID: 31177593 PMCID: PMC6771607 DOI: 10.1111/tra.12670] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 06/05/2019] [Accepted: 06/05/2019] [Indexed: 12/13/2022]
Abstract
The endosomal system plays an essential role in cell homeostasis by controlling cellular signaling, nutrient sensing, cell polarity and cell migration. However, its place in the regulation of tissue, organ and whole body physiology is less well understood. Recent studies have revealed an important role for the endosomal system in regulating glucose and lipid homeostasis, with implications for metabolic disorders such as type 2 diabetes, hypercholesterolemia and non-alcoholic fatty liver disease. By taking insights from in vitro studies of endocytosis and exploring their effects on metabolism, we can begin to connect the fields of endosomal transport and metabolic homeostasis. In this review, we explore current understanding of how the endosomal system influences the systemic regulation of glucose and lipid metabolism in mice and humans. We highlight exciting new insights that help translate findings from single cells to a wider physiological level and open up new directions for endosomal research.
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Affiliation(s)
- Jerome Gilleron
- Université Côte d'Azur, Institut National de la Santé et de la Recherche Médicale (INSERM), Mediterranean Center of Molecular Medicine (C3M)NiceFrance
| | - Jantje M. Gerdes
- Institute for Diabetes and RegenerationHelmholtz Center MunichNeuherbergGermany
- German Center for Diabetes Research (DZD)NeuherbergGermany
| | - Anja Zeigerer
- German Center for Diabetes Research (DZD)NeuherbergGermany
- Institute for Diabetes and CancerHelmholtz Center MunichNeuherbergGermany
- Joint Heidelberg‐IDC Translational Diabetes ProgramHeidelberg University HospitalHeidelbergGermany
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24
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Maity S, Ambatipudi K. Quantitative proteomics of milk whey reveals breed and season specific variation in protein abundance in Holstein Friesian cow and Murrah buffalo. Res Vet Sci 2019; 125:244-252. [DOI: 10.1016/j.rvsc.2019.07.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 04/22/2019] [Accepted: 07/09/2019] [Indexed: 12/13/2022]
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25
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Lu TJ, Kan WC, Yang SS, Jiang ST, Wu SN, Ling P, Bao BY, Lin CY, Yang ZY, Weng YP, Chan CH, Lu TL. MST3 is involved in ENaC-mediated hypertension. Am J Physiol Renal Physiol 2019; 317:F30-F42. [PMID: 30969802 DOI: 10.1152/ajprenal.00455.2018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Liddle syndrome is an inherited form of human hypertension caused by increasing epithelial Na+ channel (ENaC) expression. Increased Na+ retention through ENaC with subsequent volume expansion causes hypertension. In addition to ENaC, the Na+-K+-Cl- cotransporter (NKCC) and Na+-Cl- symporter (NCC) are responsible for Na+ reabsorption in the kidneys. Several Na+ transporters are evolutionarily regulated by the Ste20 kinase family. Ste20-related proline/alanine-rich kinase and oxidative stress-responsive kinase-1 phosphorylate downstream NKCC2 and NCC to maintain Na+ and blood pressure (BP) homeostasis. Mammalian Ste20 kinase 3 (MST3) is another member of the Ste20 family. We previously reported that reduced MST3 levels were found in the kidneys in spontaneously hypertensive rats and that MST3 was involved in Na+ regulation. To determine whether MST3 is involved in BP stability through Na+ regulation, we generated a MST3 hypomorphic mutation and designated MST3+/- and MST3-/- mice to examine BP and serum Na+ and K+ concentrations. MST3-/- mice exhibited hypernatremia, hypokalemia, and hypertension. The increased ENaC in the kidney played roles in hypernatremia. The reabsorption of more Na+ promoted more K+ secretion in the kidney and caused hypokalemia. The hypernatremia and hypokalemia in MST3-/- mice were significantly reversed by the ENaC inhibitor amiloride, indicating that MST3-/- mice reabsorbed more Na+ through ENaC. Furthermore, Madin-Darby canine kidney cells stably expressing kinase-dead MST3 displayed elevated ENaC currents. Both the in vivo and in vitro results indicated that MST3 maintained Na+ homeostasis through ENaC regulation. We are the first to report that MST3 maintains BP stability through ENaC regulation.
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Affiliation(s)
- Te-Jung Lu
- Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology , Tainan , Taiwan
| | - Wei-Chih Kan
- Department of Nephrology, Chi-Mei Medical Center , Tainan , Taiwan.,Department of Biological Science and Technology, Chung Hwa University of Medical Technology , Tainan , Taiwan
| | - Sung-Sen Yang
- Division of Nephrology, Department of Medicine, Tri-service General Hospital, Graduate Institute of Medical Sciences, National Defense Medical Center , Taipei , Taiwan
| | - Si-Tse Jiang
- Department of Research and Development, National Laboratory Animal Center, National Applied Research Laboratories , Tainan , Taiwan
| | - Sheng-Nan Wu
- Department of Physiology, College of Medicine, National Cheng Kung University , Tainan , Taiwan
| | - Pin Ling
- Department of Physiology, College of Medicine, National Cheng Kung University , Tainan , Taiwan.,Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University , Tainan , Taiwan
| | - Bo-Ying Bao
- School of Pharmacy, China Medical University , Taichung , Taiwan
| | - Chia-Yu Lin
- Department of Medical Laboratory Science and Biotechnology, China Medical University , Taichung , Taiwan
| | - Zin-Ya Yang
- Department of Medical Laboratory Science and Biotechnology, China Medical University , Taichung , Taiwan
| | - Yui-Ping Weng
- Department of Biological Science and Technology, Chung Hwa University of Medical Technology , Tainan , Taiwan
| | - Chee-Hong Chan
- Department of Nephrology, Chang Bing Show Chwan Memorial Hospital, Lukang, Changhua, Taiwan
| | - Te Ling Lu
- School of Pharmacy, China Medical University , Taichung , Taiwan
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26
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Michałek K, Grabowska M, Lepczyński A. Cellular localization and putative role of aquaporin-2 Ser-261 in the bovine kidney. JOURNAL OF ANIMAL AND FEED SCIENCES 2019. [DOI: 10.22358/jafs/103815/2019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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27
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A New Genotype of Feline Morbillivirus Infects Primary Cells of the Lung, Kidney, Brain and Peripheral Blood. Viruses 2019; 11:v11020146. [PMID: 30744110 PMCID: PMC6410220 DOI: 10.3390/v11020146] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 02/05/2019] [Accepted: 02/07/2019] [Indexed: 12/12/2022] Open
Abstract
Paramyxoviruses comprise a large number of diverse viruses which in part give rise to severe diseases in affected hosts. A new genotype of feline morbillivirus, tentatively named feline morbillivirus genotype 2 (FeMV-GT2), was isolated from urine of cats with urinary tract diseases. Whole genome sequencing showed about 78% nucleotide homology to known feline morbilliviruses. The virus was isolated in permanent cell lines of feline and simian origin. To investigate the cell tropism of FeMV-GT2 feline primary epithelial cells from the kidney, the urinary bladder and the lung, peripheral blood mononuclear cells (PBMC), as well as organotypic brain slice cultures were used for infection experiments. We demonstrate that FeMV-GT2 is able to infect renal and pulmonary epithelial cells, primary cells from the cerebrum and cerebellum, as well as immune cells in the blood, especially CD4⁺ T cells, CD20⁺ B cells and monocytes. The cats used for virus isolation shed FeMV-GT2 continuously for several months despite the presence of neutralizing antibodies in the blood. Our results point towards the necessity of increased awareness for this virus when clinical signs of the aforementioned organs are encountered in cats which cannot be explained by other etiologies.
