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Barr SI, Abd El-Azeem EM, Bessa SS, Mohamed TM. Role of exosomes in pathogenesis, diagnosis, and treatment of diabetic nephropathy. BMC Nephrol 2025; 26:230. [PMID: 40340661 PMCID: PMC12063312 DOI: 10.1186/s12882-025-04120-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Accepted: 04/11/2025] [Indexed: 05/10/2025] Open
Abstract
Diabetic nephropathy (DN) is a serious microvascular complication that can progress to end-stage renal disease, with its prevalence and associated mortality increasing globally. However extensive research, the precise mechanisms underlying DN pathogenesis remain unclear, and the current treatment options for DN are limited to dialysis or renal replacement therapy, although several experimental approaches have shown potential, they remain investigational and lack clinical translation. Exosomes play a pivotal role in disease diagnosis and prognosis. Urinary exosomes, originating from various kidney cells, reflect the kidney's pathological condition and are involved in cell-to-cell communication through autocrine or paracrine signaling; therefore, they could contribute to the pathogenesis of DN and potential therapeutic approaches. Additionally, due to their diverse cargo, which depend on cellular origin and pathological state, exosomes may act as biomarkers for the early prediction of DN. This review presents a comprehensive overview of the latest findings on the role of exosomes in the diagnosis, pathogenesis, and treatment of DN.
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Affiliation(s)
- Shaimaa I Barr
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt.
| | - Eman M Abd El-Azeem
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Sahar S Bessa
- Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Tarek M Mohamed
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta, Egypt
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Nandula SR, Brichacek B, Sen S. Podocyte-Specific Protein Expression in Urine Exosome Acts as a Marker for Renal Injury in Post-COVID State. Metab Syndr Relat Disord 2025; 23:205-210. [PMID: 40100769 DOI: 10.1089/met.2024.0199] [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] [Indexed: 03/20/2025] Open
Abstract
Introduction: Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) has been associated with the development of COVID-19. COVID-19 may cause endothelial cell dysfunction (ECD), which can lead to cardiometabolic diseases and podocytopathy. In this study, we explored whether presence of hyperglycemia predisposes to SARS-CoV-2 infection, in vitro, and whether COVID-19 can put an individual at a higher risk of persistent renal damage in the long-term following acute COVID infection. To estimate renal damage, we evaluated albuminuria and podocytopathy. Podocytopathy was estimated by measuring podocyte-specific protein levels in urine-derived exosomes from patients who were admitted with acute COVID-19 at 10 days, 6 months, and 12 months post-acute SARS-CoV-2 infection. Methods: Blood and urine samples from patients with SARS-CoV-2 post-infection were procured from the George Washington University COVID repository. Peripheral blood mononuclear cells and urine exosomes were isolated. Podocyte-specific proteins Podocalyxin (PODXL) and Nephrin (NEPH) were identified from urine exosomes. Results: Urine exosomal podocalyxin levels were significantly high at 10 week (n = 18; P = 0.001), 6 month (n = 25; P = 0.003) and 12 month (n = 14; P = 0.0001) time points. Nephrin levels were also noted to be high at 10 week (n = 18; P = 0.001) and 12 month (n = 14; P = 0.007) time points, compared with urine samples obtained from type 2 diabetes subjects who never had COVID-19. Though urinary podocyte-specific proteins were high, compared to control, there were no significant differences noted on urine albumin:creatinine ratios (UACR) between the groups. Conclusion: Persistent high levels of podocyte-specific proteins noted in urinary exosomes even at 12 months post-Covid may lead to the development of chronic kidney disease.
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Affiliation(s)
- Seshagiri Rao Nandula
- Department of Medicine and Biochemistry, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA
| | - Beda Brichacek
- Department of Medicine and Biochemistry, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA
| | - Sabyasachi Sen
- Department of Medicine and Biochemistry, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA
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Cao H, Li Z, Ye J, Lv Y, Zhang C, Liang T, Wang Y. Emerging roles of exosomes in the diagnosis and treatment of kidney diseases. Front Pharmacol 2025; 16:1525314. [PMID: 40308771 PMCID: PMC12041035 DOI: 10.3389/fphar.2025.1525314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 03/20/2025] [Indexed: 05/02/2025] Open
Abstract
The complex etiology and spectrum of kidney diseases necessitate vigilant attention; the focus on early diagnosis and intervention in kidney diseases remains a critical issue in medical research. Recently, with the expanding studies on extracellular vesicles, exosomes have garnered increasing interest as a promising tool for the diagnosis and treatment of kidney diseases. Exosomes are nano-sized extracellular vesicles that transport a diverse array of bioactive substances, which can influence various pathological processes associated with kidney diseases and exhibit detrimental or beneficial effects. Within the kidney, exosomes derived from the glomeruli and renal tubules possess the ability to enter systemic circulation or urine. The biomarkers they carry can reflect alterations in the pathological state of the kidneys, thereby offering novel avenues for early diagnosis. Furthermore, research studies have confirmed that exosomes originating from multiple cell types exhibit therapeutic potential in treating kidney disease; notably, those derived from mesenchymal stem cells (MSCs) have shown significant treatment efficacy. This comprehensive review summarizes the contributions of exosomes from different cell types within the kidneys while exploring their physiological and pathological roles therein. Additionally, we emphasize recent advancements in exosome applications for the diagnosis and treatment of various forms of kidney diseases over the past decades. We not only introduce the urinary and blood biomarkers linked to kidney diseases found within exosomes but also explore their therapeutic effects. Finally, we discuss existing challenges and future directions concerning the clinical applications of exosomes for diagnostic and therapeutic purposes.