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Shen M, Bao LZ, Zheng X, Zhao XX, Guo ZF. Obestatin Downregulating Aquaporin 2 Plasma Membrane Distribution Through a Short-Term Regulatory Effect. Am J Med Sci 2018; 357:247-254. [PMID: 30797506 DOI: 10.1016/j.amjms.2018.12.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 11/27/2018] [Accepted: 12/22/2018] [Indexed: 01/20/2023]
Abstract
BACKGROUND Previous studies have found that obestatin significantly inhibited water drinking and reduced the arginine vasopressin levels in the brain to decrease renal water reabsorption. However, obestatin is unable to cross the blood-brain barrier. Its effect on the body's kidney water metabolism in peripheral remains unknown. MATERIALS AND METHODS Expression and subcellular distribution of aquaporin 2 (AQP2) were detected by immunoblotting and immunofluorescence in mouse inner medullary collecting duct-3 (mIMCD-3) cells and congestive heart failure model rats. Moreover, expression of phosphorylated AQP2 (P-AQP2; Ser256) in mIMCD-3 cells was evaluated by immunoblotting. RESULTS After a 30-minute treatment with obestatin in mIMCD-3 cells and congestive heart failure model rats, the AQP2 plasma membrane distribution decreased, while AQP2 protein level, P-AQP2 (Ser256) protein level and phosphorylation ratio of AQP2 showed no significant change. CONCLUSIONS These findings suggest that obestatin has a short-term regulatory effect on the AQP2 plasma membrane distribution. In addition, obestatin decreases the APQ2 plasma membrane distribution probably by promoting the endocytosis of AQP2.
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Affiliation(s)
- Ming Shen
- Department of Cardiovascular Diseases, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Li-Zhi Bao
- Department of Cardiovascular Diseases, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Xing Zheng
- Department of Cardiovascular Diseases, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Xian-Xian Zhao
- Department of Cardiovascular Diseases, Changhai Hospital, Second Military Medical University, Shanghai, China.
| | - Zhi-Fu Guo
- Department of Cardiovascular Diseases, Changhai Hospital, Second Military Medical University, Shanghai, China.
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29
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Abstract
Abstract
Introduction: The metanephrogenic zone, renal cortex and renal pyramids develop into their final form by week 13. The metanephric kidney produces large quantities of diluted urine in order to maintain volumes of amniotic fluid. Aquaporins are transmembrane protein channels that enable water transport through biological membranes. Aquaporin 2 (AQP2) is a water channel found in the supranuclear region and apical area of the cell membrane of the kidneys collecting tubule cells. Its main function is reabsorption of water through vasopressin stimulation.
Materials and methods: Immunohistochemistry was used to study fetal renal tissue of 34 post-mortem fetuses of 9 weeks to 24 weeks gestational age.
Results: AQP2 expression is present in connecting tubules and collecting tubules during the targeted time period. From week 9 to 12, the expression is cytoplasmic. From week 13 to 20 the enhancement of expression in the apical cell membrane occurs with the advancement of fetal age. At the end of the studied period, from week 21 to 24, both cytoplasmic and apical expression were observed. In animal studies AQP2 expression has an increasing trend during development. In contradiction with these results, other authors described low AQP2 levels in the human fetal kidney.
Conclusions: This study helps to understand the amniotic fluid’s homeostasis during pregnancy. In the beginning of the fetal period AQP2 protein is present in the cytoplasm of epithelial cells of the collecting duct and distal connecting duct. During the fetal period, AQP2 expression in collecting ducts becomes more enhanced in the apical membrane of the cells.
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30
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Huang J, Montani JP, Verrey F, Feraille E, Ming XF, Yang Z. Arginase-II negatively regulates renal aquaporin-2 and water reabsorption. FASEB J 2018; 32:5520-5531. [PMID: 29718707 PMCID: PMC6405175 DOI: 10.1096/fj.201701209r] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Type-II l-arginine:ureahydrolase, arginase-II (Arg-II), is abundantly
expressed in the kidney. The physiologic role played by Arg-II in the kidney remains
unknown. Herein, we report that in mice that are deficient in Arg-II
(Arg-II−/−), total and membrane-associated aquaporin-2
(AQP2) protein levels were significantly higher compared with wild-type (WT)
controls. Water deprivation enhanced Arg-II expression, AQP2 levels, and membrane
association in collecting ducts. Effects of water deprivation on AQP2 were stronger
in Arg-II−/− mice than in WT mice. Accordingly, a decrease
in urine volume and an increase in urine osmolality under water deprivation were more
pronounced in Arg-II−/− mice than in WT mice, which
correlated with a weaker increase in plasma osmolality in
Arg-II−/− mice. There was no difference in vasopressin
release under water deprivation conditions between either genotype of mice. Although
total AQP2 and phosphorylated AQP2-S256 levels (mediated by PKA) in kidneys under
water deprivation conditions were significantly higher in
Arg-II−/− mice compared with WT animals, there is no
difference in the ratio of AQP2-S256:AQP2. In cultured mouse collecting duct
principal mCCDcl1 cells, expression of both Arg-II and AQP2 were enhanced
by the vasopressin type 2 receptor agonist, desamino-d-arginine
vasopressin (dDAVP). Silencing Arg-II enhanced the expression and membrane
association of AQP2 by dDAVP without influencing cAMP levels. In conclusion,
in vivo and in vitro experiments demonstrate
that Arg-II negatively regulates AQP2 and the urine-concentrating capability in
kidneys via a mechanism that is not associated with the modulation
of the cAMP pathway.—Huang, J., Montani, J.-P., Verrey, F., Feraille, E.,
Ming, X.-F., Yang, Z. Arginase-II negatively regulates renal aquaporin-2 and water
reabsorption.