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Affiliation(s)
- Huanhuan Cao
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zixi Li
- Department of Clinical Laboratory, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiajia Ye
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Lv
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Liang
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yumei Wang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Wei J, Xie Z, Kuang X. Extracellular Vesicles in Renal Inflammatory Diseases: Revealing Mechanisms of Extracellular Vesicle-Mediated Macrophage Regulation. Int J Mol Sci 2025; 26:3646. [PMID: 40332144 PMCID: PMC12027779 DOI: 10.3390/ijms26083646] [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: 03/12/2025] [Revised: 04/06/2025] [Accepted: 04/07/2025] [Indexed: 05/08/2025] Open
Abstract
Renal inflammatory diseases are a group of severe conditions marked by significant morbidity and mortality. Extracellular vesicles (EVs), as facilitators of intercellular communication, have been recognized as pivotal regulators of renal inflammatory diseases, significantly contributing to these conditions by modulating immune responses among other mechanisms. This review highlights the intricate mechanisms through which EVs modulate macrophage-kidney cell interactions by regulating macrophages, the principal immune cells within the renal milieu. This regulation subsequently influences the pathophysiology of renal inflammatory diseases such as acute kidney injury and chronic kidney disease. Furthermore, understanding these mechanisms offers novel opportunities to alleviate the severe consequences associated with renal inflammatory diseases. In addition, we summarize the therapeutic landscape based on EV-mediated macrophage regulatory mechanisms, highlighting the potential of EVs as biomarkers and therapeutic targets as well as the challenges and limitations of translating therapies into clinical practice.
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Affiliation(s)
- Jiatai Wei
- The Second Clinical Medical College, Nanchang University, Nanchang 330031, China; (J.W.); (Z.X.)
| | - Zijie Xie
- The Second Clinical Medical College, Nanchang University, Nanchang 330031, China; (J.W.); (Z.X.)
| | - Xiaodong Kuang
- Pathology Teaching and Research Office, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
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Araujo-Abad S, Berna JM, Lloret-Lopez E, López-Cortés A, Saceda M, de Juan Romero C. Exosomes: from basic research to clinical diagnostic and therapeutic applications in cancer. Cell Oncol (Dordr) 2025; 48:269-293. [PMID: 39298081 PMCID: PMC11997007 DOI: 10.1007/s13402-024-00990-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2024] [Indexed: 09/21/2024] Open
Abstract
Cancer continues to pose a global threat despite potent anticancer drugs, often accompanied by undesired side effects. To enhance patient outcomes, sophisticated multifunctional approaches are imperative. Small extracellular vesicles (EVs), a diverse family of naturally occurring vesicles derived from cells, offer advantages over synthetic carriers. Among the EVs, the exosomes are facilitating intercellular communication with minimal toxicity, high biocompatibility, and low immunogenicity. Their tissue-specific targeting ability, mediated by surface molecules, enables precise transport of biomolecules to cancer cells. Here, we explore the potential of exosomes as innovative therapeutic agents, including cancer vaccines, and their clinical relevance as biomarkers for clinical diagnosis. We highlight the cargo possibilities, including nucleic acids and drugs, which make them a good delivery system for targeted cancer treatment and contrast agents for disease monitoring. Other general aspects, sources, and the methodology associated with therapeutic cancer applications are also reviewed. Additionally, the challenges associated with translating exosome-based therapies into clinical practice are discussed, together with the future prospects for this innovative approach.
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Affiliation(s)
- Salomé Araujo-Abad
- Cancer Research Group, Faculty of Engineering and Applied Sciences, Universidad de Las Américas, Quito, 170124, Ecuador
| | - José Marcos Berna
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, Alicante, 03203, Spain
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda. Universidad s/n, Ed. Torregaitán, Elche, Alicante, 03202, Spain
| | - Elena Lloret-Lopez
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, Alicante, 03203, Spain
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda. Universidad s/n, Ed. Torregaitán, Elche, Alicante, 03202, Spain
| | - Andrés López-Cortés
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, 170124, Ecuador
| | - Miguel Saceda
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, Alicante, 03203, Spain
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda. Universidad s/n, Ed. Torregaitán, Elche, Alicante, 03202, Spain
| | - Camino de Juan Romero
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, Alicante, 03203, Spain.
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda. Universidad s/n, Ed. Torregaitán, Elche, Alicante, 03202, Spain.
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Wu HHL, Bhagavath V, Nguyen LT, Chinnadurai R, Goldys EM, Pollock CA, Saad S. Association Between Glycemic Control and Complications With Concentration of Urinary Exfoliated Proximal Tubule Kidney Cells in People With Diabetes Mellitus. J Diabetes Res 2025; 2025:1273073. [PMID: 39850513 PMCID: PMC11756946 DOI: 10.1155/jdr/1273073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 01/06/2025] [Indexed: 01/25/2025] Open
Abstract
Background: Emerging evidence suggests cell exfoliation could be operating under the control of cell metabolism. It is unclear if there are associations between the concentration of exfoliated kidney proximal tubule cells (PTCs) in urine with glycemic control and complications. Our study is aimed at exploring this. Methods: Urine samples were collected from 122 adult study participants and stored at -80°C. Exfoliated PTCs were extracted from thawed urine using a validated specific immunomagnetic separation method based on anti-CD13 and anti-SGLT-2 antibodies. The number of PTCs was assessed using brightfield microscopy. Study participants were grouped into those with no diabetes mellitus (DM) and those with DM. Individuals with DM were further subgrouped into those with and without retinopathy. Adjusted Poisson regression analysis was conducted for the DM cohort, investigating associations between demographic, clinical, and biochemical parameters with mean urinary exfoliated PTCs. Results: The adjusted Poisson regression analysis noted sex to have a significant association with mean number of urinary exfoliated PTCs, with a lower incidence rate in males compared to females (incidence rate ratio (IRR) 0.56, 95% CI 0.35-0.89, p = 0.014). Each 1% increase in glycated haemoglobin (HbA1c) was associated with an increase of 1.03 times in mean exfoliated PTCs (IRR 1.03, 95% CI 1.01-1.04, p = 0.007), and DM patients with retinopathy had an increase of 1.68 times in mean exfoliated PTCs compared to those without retinopathy (IRR 1.68, 95% CI 1.07-2.62, p = 0.024). No significant associations were observed with albuminuria or estimated glomerular filtration rate (eGFR). Conclusions: Our results indicate increased shedding of PTCs into the urinary tract in patients with poorer glycemic control, particularly those with diabetic retinopathy and in females.
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Affiliation(s)
- Henry H. L. Wu
- Renal Research Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital & The University of Sydney, Sydney, Australia
- ARC Centre of Excellence for Nanoscale Biophotonics, School of Biomedical Engineering, The University of New South Wales, Sydney, Australia
| | - Venkatesha Bhagavath
- Biostatistics Support and Consultation Services, Northern Sydney Local Health District, Sydney, Australia
| | - Long The Nguyen
- Renal Research Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital & The University of Sydney, Sydney, Australia
| | - Rajkumar Chinnadurai
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Ewa M. Goldys
- ARC Centre of Excellence for Nanoscale Biophotonics, School of Biomedical Engineering, The University of New South Wales, Sydney, Australia
| | - Carol A. Pollock
- Renal Research Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital & The University of Sydney, Sydney, Australia
- Department of Renal Medicine, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, Australia
| | - Sonia Saad
- Renal Research Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital & The University of Sydney, Sydney, Australia
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Kumari S, Lausted C, Scherler K, Ng AHC, Lu Y, Lee I, Hood L, Wang K. Approaches and Challenges in Characterizing the Molecular Content of Extracellular Vesicles for Biomarker Discovery. Biomolecules 2024; 14:1599. [PMID: 39766306 PMCID: PMC11674167 DOI: 10.3390/biom14121599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 12/04/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025] Open
Abstract
Extracellular vesicles (EVs) are lipid bilayer nanoparticles released from all known cells and are involved in cell-to-cell communication via their molecular content. EVs have been found in all tissues and body fluids, carrying a variety of biomolecules, including DNA, RNA, proteins, metabolites, and lipids, offering insights into cellular and pathophysiological conditions. Despite the emergence of EVs and their molecular contents as important biological indicators, it remains difficult to explore EV-mediated biological processes due to their small size and heterogeneity and the technical challenges in characterizing their molecular content. EV-associated small RNAs, especially microRNAs, have been extensively studied. However, other less characterized RNAs, including protein-coding mRNAs, long noncoding RNAs, circular RNAs, and tRNAs, have also been found in EVs. Furthermore, the EV-associated proteins can be used to distinguish different types of EVs. The spectrum of EV-associated RNAs, as well as proteins, may be associated with different pathophysiological conditions. Therefore, the ability to comprehensively characterize EVs' molecular content is critical for understanding their biological function and potential applications in disease diagnosis. Here, we set out to provide an overview of EV-associated RNAs and proteins as well as approaches currently being used to characterize them.
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Affiliation(s)
- Suman Kumari
- Institute for Systems Biology, Seattle, WA 98109, USA; (S.K.); (C.L.); (K.S.); (L.H.)
| | - Christopher Lausted
- Institute for Systems Biology, Seattle, WA 98109, USA; (S.K.); (C.L.); (K.S.); (L.H.)
| | - Kelsey Scherler
- Institute for Systems Biology, Seattle, WA 98109, USA; (S.K.); (C.L.); (K.S.); (L.H.)
| | - Alphonsus H. C. Ng
- Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT 84112, USA; (A.H.C.N.); (Y.L.)
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA
| | - Yue Lu
- Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT 84112, USA; (A.H.C.N.); (Y.L.)
| | - Inyoul Lee
- Institute for Systems Biology, Seattle, WA 98109, USA; (S.K.); (C.L.); (K.S.); (L.H.)
| | - Leroy Hood
- Institute for Systems Biology, Seattle, WA 98109, USA; (S.K.); (C.L.); (K.S.); (L.H.)
| | - Kai Wang
- Institute for Systems Biology, Seattle, WA 98109, USA; (S.K.); (C.L.); (K.S.); (L.H.)