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Affiliation(s)
- Ji Huang
- Division of Physiology, Department of Medicine, Cardiovascular and Aging Research, University of Fribourg, Fribourg, Switzerland.,Kidney Control of Homeostasis, National Center of Competence in Research, Zurich, Switzerland
| | - Jean-Pierre Montani
- Division of Physiology, Department of Medicine, Cardiovascular and Aging Research, University of Fribourg, Fribourg, Switzerland.,Kidney Control of Homeostasis, National Center of Competence in Research, Zurich, Switzerland
| | - François Verrey
- Kidney Control of Homeostasis, National Center of Competence in Research, Zurich, Switzerland.,Institute of Physiology, University of Zurich, Zurich, Switzerland
| | - Eric Feraille
- Kidney Control of Homeostasis, National Center of Competence in Research, Zurich, Switzerland.,Department of Cell Biology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Xiu-Fen Ming
- Division of Physiology, Department of Medicine, Cardiovascular and Aging Research, University of Fribourg, Fribourg, Switzerland.,Kidney Control of Homeostasis, National Center of Competence in Research, Zurich, Switzerland
| | - Zhihong Yang
- Division of Physiology, Department of Medicine, Cardiovascular and Aging Research, University of Fribourg, Fribourg, Switzerland.,Kidney Control of Homeostasis, National Center of Competence in Research, Zurich, Switzerland
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Kim YS, Ahn JS, Kim S, Kim HJ, Kim SH, Kang JS. The potential theragnostic (diagnostic+therapeutic) application of exosomes in diverse biomedical fields. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2018; 22:113-125. [PMID: 29520164 PMCID: PMC5840070 DOI: 10.4196/kjpp.2018.22.2.113] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 12/21/2017] [Accepted: 01/27/2018] [Indexed: 01/07/2023]
Abstract
Exosomes are membranous vesicles of 30-150 nm in diameter that are derived from the exocytosis of the intraluminal vesicles of many cell types including immune cells, stem cells, cardiovascular cells and tumor cells. Exosomes participate in intercellular communication by delivering their contents to recipient cells, with or without direct contact between cells, and thereby influence physiological and pathological processes. They are present in various body fluids and contain proteins, nucleic acids, lipids, and microRNAs that can be transported to surrounding cells. Theragnosis is a concept in next-generation medicine that simultaneously combines accurate diagnostics with therapeutic effects. Molecular components in exosomes have been found to be related to certain diseases and treatment responses, indicating that they may have applications in diagnosis via molecular imaging and biomarker detection. In addition, recent studies have reported that exosomes have immunotherapeutic applications or can act as a drug delivery system for targeted therapies with drugs and biomolecules. In this review, we describe the formation, structure, and physiological roles of exosomes. We also discuss their roles in the pathogenesis and progression of diseases including neurodegenerative diseases, cardiovascular diseases, and cancer. The potential applications of exosomes for theragnostic purposes in various diseases are also discussed. This review summarizes the current knowledge about the physiological and pathological roles of exosomes as well as their diagnostic and therapeutic uses, including emerging exosome-based therapies that could not be applied until now.
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Affiliation(s)
- Yong-Seok Kim
- Department of Biochemistry and Molecular Biology, College of Medicine, Seoul 04763, Korea
| | - Jae-Sung Ahn
- Department of Pharmacology and Clinical Pharmacology Laboratory, College of Medicine, Hanyang University, Seoul 04763, Korea
| | - Semi Kim
- Department of Pharmacology and Clinical Pharmacology Laboratory, College of Medicine, Hanyang University, Seoul 04763, Korea
| | - Hyun-Jin Kim
- Department of Pharmacology and Clinical Pharmacology Laboratory, College of Medicine, Hanyang University, Seoul 04763, Korea
| | - Shin-Hee Kim
- Department of Pharmacology and Clinical Pharmacology Laboratory, College of Medicine, Hanyang University, Seoul 04763, Korea
| | - Ju-Seop Kang
- Department of Pharmacology and Clinical Pharmacology Laboratory, College of Medicine, Hanyang University, Seoul 04763, Korea
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Pathare G, Dhayat NA, Mohebbi N, Wagner CA, Bobulescu IA, Moe OW, Fuster DG. Changes in V-ATPase subunits of human urinary exosomes reflect the renal response to acute acid/alkali loading and the defects in distal renal tubular acidosis. Kidney Int 2018; 93:871-880. [PMID: 29310826 DOI: 10.1016/j.kint.2017.10.018] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 10/02/2017] [Accepted: 10/05/2017] [Indexed: 12/26/2022]
Abstract
In the kidney, final urinary acidification is achieved by V-ATPases expressed in type A intercalated cells. The B1 subunit of the V-ATPase is required for maximal urinary acidification, while the role of the homologous B2 subunit is less clear. Here we examined the effect of acute acid/alkali loading in humans on B1 and B2 subunit abundance in urinary exosomes in normal individuals and of acid loading in patients with distal renal tubular acidosis (dRTA). Specificities of B1 and B2 subunit antibodies were verified by yeast heterologously expressing human B1 and B2 subunits, and murine wild-type and B1-deleted kidney lysates. Acute ammonium chloride loading elicited systemic acidemia, a drop in urinary pH, and increased urinary ammonium excretion. Nadir urinary pH was achieved at four to five hours, and exosomal B1 abundance was significantly increased at two through six hours after ammonium chloride loading. After acute equimolar sodium bicarbonate loading, blood and urinary pH rose rapidly, with a concomitant reduction of exosomal B1 abundance within two hours, which remained lower throughout the test. In contrast, no change in exosomal B2 abundance was found following acid or alkali loading. In patients with inherited or acquired distal RTA, the urinary B1 subunit was extremely low or undetectable and did not respond to acid loading in urine, whereas no change in B2 subunit was found. Thus, both B1 and B2 subunits of the V-ATPase are detectable in human urinary exosomes, and acid and alkali loading or distal RTA cause changes in the B1 but not B2 subunit abundance in urinary exosomes.
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Affiliation(s)
- Ganesh Pathare
- Division of Nephrology and Hypertension, Bern University Hospital, University of Bern, Bern, Switzerland; Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland; National Centre of Competence in Research Transcure, University of Bern, Bern, Switzerland
| | - Nasser A Dhayat
- Division of Nephrology and Hypertension, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Nilufar Mohebbi
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Carsten A Wagner
- Institute of Physiology, University of Zurich, Zurich, Switzerland; National Center for Competence in Research Kidney.CH, Zurich, Switzerland
| | - Ion A Bobulescu
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Orson W Moe
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Daniel G Fuster
- Division of Nephrology and Hypertension, Bern University Hospital, University of Bern, Bern, Switzerland; Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland; National Centre of Competence in Research Transcure, University of Bern, Bern, Switzerland.
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Basolateral cholesterol depletion alters Aquaporin-2 post-translational modifications and disrupts apical plasma membrane targeting. Biochem Biophys Res Commun 2018; 495:157-162. [DOI: 10.1016/j.bbrc.2017.11.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 11/01/2017] [Indexed: 11/22/2022]
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Warden CH, Bettaieb A, Min E, Fisler JS, Haj FG, Stern JS. Chow fed UC Davis strain female Lepr fatty Zucker rats exhibit mild glucose intolerance, hypertriglyceridemia, and increased urine volume, all reduced by a Brown Norway strain chromosome 1 congenic donor region. PLoS One 2017; 12:e0188175. [PMID: 29211750 PMCID: PMC5718614 DOI: 10.1371/journal.pone.0188175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 10/23/2017] [Indexed: 12/01/2022] Open
Abstract
Our objective is to identify genes that influence the development of any phenotypes of type 2 diabetes (T2D) or kidney disease in obese animals. We use the reproductively isolated UC Davis fatty Zucker strain rat model in which the defective chromosome 4 leptin receptor (LeprfaSte/faSte) results in fatty obesity. We previously produced a congenic strain with the distal half of chromosome 1 from the Brown Norway strain (BN) on a Zucker (ZUC) background (BN.ZUC-D1Rat183–D1Rat90). Previously published studies in males showed that the BN congenic donor region protects from some phenotypes of renal dysfunction and T2D. We now expand our studies to include females and expand phenotyping to gene expression. We performed diabetes and kidney disease phenotyping in chow-fed females of the BN.ZUC-D1Rat183-D1Rat90 congenic strain to determine the specific characteristics of the UC Davis model. Fatty LeprfaSte/faSte animals of both BN and ZUC genotype in the congenic donor region had prediabetic levels of fasting blood glucose and blood glucose 2 hours after a glucose tolerance test. We observed significant congenic strain chromosome 1 genotype effects of the BN donor region in fatty females that resulted in decreased food intake, urine volume, glucose area under the curve during glucose tolerance test, plasma triglyceride levels, and urine glucose excretion per day. In fatty females, there were significant congenic strain BN genotype effects on non-fasted plasma urea nitrogen, triglyceride, and creatinine. Congenic region genotype effects were observed by quantitative PCR of mRNA from the kidney for six genes, all located in the chromosome 1 BN donor region, with potential effects on T2D or kidney function. The results are consistent with the hypothesis that the BN genotype chromosome 1 congenic region influences traits of both type 2 diabetes and kidney function in fatty UC Davis ZUC females and that there are many positional candidate genes.
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Affiliation(s)
- Craig H. Warden
- Departments of Pediatrics, Neurobiology Physiology and Behavior, University of California, Davis, Davis, CA, United States of America
- * E-mail:
| | - Ahmed Bettaieb
- Department of Nutrition, University of Tennessee, Knoxville, TN, United States of America
| | - Esther Min
- Department of Nutrition, University of California, Davis, Davis, CA, United States of America
| | - Janis S. Fisler
- Department of Nutrition, University of California, Davis, Davis, CA, United States of America
| | - Fawaz G. Haj
- Department of Nutrition, University of California, Davis, Davis, CA, United States of America
| | - Judith S. Stern
- Department of Nutrition, University of California, Davis, Davis, CA, United States of America
- Internal Medicine, University of California, Davis, Davis, CA, United States of America
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35
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Acute regulated expression of pendrin in human urinary exosomes. Pflugers Arch 2017; 470:427-438. [PMID: 28803436 DOI: 10.1007/s00424-017-2049-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 07/23/2017] [Accepted: 07/26/2017] [Indexed: 10/19/2022]
Abstract
It is well known that pendrin, an apical Cl-/HCO3-exchanger in type B intercalated cells, is modulated by chronic acid-base disturbances and electrolyte intake. To study this adaptation further at the acute level, we analyzed urinary exosomes from individuals subjected to oral acute acid, alkali, and NaCl loading. Acute oral NH4Cl loading (n = 8) elicited systemic acidemia with a drop in urinary pH and an increase in urinary NH4 excretion. Nadir urinary pH was achieved 5 h after NH4Cl loading. Exosomal pendrin abundance was dramatically decreased at 3 h after acid loading. In contrast, after acute equimolar oral NaHCO3 loading (n = 8), urinary and venous blood pH rose rapidly with a significant attenuation of urinary NH4 excretion. Alkali loading caused rapid upregulation of exosomal pendrin abundance at 1 h and normalized within 3 h of treatment. Equimolar NaCl loading (n = 6) did not alter urinary or venous blood pH or urinary NH4 excretion. However, pendrin abundance in urinary exosomes was significantly reduced at 2 h of NaCl ingestion with lowest levels observed at 4 h after treatment. In patients with inherited distal renal tubular acidosis (dRTA), pendrin abundance in urinary exosomes was greatly reduced and did not change upon oral NH4Cl loading. In summary, pendrin can be detected and quantified in human urinary exosomes by immunoblotting. Acid, alkali, and NaCl loadings cause acute changes in pendrin abundance in urinary exosomes within a few hours. Our data suggest that exosomal pendrin is a promising urinary biomarker for acute acid-base and volume status changes in humans.
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Farinha CM, Matos P. Rab GTPases regulate the trafficking of channels and transporters - a focus on cystic fibrosis. Small GTPases 2017; 9:136-144. [PMID: 28463591 DOI: 10.1080/21541248.2017.1317700] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
The amount of ion channels and transporters present at the plasma membrane is a crucial component of the overall regulation of ion transport. The number of channels present result from an intricate network of proteins that controls the late events of channel trafficking, such as endocytosis, recycling and targeting to lysosomal degradation. Small GTPases of the Rab family are key players in these processes thus contributing to regulation of fluid secretion and ion homeostasis. In epithelia, this involves mainly the balance between the chloride channel CFTR and the sodium channel ENaC, whose misfunction is a hallmark of cystic fibrosis - the commonest recessive disorder in Caucasians. Here, we review the role of GTPases in regulating trafficking of ion channels and transporters, comparing what is known for CFTR and ENaC with other types of channels. We also discuss how feasible would be to target the Rab machinery to handle a disorder such as CF.