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Zheng Y, Xu C, Jin Y. The role of exosomes in the pathogenesis and management of diabetic kidney disease: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2024; 15:1398382. [PMID: 39703859 PMCID: PMC11658263 DOI: 10.3389/fendo.2024.1398382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 10/18/2024] [Indexed: 12/21/2024] Open
Abstract
Objective This systematic review and meta-analysis aimed to synthesize the role of exosomes in the pathogenesis and management of diabetic kidney disease. Methods PubMed, Embase, Cochrane Library, and Web of Science were searched for studies that compared the levels of exosomes between patients with diabetic kidney disease and controls published up to 27 November 2023. Methodological quality was assessed using the JBI Appraisal Checklist for Case-Control Studies. The methodology of the samples and the main results were summarized. A meta-analysis of the diagnostic performance of exosomes was performed using estimates of test sensitivity and specificity, and these values were summarized using summary receiver-operating characteristic curves. The results were reported following the PRISMA 2020 checklist. Results A total of 32 studies, including 1,119 patients with diabetic kidney disease and 1,328 controls, met the inclusion criteria. A total of 78 upregulated and 22 downregulated microRNAs, 2 upregulated and 4 downregulated mRNAs, 6 upregulated and 1 downregulated proteins, and 4 upregulated lipids were identified. The miR-126, miR-145, miR-150, miR-21, and WT1 mRNA dysregulation were consistently reported in at least two studies. The overall sensitivity and specificity of the exosomes in diabetic kidney disease diagnosis were 0.70 (95% CI: 0.59-0.80) and 0.79 (95% CI: 0.70-0.85), respectively. The summary receiver operating characteristic curve was plotted to assess diagnostic accuracy with the area under the curve (AUC) of 0.82 (95% CI: 0.78-0.85). Conclusion Exosomes have great potential to become effective diagnostic biomarkers for diabetic kidney disease. Panels of exosomes or the combination of exosomes with other clinical indicators seemed more accurate than single exosomes.
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Affiliation(s)
- Yan Zheng
- Department of Endocrinology, Zhoushan Hospital, Zhejiang Province, Zhoushan, Zhejiang, China
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Jin J, Zhang M. Research progress on the role of extracellular vesicles in the pathogenesis of diabetic kidney disease. Ren Fail 2024; 46:2352629. [PMID: 38769599 PMCID: PMC11107856 DOI: 10.1080/0886022x.2024.2352629] [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: 03/01/2024] [Accepted: 05/02/2024] [Indexed: 05/22/2024] Open
Abstract
Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus (DM) and has become the main cause of end-stage renal disease worldwide. In recent years, with the increasing incidence of DM, the pathogenesis of DKD has received increasing attention. The pathogenesis of DKD is diverse and complex. Extracellular vesicles (EVs) contain cell-derived membrane proteins, nucleic acids (such as DNA and RNA) and other important cellular components and are involved in intercellular information and substance transmission. In recent years, an increasing number of studies have confirmed that EVs play an important role in the development of DKD. The purpose of this paper is to explain the potential diagnostic value of EVs in DKD, analyze the mechanism by which EVs participate in intercellular communication, and explore whether EVs may become drug carriers for targeted therapy to provide a reference for promoting the implementation and application of exosome therapy strategies in clinical practice.
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Affiliation(s)
- Jiangyuan Jin
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Mianzhi Zhang
- Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China
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Wilczak M, Surman M, Przybyło M. Towards Understanding the Role of the Glycosylation of Proteins Present in Extracellular Vesicles in Urinary Tract Diseases: Contributions to Cancer and Beyond. Molecules 2024; 29:5241. [PMID: 39598633 PMCID: PMC11596185 DOI: 10.3390/molecules29225241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 10/28/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
Extracellular vesicles (EVs) are a population of nanoscale particles surrounded by a phospholipid bilayer, enabling intercellular transfer of bioactive molecules. Once released from the parental cell, EVs can be found in most biological fluids in the human body and can be isolated from them. For this reason, EVs have significant diagnostic potential and can serve as an excellent source of circulating disease biomarkers. Protein glycosylation plays a key role in many biological processes, and aberrant glycosylation is a hallmark of various diseases. EVs have been shown to carry multiple glycoproteins, but little is known about the specific biological roles of these glycoproteins in the context of EVs. Moreover, specific changes in EV glycosylation have been described for several diseases, including cancers and metabolic, cardiovascular, neurological or kidney diseases. Urine is the richest source of EVs, providing almost unlimited (in terms of volume) opportunities for non-invasive EV isolation. Recent studies have also revealed a pathological link between urinary EV glycosylation and urological cancers, as well as other pathologies of the urinary tract. In this review, we discuss recent research advances in this field and the diagnostic/prognostic potential of urinary EV glycosylation. In addition, we summarize common methods for isolating EVs from urine and techniques used to study their glycosylation.
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Affiliation(s)
- Magdalena Wilczak
- Department of Glycoconjugate Biochemistry, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Gronostajowa 9 Street, 30-387 Krakow, Poland; (M.W.); (M.S.)