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Affiliation(s)
- Carlos M Farinha
- a University of Lisboa, Faculty of Sciences, BioISI - Biosystems & Integrative Sciences Institute , Campo Grande, Lisboa , Portugal
| | - Paulo Matos
- a University of Lisboa, Faculty of Sciences, BioISI - Biosystems & Integrative Sciences Institute , Campo Grande, Lisboa , Portugal.,b Department of Human Genetics , National Health Institute 'Dr. Ricardo Jorge' , Av. Padre Cruz, Lisboa , Portugal
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Blanc L, Vidal M. New insights into the function of Rab GTPases in the context of exosomal secretion. Small GTPases 2017; 9:95-106. [PMID: 28135905 PMCID: PMC5902209 DOI: 10.1080/21541248.2016.1264352] [Citation(s) in RCA: 228] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
In the last two decades, extracellular vesicle-mediated communication between cells has become a major field in cell biology. However, the function of extracellular vesicles is far from clear, especially due to the disparity of released vesicles by cells. Basically, one must consider vesicles budding from the cell plasma membrane (ectosomes) and vesicles released upon fusion of an endosomal multivesicular compartment (exosomes). Moreover, even for exosomes, we report and discuss here the possibility that different routes regulated by specific Rab GTPases might produce exosomes having various biologic functions.
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Affiliation(s)
- Lionel Blanc
- a Laboratory of Developmental Erythropoiesis, The Feinstein Institute for Medical Research Hofstra Northwell School of Medicine , Manhasset , NY , USA
| | - Michel Vidal
- b UMR 5235, CNRS, Université Montpellier , cc107, Montpellier , France
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Barros ER, Carvajal CA. Urinary Exosomes and Their Cargo: Potential Biomarkers for Mineralocorticoid Arterial Hypertension? Front Endocrinol (Lausanne) 2017; 8:230. [PMID: 28951728 PMCID: PMC5599782 DOI: 10.3389/fendo.2017.00230] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 08/23/2017] [Indexed: 12/13/2022] Open
Abstract
Arterial hypertension (AHT) currently affects approximately 40% of adults worldwide, and its pathological mechanisms are mainly related to renal, vascular, and endocrine systems. Steroid hormones as aldosterone and cortisol are highly relevant to human endocrine physiology, and also to endocrine hypertension. Pathophysiological conditions, such as primary aldosteronism, affect approximately 10% of patients diagnosed with AHT and are secondary to a high production of aldosterone, increasing the risk also for cardiovascular damage and heart diseases. Excess of aldosterone or cortisol increases the activity of the mineralocorticoid receptor (MR) in epithelial and non-epithelial cells. Current research in this field highlights the potential regulatory mechanisms of the MR pathway, including pre-receptor regulation of the MR (action of 11BHSD2), MR activating proteins, and the downstream genes/proteins sensitive to MR (e.g., epithelial sodium channel, NCC, NKCC2). Mineralocorticoid AHT is present in 15-20% of hypertensive subjects, but the mechanisms associated to this condition have been poorly described, due mainly to the absence of reliable biomarkers. In this way, steroids, peptides, and lately urinary exosomes are thought to be potential reporters of biological processes. This review highlight exosomes and their cargo as potential biomarkers of metabolic changes associated to mineralocorticoid AHT. Recent reports have shown the presence of RNA, microRNAs, and proteins in urinary exosomes, which could be used as biomarkers in physiological and pathophysiological conditions. However, more studies are needed in order to benefit from exosomes and the exosomal cargo as a diagnostic tool in mineralocorticoid AHT.
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Affiliation(s)
- Eric R. Barros
- Center of Translational Endocrinology (CETREN), Faculty of Medicine, Endocrinology Department, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Cristian A. Carvajal
- Center of Translational Endocrinology (CETREN), Faculty of Medicine, Endocrinology Department, Pontificia Universidad Católica de Chile, Santiago, Chile
- *Correspondence: Cristian A. Carvajal,
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Shimizu K, Sano M, Kita A, Sawai N, Iizuka-Kogo A, Kogo H, Aoki T, Takata K, Matsuzaki T. Phosphorylation and dephosphorylation of aquaporin-2 at serine 269 and its subcellular distribution during vasopressin-induced exocytosis and subsequent endocytosis in the rat kidney . ACTA ACUST UNITED AC 2017. [DOI: 10.1679/aohc.77.25] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
| | | | | | - Nobuhiko Sawai
- Present address: Department of Molecular Medicine and Anatomy, Nippon Medical School,
| | | | | | - Takeo Aoki
- Present address: School of Radiological Technology, Gunma Prefectural College of Health Sciences,
| | - Kuniaki Takata
- Present address: Gunma Prefectural College of Health Sciences,
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Li Y, Wang W, Jiang T, Yang B. Aquaporins in Urinary System. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 969:131-148. [PMID: 28258571 DOI: 10.1007/978-94-024-1057-0_9] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Several aquaporin (AQP )-type water channels are expressed in kidney: AQP1 in the proximal tubule, thin descending limb of Henle, and vasa recta; AQP2 -6 in the collecting duct; AQP7 in the proximal tubule; AQP8 in the proximal tubule and collecting duct; and AQP11 in the endoplasmic reticulum of proximal tubule cells. AQP2 is the vasopressin-regulated water channel that is important in hereditary and acquired diseases affecting urine-concentrating ability. The roles of AQPs in renal physiology and transepithelial water transport have been determined using AQP knockout mouse models. This chapter describes renal physiologic insights revealed by phenotypic analysis of AQP knockout mice and the prospects for further basic and clinical studies.
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Affiliation(s)
- Yingjie Li
- Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Weiling Wang
- State Key Laboratory of Natural and Biomimetic Drugs, and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Tao Jiang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Baoxue Yang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China.
- Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, 100191, China.
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Loh SY, Giribabu N, Gholami K, Salleh N. Effects of testosterone on mean arterial pressure and aquaporin (AQP)-1, 2, 3, 4, 6 and 7 expressions in the kidney of orchidectomized, adult male Sprague-Dawley rats. Arch Biochem Biophys 2016; 614:41-49. [PMID: 28024836 DOI: 10.1016/j.abb.2016.12.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Revised: 12/17/2016] [Accepted: 12/22/2016] [Indexed: 11/18/2022]
Abstract
We hypothesized that higher blood pressure in males than females could be due to testosterone effects on aquaporin (AQP) expression in kidneys. METHODS Orchidectomized adult male Sprague-Dawley (SD) rats received seven days subcutaneous testosterone treatment (125 μg/kg/day or 250 μg/kg/day), with or without flutamide or finasteride. Following completion of treatment, MAP was determined in rats under anaesthesia via carotid artery cannulation. In another cohort of rats, kidneys were removed following sacrifice and AQP-1, 2, 3, 4, 6 and 7 protein and mRNA levels were determined by Western blotting and Real-time PCR respectively. Distribution of AQP subunits' protein in the nephrons were visualized by immunofluorescence. RESULTS Testosterone caused MAP, AQP-1, 2, 4, 6 and 7 protein and mRNA levels in kidneys to increase while AQP-3 protein and mRNA levels in kidneys to decrease (p < 0.05). AQP-1 and 7 were found to be distributed in the proximal convoluted tubule (PCT) while AQP-2, 3, 4 and 6 were found to be distributed in the collecting ducts (CD). Effects of testosterone were antagonized by flutamide and finasteride. CONCLUSIONS Elevated expression of AQP-1, 2, 4, 6 and 7 under testosterone influence in kidneys could lead to increase H2O reabsorption which eventually lead to increase in blood pressure.