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Prof. S. Lojasiewicza 11 Street, 30-348 Krakow, Poland
| | - Magdalena Surman
- Department of Glycoconjugate Biochemistry, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Gronostajowa 9 Street, 30-387 Krakow, Poland; (M.W.); (M.S.)
| | - Małgorzata Przybyło
- Department of Glycoconjugate Biochemistry, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Gronostajowa 9 Street, 30-387 Krakow, Poland; (M.W.); (M.S.)
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11
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Cai F, Xu LL, Tang X, Wang LL. Clinical Value of Urinary Wilms' Tumour-1 and Mu-Glutathione S-Transferase Gene Expression in Kidney Injury in Type 2 Diabetes Mellitus. Diabetes Metab Syndr Obes 2024; 17:4167-4176. [PMID: 39526202 PMCID: PMC11549887 DOI: 10.2147/dmso.s483457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
Objective To investigate the diagnostic value of urinary Wilms' tumour-1 (WT-1) and mu-glutathione S-transferase (Mu-GST) gene expression for detecting kidney injury in type 2 diabetes mellitus (T2DM). Methods Patients treated between October 2022 and June 2023 were divided into two groups: a diabetic nephropathy (DN) group (105 patients) and a diabetes mellitus (DM) group (100 patients). Additionally, 100 healthy individuals undergoing routine medical check-ups were selected as the control group. The urinary albumin/creatinine ratio (ACR), as well as urinary WT-1 and Mu-GST expression levels, were measured. The sensitivity and specificity of these markers for predicting renal injury were evaluated. Results The levels of ACR, WT-1 and Mu-GST in the DN group were significantly higher than those in the DM and control groups. The ACR in the DM group was also significantly higher than that in the control group (P < 0.05), and WT-1 and Mu-GST gene expression levels demonstrated a positive correlation with ACR (r = 0.391 and 0.342, respectively). The sensitivity and specificity of WT-1 were 74% and 95%, respectively, whereas those of Mu-GST were 70% and 96%, respectively. The combined detection of WT-1 and Mu-GST yielded a sensitivity of 82% and a specificity of 97%. Conclusion The levels of WT-1 and Mu-GST gene expression are closely related to T2DM kidney injury, helping to identify the location of kidney injury to some extent, which provides valuable information for the clinical diagnosis and treatment of kidney injury.
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Affiliation(s)
- Feng Cai
- Department of Laboratory Medicine, Kongjiang Hospital, Shanghai, 200093, People’s Republic of China
| | - Li-Li Xu
- Department of Laboratory Medicine, Kongjiang Hospital, Shanghai, 200093, People’s Republic of China
| | - Xin Tang
- Shanghai Libai Biotechnology Co., Ltd, Shanghai, 200444, People’s Republic of China
| | - Lin-Lin Wang
- Department of Laboratory Medicine, Kongjiang Hospital, Shanghai, 200093, People’s Republic of China
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Mishra DD, Maurya PK, Tiwari S. Reference gene panel for urinary exosome-based molecular diagnostics in patients with kidney disease. World J Nephrol 2024; 13:99105. [PMID: 39351186 PMCID: PMC11439094 DOI: 10.5527/wjn.v13.i3.99105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 08/27/2024] [Accepted: 08/30/2024] [Indexed: 09/19/2024] Open
Abstract
BACKGROUND Kidney disease is a severe complication of diabetes that often leads to end-stage renal disease. Early diagnosis is crucial for prevention or delay. However, the current diagnostic methods, with their limitations in detecting the disease in its early stages, underscore the urgency and importance of finding new solutions. miRNAs encapsulated inside urinary exosomes (UEs) have potential as early biomarkers for kidney diseases. The need for reference miRNAs for accurate interpretation currently limits their translational potential. AIM To identify consistently expressing reference miRNAs from UEs of controls and patients with type 2 diabetesmellitus (T2DM) and biopsy-confirmed kidney diseases. METHODS miRNA profiling was performed on UEs from 31 human urine samples using a rigorous and unbiased method. The UEs were isolated from urine samples collected from healthy individuals (n = 6), patients with T2DM (n = 13), and T2DM patients who also had kidney diseases (including diabetic nephropathy, n = 5; membranous nephropathy, n = 5; and IgA nephropathy, n = 2) through differential ultracentrifugation. After characterizing the UEs, miRNA expression profiling using microarray technology was conducted. RESULTS Microarray data analysis identified 14 miRNAs that were consistently expressed in UEs from 31 human samples, representing various kidney conditions: diabetic controls, diabetic nephropathy, membrane nephropathy, IgA nephropathy, and healthy controls. Through in silico analysis, we determined that 10 of these miRNAs had significant potential to serve as reference genes in UEs. CONCLUSION We identified uniformly expressing UE miRNAs that could serve as reference genes kidney disease biomarkers.