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Affiliation(s)
- Su Yi Loh
- Department of Physiology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Nelli Giribabu
- Department of Physiology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Khadijeh Gholami
- Department of Physiology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Naguib Salleh
- Department of Physiology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
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Mamuya FA, Cano-Peñalver JL, Li W, Rodriguez Puyol D, Rodriguez Puyol M, Brown D, de Frutos S, Lu HAJ. ILK and cytoskeletal architecture: an important determinant of AQP2 recycling and subsequent entry into the exocytotic pathway. Am J Physiol Renal Physiol 2016; 311:F1346-F1357. [PMID: 27760768 DOI: 10.1152/ajprenal.00336.2016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 09/29/2016] [Accepted: 10/11/2016] [Indexed: 12/20/2022] Open
Abstract
Within the past decade tremendous efforts have been made to understand the mechanism behind aquaporin-2 (AQP2) water channel trafficking and recycling, to open a path toward effective diabetes insipidus therapeutics. A recent study has shown that integrin-linked kinase (ILK) conditional-knockdown mice developed polyuria along with decreased AQP2 expression. To understand whether ILK also regulates AQP2 trafficking in kidney tubular cells, we performed in vitro analysis using LLCPK1 cells stably expressing rat AQP2 (LLC-AQP2 cells). Upon treatment of LLC-AQP2 cells with ILK inhibitor cpd22 and ILK-siRNA, we observed increased accumulation of AQP2 in the perinuclear region, without any significant increase in the rate of endocytosis. This perinuclear accumulation did not occur in cells expressing a serine-256-aspartic acid mutation that retains AQP2 in the plasma membrane. We then examined clathrin-mediated endocytosis after ILK inhibition using rhodamine-conjugated transferrin. Despite no differences in overall transferrin endocytosis, the endocytosed transferrin also accumulated in the perinuclear region where it colocalized with AQP2. These accumulated vesicles also contained the recycling endosome marker Rab11. In parallel, the usual vasopressin-induced AQP2 membrane accumulation was prevented after ILK inhibition; however, ILK inhibition did not measurably affect AQP2 phosphorylation at serine-256 or its dephosphorylation at serine-261. Instead, we found that inhibition of ILK increased F-actin polymerization. When F-actin was depolymerized with latrunculin, the perinuclear located AQP2 dispersed. We conclude that ILK is important in orchestrating dynamic cytoskeletal architecture during recycling of AQP2, which is necessary for its subsequent entry into the exocytotic pathway.
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Affiliation(s)
- Fahmy A Mamuya
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jose Luis Cano-Peñalver
- Department of Systems Biology, Physiology Unit, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain; Instituto Reina Sofia de Investigación Renal and Red de Investigación Renal (REDinREN), Instituto de Salud Carlos III, Madrid, Spain; and
| | - Wei Li
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Diego Rodriguez Puyol
- Biomedical Research Foundation and Nephrology Department, Hospital Príncipe de Asturias, Alcalá de Henares, and Instituto Reina Sofia de Investigación Renal and REDinREN from Instituto de Salud Carlos III, Madrid, Spain
| | - Manuel Rodriguez Puyol
- Department of Systems Biology, Physiology Unit, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain; Instituto Reina Sofia de Investigación Renal and Red de Investigación Renal (REDinREN), Instituto de Salud Carlos III, Madrid, Spain; and
| | - Dennis Brown
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Sergio de Frutos
- Department of Systems Biology, Physiology Unit, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain; Instituto Reina Sofia de Investigación Renal and Red de Investigación Renal (REDinREN), Instituto de Salud Carlos III, Madrid, Spain; and
| | - Hua Ann Jenny Lu
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
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Well-organized spheroids as a new platform to examine cell interaction and behaviour during organ development. Cell Tissue Res 2016; 366:601-615. [PMID: 27599480 DOI: 10.1007/s00441-016-2487-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 08/05/2016] [Indexed: 10/21/2022]
Abstract
We present an experimental method allowing the production of three-dimensional organ-like structures, namely microtissues (MTs), in vitro without the need for exogenous extracellular matrix (ECM) or growth factors. Submandibular salivary glands (embryonic day ED14), kidneys (ED13) and lungs (ED13) were harvested from mouse embryos and dissociated into single cells by enzyme treatment. Single cells were seeded into special hanging drop culture plates (InSphero) and cultured for up to 14 days to obtain MTs. This strategy permitted full control of the quantity of seeded cells. The development of the MTs into organs was followed histologically and immunohistochemically. Well-organized epithelial structures surrounded by a basal lamina were formed, as confirmed by transmission electron microscopy. Expression of E-cadherin, vimentin, fibronectin and α-SMA was compared in organs and corresponding MTs by real-time quantitative polymerase chain reaction. Branching morphogenesis was induced in MTs (as shown by histology and immunostaining for fibronectin and perlecan) and was conserved even after 14 days of culture. MTs continued their development and their epithelial structures were comparable with those of the physiological organ at postnatal day 2 (PN2). Expression of aquaporins was investigated to obtain better support for the functional differentiation of epithelial cells. Histogenesis proceeded and led to the start of organogenesis. This experimental model might improve our knowledge of epithelial-mesenchymal histogenesis and can be employed to study development or cellular organization during the embryonic formation of organs.
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Maugeri R, Schiera G, Di Liegro CM, Fricano A, Iacopino DG, Di Liegro I. Aquaporins and Brain Tumors. Int J Mol Sci 2016; 17:ijms17071029. [PMID: 27367682 PMCID: PMC4964405 DOI: 10.3390/ijms17071029] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 06/22/2016] [Accepted: 06/22/2016] [Indexed: 01/04/2023] Open
Abstract
Brain primary tumors are among the most diverse and complex human cancers, and they are normally classified on the basis of the cell-type and/or the grade of malignancy (the most malignant being glioblastoma multiforme (GBM), grade IV). Glioma cells are able to migrate throughout the brain and to stimulate angiogenesis, by inducing brain capillary endothelial cell proliferation. This in turn causes loss of tight junctions and fragility of the blood–brain barrier, which becomes leaky. As a consequence, the most serious clinical complication of glioblastoma is the vasogenic brain edema. Both glioma cell migration and edema have been correlated with modification of the expression/localization of different isoforms of aquaporins (AQPs), a family of water channels, some of which are also involved in the transport of other small molecules, such as glycerol and urea. In this review, we discuss relationships among expression/localization of AQPs and brain tumors/edema, also focusing on the possible role of these molecules as both diagnostic biomarkers of cancer progression, and therapeutic targets. Finally, we will discuss the possibility that AQPs, together with other cancer promoting factors, can be exchanged among brain cells via extracellular vesicles (EVs).
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Affiliation(s)
- Rosario Maugeri
- Department of Experimental Biomedicine and Clinical Neurosciences (BIONEC), University of Palermo, Palermo I-90127, Italy.
| | - Gabriella Schiera
- Department of Biological Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo (UNIPA), Palermo I-90128, Italy.
| | - Carlo Maria Di Liegro
- Department of Biological Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo (UNIPA), Palermo I-90128, Italy.
| | - Anna Fricano
- Department of Experimental Biomedicine and Clinical Neurosciences (BIONEC), University of Palermo, Palermo I-90127, Italy.
- Department of Biological Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo (UNIPA), Palermo I-90128, Italy.
| | - Domenico Gerardo Iacopino
- Department of Experimental Biomedicine and Clinical Neurosciences (BIONEC), University of Palermo, Palermo I-90127, Italy.
| | - Italia Di Liegro
- Department of Experimental Biomedicine and Clinical Neurosciences (BIONEC), University of Palermo, Palermo I-90127, Italy.
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Erikci A, Ucar G, Yabanoglu-Ciftci S. Role of serotonin in the regulation of renal proximal tubular epithelial cells. Ren Fail 2016; 38:1141-50. [PMID: 27277500 DOI: 10.1080/0886022x.2016.1194165] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
In various renal injuries, tissue damage occurs and platelet activation is observed. Recent studies suggest that some factors, such as serotonin, are released into microenvironment upon platelet activation following renal injury. In the present study, we aimed to investigate whether platelets and platelet-released serotonin are involved in the functional regulation of renal proximal tubular epithelial cells (PTECs). PTECs were obtained by primary cell culture and treated with platelet lysate (PL) (2 × 10(6)/mL, 4 × 10(6)/mL, 8 × 10(6)/mL) or serotonin (1 μM or 5 μM) for 12 or 24 h. Phenotypic transdifferentiation of epithelial cells into myofibroblasts were demonstrated under light microscope and confirmed by the determination of α-smooth muscle actin gene expression. Serotonin and PL were shown to induce epithelial-mesenchymal transdifferentiation of PTECs. After stimulation of PTECs with serotonin or PL, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, and collagen-α1 gene expressions, which were reported to be elevated in renal injury, were determined by real-time PCR and found to be upregulated. Expressions of some inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and transforming growth factor-β1 were found to be increased in both protein and gene levels. Recently there is no published report on the effect of serotonin on renal PTECs. Results obtained in this study have lightened the role of serotonin and platelet-mediated effects of serotonin on fibrotic and inflammatory processes in PTECs.
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Affiliation(s)
- Acelya Erikci
- a Department of Biochemistry, Faculty of Pharmacy , Hacettepe University , Ankara , Turkey
| | - Gulberk Ucar
- a Department of Biochemistry, Faculty of Pharmacy , Hacettepe University , Ankara , Turkey
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Chen C, Chen RP, Lin HH, Zhang WY, Huang XL, Huang ZM. Tolvaptan regulates aquaporin-2 and fecal water in cirrhotic rats with ascites. World J Gastroenterol 2016; 22:3363-3371. [PMID: 27022218 PMCID: PMC4806194 DOI: 10.3748/wjg.v22.i12.3363] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 11/19/2015] [Accepted: 12/08/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of tolvaptan in regulating aquaporin (AQP)-2 expression and fecal water content in cirrhotic rats with ascites.
METHODS: Cirrhosis with ascites was induced in rats by repetitive dorsal injection of CCl4 for 14 wk. In total, 84 cirrhotic rats with ascites divided into three groups (vehicle, 3 mg/kg and 5 mg/kg tolvaptan), and then further divided into five subgroups (days 1, 2, 3, 4, and 5). Blood samples were obtained to measure vasopressin and sodium concentrations. Rats were killed and colonic mucosa was scraped for analysis of protein expression and AQP-2 transcriptional level. The whole layer was fixed for hematoxylin&eosin (HE) staining and feces were collected for determination of fecal water content.
CONCLUSION: Compared with vehicle, vasopressin decreased significantly in the tolvaptan groups from day 2 to a similar level in each treatment group. AQP-2 showed significant upregulation in cirrhotic rats with ascites compared with an untreated control group (100% ± 22.9% vs 22.2% ± 10.23%, P < 0.01). After administration of tolvaptan, AQP-2 expression began to decrease significantly from day 2 in each treatment group, but no significant difference was finally found between the treatment groups. Fecal water content in the distal colon was increased by 5 mg/kg tolvaptan on day 1 (66.8% ± 9.3% vs 41.4% ± 6.3%, in the vehicle group, P < 0.05). Fecal water content returned to baseline at day 4 at the latest in both treatment groups, and did not correspond to the change in AQP-2 expression. HE staining of the colonic mucosa showed no mucosal damage related to tolvaptan.
CONCLUSION: Upregulation of AQP-2 in the distal colon is found in cirrhotic rats with ascites. Tolvaptan inhibits its expression and may decrease water reabsorption and induce diarrhea.
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Muhl L, Moessinger C, Adzemovic MZ, Dijkstra MH, Nilsson I, Zeitelhofer M, Hagberg CE, Huusko J, Falkevall A, Ylä-Herttuala S, Eriksson U. Expression of vascular endothelial growth factor (VEGF)-B and its receptor (VEGFR1) in murine heart, lung and kidney. Cell Tissue Res 2016; 365:51-63. [DOI: 10.1007/s00441-016-2377-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 02/11/2016] [Indexed: 12/31/2022]
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48
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Matsuzaki T, Yaguchi T, Shimizu K, Kita A, Ishibashi K, Takata K. The distribution and function of aquaporins in the kidney: resolved and unresolved questions. Anat Sci Int 2016; 92:187-199. [PMID: 26798062 DOI: 10.1007/s12565-016-0325-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 12/31/2015] [Indexed: 11/25/2022]
Abstract
The membrane water channel aquaporin (AQP) family is composed of 13 isoforms in mammals, eight of which are reportedly expressed in the kidney: AQP1, 2, 3, 4, 6, 7, 8, and 11. These isoforms are differentially expressed along the renal tubules and collecting ducts. AQP1 and 7 are distributed in the proximal tubules, whereas AQP2, 3, and 4 occur in the collecting duct system. They play important roles in the reabsorption of water and some solutes across the plasma membrane. In contrast to other aquaporins found in the kidney, AQP6, 8, and 11 are localized to the cytoplasm rather than to the apical or basolateral membranes. It is therefore doubtful that these isoforms are directly involved in water or solute reabsorption. AQP6 is localized in acid-secreting type A intercalated cells of the collecting duct. AQP8 has been found in the proximal tubule but its cellular location has not yet been defined by immunohistochemistry. AQP11 seems to be localized in the endoplasmic reticulum (ER) of proximal tubule cells. Interestingly, polycystic kidneys develop in AQP11-null mice. Many vacuole-like structures are seen in proximal tubule cells in kidneys of newborn AQP11-null mice. Subsequently, cysts are generated, and most of the mice die within a month due to severe renal failure. Although ER stress and impairment of polycystin-1, the product of the gene mutated in autosomal-dominant polycystic kidney disease, are possible causes of cystogenesis in AQP11-null mice, the exact mechanism of pathogenesis and the physiological function of AQP11 are yet to be resolved.