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Affiliation(s)
- Deendayal D Mishra
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Pramod K Maurya
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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13
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Li B, Qi C, Zhang Y, Shi L, Zhang J, Qian H, Ji C. Frontier role of extracellular vesicles in kidney disease. J Nanobiotechnology 2024; 22:583. [PMID: 39304945 DOI: 10.1186/s12951-024-02852-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 09/11/2024] [Indexed: 09/22/2024] Open
Abstract
Kidney diseases represent a diverse range of conditions that compromise renal function and structure which characterized by a progressive deterioration of kidney function, may ultimately necessitate dialysis or kidney transplantation as end-stage treatment options. This review explores the complex landscape of kidney diseases, highlighting the limitations of existing treatments and the pressing need for innovative strategies. The paper delves into the role of extracellular vesicles (EVs) as emerging biomarkers and therapeutic agents in the context of kidney pathophysiology. Urinary extracellular vesicles (uEVs), in particular, offer a non-invasive means of assessing renal injury and monitoring disease progression. Additionally, mesenchymal stem cell-derived EVs (MSC-EVs) are examined for their immunomodulatory and tissue repair capabilities, presenting a promising avenue for novel therapeutic interventions. And discusses the potential of engineering EVs to enhance their targeting and therapeutic efficacy. This paper systematically integrates the latest research findings and aims to provide a comprehensive overview of the role of EVs in kidney disease, providing cutting-edge insights into their potential as a diagnostic and therapeutic tool.
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Affiliation(s)
- Bei Li
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Chen Qi
- Department of Clinical Laboratory, Suzhou Municipal Hospital of Anhui Province, Anhui, 234000, China
| | - Yifan Zhang
- College of Medical Imaging, Dalian Medical University, Dalian, Liaoning, 116000, China
| | - Linru Shi
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Jiahui Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Hui Qian
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
| | - Cheng Ji
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
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Wang L, Wang J, Xu A, Wei L, Pei M, Shen T, Xian X, Yang K, Fei L, Pan Y, Yang H, Wang X. Future embracing: exosomes driving a revolutionary approach to the diagnosis and treatment of idiopathic membranous nephropathy. J Nanobiotechnology 2024; 22:472. [PMID: 39118155 PMCID: PMC11312222 DOI: 10.1186/s12951-024-02633-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 06/13/2024] [Indexed: 08/10/2024] Open
Abstract
Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults and is associated with high rates of end-stage renal disease. Early detection and precise interventions are crucial for improving patient prognosis and quality of life. However, the current diagnosis primarily relies on renal biopsies and traditional biomarkers, which have limitations. Additionally, targeted therapeutic strategies are lacking. Exosomes, small vesicles that facilitate intercellular communication, have emerged as potential noninvasive diagnostic markers due to their stability, diverse cargo, and rapid detectability. They also hold promise as carriers for gene and drug delivery, presenting innovative opportunities in renal disease prognosis and treatment. However, research on exosomes in the context of idiopathic membranous nephropathy (IMN) remains limited, with a focus on exploring urinary exosomes as IMN markers. In this review, we summarize the current status of MN diagnosis and treatment, highlight the fundamental characteristics of exosomes, and discuss recent advancements in their application to IMN diagnosis and therapy. We provide insights into the clinical prospects of exosomes in IMN and acknowledge potential challenges. This article aims to offer forward-looking insights into the future of exosome-mediated IMN diagnosis and treatment, indicating a revolutionary transformation in this field.
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Affiliation(s)
- Lin Wang
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300381, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Jinxiang Wang
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Guangdong, 518107, China
| | - Ao Xu
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300381, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Lijuan Wei
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300381, China
| | - Ming Pei
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300381, China
| | - Tuwei Shen
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300381, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Xian Xian
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300381, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Kang Yang
- Nephrology Department, The First Affiliated Hospital of Henan University of Chinese Medicine, Henan, 450099, China
| | - Lingyan Fei
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, China.
| | - Yihang Pan
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Guangdong, 518107, China.
| | - Hongtao Yang
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300381, China.
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Xianwen Wang
- School of Biomedical Engineering, Research and Engineering Center of Biomedical Materials, Anhui Medical University, Hefei, 230032, People's Republic of China.
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15
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Zhao B, Wang M, Cong Y, Song A, Lu J, Xie K, Dai H, Gu L. Urinary exosomal mRNAs as biomarkers for predicting the therapeutic effect of renin-angiotensin system inhibitors in IgA nephropathy patients. Clin Chim Acta 2024; 561:119750. [PMID: 38885756 DOI: 10.1016/j.cca.2024.119750] [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: 12/14/2023] [Revised: 02/08/2024] [Accepted: 05/22/2024] [Indexed: 06/20/2024]
Abstract
BACKGROUND Renin-angiotensin system inhibitors (RASi) treatment is the basic therapy for IgA nephropathy (IgAN) patients. However, there is few of biomarker that can predict the efficacy of RASi. This study aimed to find urinary exosomal mRNAs related to the therapeutic effect of RASi in the treatment of proteinuria in IgAN patients. METHODS We divided IgAN patients in screening cohort into A1 (proteinuria increase at 3 months), B1 (proteinuria decrease less than 50 % at 3 months), C1 (proteinuria decrease more than 50 % at 3 months) groups according to changes of proteinuria after treatment. The urinary exosomes were collected before biopsy, RNAs were extracted and analyzed with the microarray assay. The candidate genes were screened by differentially expressed genes (DEGs) analysis and then validated by quantitative real-time polymerase chain reaction (qPCR) in a validation cohort. A receiver operating characteristic (ROC) curve was used to evaluate gene performance in predicting therapeutic effect on RASi reducing proteinuria in IgAN patients. RESULTS ECE1 and PDE1A mRNAs were significantly different among the three groups, and were gradually decreased among A1, B1 and C1 groups. In the validation cohort, the level of urinary exosomal ECE1 and PDE1A mRNAs were also significantly lower in A2 group compared with C2 group(ECE1, P < 0.001;PDE1A, P < 0.01). Besides, the level of ECE1 mRNA was also lower in B2 group compared with C2 group (P < 0.01). The ROC curve verified that urinary exosomal ECE1 and PDE1A gene level predicted RASi efficacy in IgAN patients with area under curve (AUC) 0.68 and 0.63 respectively. CONCLUSION Urinary exosomal ECE1 and PDE1A mRNAs expression can serve as potential biomarkers for predicting the RASi efficacy to reduce proteinuria in IgAN patients.
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Affiliation(s)
- Bingru Zhao
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China
| | - Minzhou Wang
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China
| | - Yue Cong
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China; Department of Emergency Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ahui Song
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China
| | - Jiayue Lu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China
| | - Kewei Xie
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China
| | - Huili Dai
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China; Central Laboratory, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
| | - Leyi Gu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China.
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de Andrade CES, Souza KSCD, Galdino OA, de Lima MAF, de Medeiros PJ, Abbott Galvão Ururahy M, Pereira MG, de Almeida JB, de Rezende AA. New-onset diabetes after kidney transplantation: Assessing urinary Wilm's tumor-1 protein to predict renal allograft dysfunction. Adv Med Sci 2024; 69:153-159. [PMID: 38490331 DOI: 10.1016/j.advms.2024.03.002] [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: 08/25/2023] [Revised: 12/21/2023] [Accepted: 03/12/2024] [Indexed: 03/17/2024]
Abstract
PURPOSE New-onset diabetes after transplantation (NODAT) is a frequent metabolic complication associated with podocyte damage and renal allograft dysfunction. Thus, Wilm's tumor-1 (WT-1) protein, as a podocyte marker, holds promise as an option to evaluate renal allograft dysfunction in NODAT. Therefore, the study aimed to investigate urinary WT-1 levels in NODAT patients during the first year after kidney transplantation (KTx). MATERIALS AND METHODS KTx patients were categorized into non-NODAT and NODAT groups. Fasting blood glucose, glycated hemoglobin (HbA1c), urinary albumin/creatinine ratio (ACR), serum creatinine, estimated glomerular filtration rate (eGFR), and urinary WT-1 were measured at 3, 6, 9, and 12-months post-KTx. RESULTS The NODAT group manifested elevated levels of blood glucose and HbA1c during the first year post-KTx. Also, exhibited elevations in ACR and serum creatinine levels at 6, 9, and 12-months post-KTx when compared to non-NODAT group. Conversely, eGFR values in the NODAT group demonstrated significant declines at 3, 6, and 9-months post-KTx relative to non-NODAT. Furthermore, NODAT group exhibited a median annual eGFR of 47 mL/min/1.73 m2. Urinary WT-1 levels at 3, 6, 9, and 12-months post-KTx were significantly higher in the NODAT group compared to non-NODAT. Additionally, noteworthy positive correlations were identified between urinary WT-1 and HbA1c levels, along with significant negative correlations between urinary WT-1 and eGFR at the 3, 6, 9, and 12-months post-KTx. CONCLUSION The increased urinary WT-1 levels from 3-months post-KTx in NODAT patients may indicate the first sign of podocyte injury, predicting a renal allograft dysfunction in these patients.
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Affiliation(s)
| | - Karla Simone Costa de Souza
- Department of Clinical and Toxicological Analyses, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Ony Araújo Galdino
- Department of Clinical and Toxicological Analyses, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | | | - Paulo José de Medeiros
- Division of Nephrology, Department of Integrated Medicine, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | | | - Maurício Galvão Pereira
- Division of Nephrology, Department of Integrated Medicine, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - José Bruno de Almeida
- Division of Nephrology, Department of Integrated Medicine, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Adriana Augusto de Rezende
- Department of Clinical and Toxicological Analyses, Federal University of Rio Grande do Norte, Natal, RN, Brazil.
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Abinti M, Favi E, Alfieri CM, Zanoni F, Armelloni S, Ferraresso M, Cantaluppi V, Castellano G. Update on current and potential application of extracellular vesicles in kidney transplantation. Am J Transplant 2023; 23:1673-1693. [PMID: 37517555 DOI: 10.1016/j.ajt.2023.07.010] [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: 05/02/2023] [Revised: 06/28/2023] [Accepted: 07/17/2023] [Indexed: 08/01/2023]
Abstract
Kidney transplantation (KT) is the best treatment for end-stage kidney disease. However, early diagnosis of graft injury remains challenging, mainly because of the lack of accurate and noninvasive diagnostic techniques. Improving graft outcomes is equally demanding, as is the development of innovative therapies. Many research efforts are focusing on extracellular vesicles, cellular particles free in each body fluid that have shown promising results as precise markers of damage and potential therapeutic targets in many diseases, including the renal field. In fact, through their receptors and cargo, they act in damage response and immune modulation. In transplantation, they may be used to determine organ quality and aging, the presence of delayed graft function, rejection, and many other transplant-related pathologies. Moreover, their low immunogenicity and safe profile make them ideal for drug delivery and the development of therapies to improve KT outcomes. In this review, we summarize current evidence about extracellular vesicles in KT, starting with their characteristics and major laboratory techniques for isolation and characterization. Then, we discuss their use as potential markers of damage and as therapeutic targets, discussing their promising use in clinical practice as a form of liquid biopsy.