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Affiliation(s)
- Toshiyuki Matsuzaki
- Department of Anatomy and Cell Biology, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8511, Japan.
| | - Tomoyuki Yaguchi
- Department of Anatomy and Cell Biology, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8511, Japan
| | - Kinue Shimizu
- Department of Anatomy and Cell Biology, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8511, Japan
| | - Aoi Kita
- Department of Anatomy and Cell Biology, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8511, Japan
| | - Kenichi Ishibashi
- Department of Medical Physiology, Meiji Pharmaceutical University, Kiyose, Tokyo, 204-8588, Japan
| | - Kuniaki Takata
- Gunma Prefectural College of Health Sciences, 323-1 Kamioki-Machi, Maebashi, Gunma, 371-0052, Japan
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Pollow DP, Romero-Aleshire MJ, Sanchez JN, Konhilas JP, Brooks HL. ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause. Am J Physiol Regul Integr Comp Physiol 2015; 309:R1546-52. [PMID: 26491098 DOI: 10.1152/ajpregu.00170.2015] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 10/20/2015] [Indexed: 12/13/2022]
Abstract
Premenopausal females are resistant to the development of hypertension, and this protection is lost after the onset of menopause, resulting in a sharp increase in disease onset and severity. However, it is unknown how a fluctuating ovarian hormone environment during the transition from perimenopause to menopause impacts the onset of hypertension, and whether interventions during perimenopause prevent disease onset after menopause. A gradual transition to menopause was induced by repeated daily injections of 4-vinylcyclohexene diepoxide (VCD). ANG II (800 ng·kg(-1)·min(-1)) was infused into perimenopausal and menopausal female mice for 14 days. A separate cohort of mice received 17β-estradiol replacement during perimenopause. ANG II infusion produced significantly higher mean arterial pressure (MAP) in menopausal vs. cycling females, and 17β-estradiol replacement prevented this increase. In contrast, MAP was not significantly different when ANG II was infused into perimenopausal and cycling females, suggesting that female resistance to ANG II-induced hypertension is intact during perimenopause. ANG II infusion caused a significant glomerular hypertrophy, and hypertrophy was not impacted by hormonal status. Expression levels of aquaporin-2 (AQP2), a collecting duct protein, have been suggested to reflect blood pressure. AQP2 protein expression was significantly downregulated in the renal cortex of the ANG II-infused menopause group, where blood pressure was increased. AQP2 expression levels were restored to control levels with 17β-estradiol replacement. This study indicates that the changing hormonal environment in the VCD model of menopause impacts the severity of ANG II-induced hypertension. These data highlight the utility of the ovary-intact VCD model of menopause as a clinically relevant model to investigate the physiological mechanisms of hypertension that occur in women during the transition into menopause.
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Affiliation(s)
- Dennis P Pollow
- Department of Physiology, University of Arizona, Tucson, Arizona; and
| | | | - Jessica N Sanchez
- Department of Physiology, University of Arizona, Tucson, Arizona; and Sarver Heart Center, University of Arizona, Tucson, Arizona
| | - John P Konhilas
- Department of Physiology, University of Arizona, Tucson, Arizona; and Sarver Heart Center, University of Arizona, Tucson, Arizona
| | - Heddwen L Brooks
- Department of Physiology, University of Arizona, Tucson, Arizona; and Sarver Heart Center, University of Arizona, Tucson, Arizona
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Braconnier A, Vrigneaud L, Bertocchio JP. [Hyponatremias: From pathophysiology to treatments. Review for clinicians]. Nephrol Ther 2015; 11:201-12. [PMID: 26095871 DOI: 10.1016/j.nephro.2015.04.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 04/22/2015] [Accepted: 04/22/2015] [Indexed: 10/23/2022]
Abstract
Hyponatremia could be defined as a public health topic: too many patients are concerned in both hospitalized and general populations; hyponatremia induces lots of clinical outcomes and a great economic burden. Its pathophysiology involves thirst regulation (hypotonic water intakes) and losses regulation (through the kidney under vasopressin control). Diagnostic approach should insure that hyponatremia reflects hypo-osmolality and hypotonicity: first, a false hyponatremia should be ruled out, then a non-hypotonic one. Next step is clinic: extracellular status should be evaluated. When increased, any edematous status should be evoked: heart failure, liver cirrhosis or nephrotic syndrome. When decreased, any cause of extracellular dehydration should be evoked: natriuresis could help distinguishing between renal (adrenal insufficiency, diuretics use or salt-losing nephropathy) or extrarenal (digestive mostly) etiologies. When clinically normal, a secretion of inappropriate antidiuretic hormone (SIADH) should be evoked, once hypothyroidism or hypoadrenocorticism have been ruled out. Therapy depends on the severity of the clinical impact. From extracellular rehydration, through fluid restriction, the paraneoplastic and heart failure-induced SIADH benefit from a new class of drug, available among the therapeutic strategies: aquaretics act through antidiuretic hormone receptor antagonism (vaptans). Their long-term benefits still have to be proven but it is a significant step forward in the treatment of hyponatremias.
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Affiliation(s)
- Antoine Braconnier
- Service de néphrologie, hémodialyse, transplantation, hôpital Maison-Blanche, CHU de Reims, avenue Cognacq-Jay, 51092 Reims cedex, France; Faculté de médecine, université Reims Champagne Ardenne, 51000 Reims, France; Club des jeunes néphrologues, 11, rue Auguste-Mourcou, 59000 Lille, France
| | - Laurence Vrigneaud
- Club des jeunes néphrologues, 11, rue Auguste-Mourcou, 59000 Lille, France; Service de néphrologie, médecine interne, centre hospitalier de Valenciennes, avenue Désandrouin, CS 50479, 59322 Valenciennes cedex, France
| | - Jean-Philippe Bertocchio
- Club des jeunes néphrologues, 11, rue Auguste-Mourcou, 59000 Lille, France; Service d'explorations fonctionnelles rénales et métaboliques, hôpital européen Georges-Pompidou, 20, rue Leblanc, 75908 Paris cedex, France; Université Paris Descartes, 75006 Paris, France.
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