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Affiliation(s)
- Matteo Abinti
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Evaldo Favi
- Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Carlo Maria Alfieri
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Francesca Zanoni
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA
| | - Silvia Armelloni
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Mariano Ferraresso
- Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplant Unit, Department of Translational Medicine (DIMET), University of Piemonte Orientale (UPO), "Maggiore della Carita" University Hospital, Novara, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
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Lakey JRT, Wang Y, Alexander M, Chan MKS, Wong MBF, Casazza K, Jenkins I. Exosomes; a Potential Source of Biomarkers, Therapy, and Cure for Type-1 Diabetes. Int J Mol Sci 2023; 24:15713. [PMID: 37958696 PMCID: PMC10647572 DOI: 10.3390/ijms242115713] [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: 09/28/2023] [Revised: 10/21/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
The scourge of type-1 diabetes (T1D) is the morbidity and mortality it and its complications cause at a younger age. This propels the constant search for better diagnostic, treatment, and management strategies, with the ultimate quest being a cure for T1D. Recently, the therapeutic potential of exosomes has generated a lot of interest. Among the characteristics of exosomes of particular interest are (a) their regenerative capacity, which depends on their "origin", and (b) their "content", which determines the cell communication and crosstalk they influence. Other functional capacities, including paracrine and endocrine homeostatic regulation, pathogenic response ability resulting in insulin secretory defects or β-cell death under normal metabolic conditions, immunomodulation, and promotion of regeneration, have also garnered significant interest. Exosome "specificity" makes them suitable as biomarkers or predictors, and their "mobility" and "content" lend credence to drug delivery and therapeutic suitability. This review aims to highlight the functional capacities of exosomes and their established as well as novel contributions at various pathways in the onset and progression of T1D. The pathogenesis of T1D involves a complex crosstalk between insulin-secreting pancreatic β-cells and immune cells, which is partially mediated by exosomes. We also examine the potential implications for type 2 diabetes (T2D), as the link in T2D has guided T1D exploration. The collective landscape presented is expected to help identify how a deeper understanding of exosomes (and their cargo) can provide a framework for actionable solutions to prevent, halt, or change the very course of T1D and its complications.
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Affiliation(s)
- Jonathan R. T. Lakey
- Department of Surgery, University of California Irvine, Irvine, CA 92617, USA;
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA 92617, USA
| | - Yanmin Wang
- California Medical Innovations Institute, 11107 Roselle Street, San Diego, CA 92121, USA;
| | - Michael Alexander
- Department of Surgery, University of California Irvine, Irvine, CA 92617, USA;
| | - Mike K. S. Chan
- Uropean Wellness Group, Klosterstrasse 205ID, 67480 Edenkoben, Germany; (M.K.S.C.); (M.B.F.W.)
- Baden R&D Laboratories GmbH, z Hd.v. Sabine Conrad, Ferdinand-Lassalle-Strasse 40, 72770 Reutlingen, Germany
| | - Michelle B. F. Wong
- Uropean Wellness Group, Klosterstrasse 205ID, 67480 Edenkoben, Germany; (M.K.S.C.); (M.B.F.W.)
- Baden R&D Laboratories GmbH, z Hd.v. Sabine Conrad, Ferdinand-Lassalle-Strasse 40, 72770 Reutlingen, Germany
| | - Krista Casazza
- GATC Health Inc., Suite 600, 2030 Main Street, Irvine, CA 92718, USA; (K.C.); (I.J.)
| | - Ian Jenkins
- GATC Health Inc., Suite 600, 2030 Main Street, Irvine, CA 92718, USA; (K.C.); (I.J.)
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Khandpur S, Srivastava M, Sharma R, Asif S, Bhadauria DS, Mishra P, Purty AJ, Tiwari S. Association of Wilms tumor-1 protein in urinary exosomes with kidney injury: a population-based cross-sectional study. Front Med (Lausanne) 2023; 10:1220309. [PMID: 37795410 PMCID: PMC10545876 DOI: 10.3389/fmed.2023.1220309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 08/25/2023] [Indexed: 10/06/2023] Open
Abstract
Objective Loss of Wilms tumor-1 (WT1) protein, a podocytopathy marker, through urine exosome (uE), could be an early indication of kidney injury. We examined WT1 in uE (uE-WT1), along with other urine markers of glomerular and kidney tubule injury, in individuals without chronic kidney disease (CKD). Methodology The cross-sectional study included individuals who reported having no evidence of chronic kidney disease (CKD). Albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were used to assess kidney function. eGFR was calculated using the 2009 CKD-EPI (CKD-Epidemiological) equation. WT1 was analyzed in uE from humans and Wistar rats (before and after the 9th week of diabetes, n = 20). uE-WT1, urinary neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) were estimated using ELISA. The Kruskal-Wallis H test, Mann-Whitney U test, and stepwise multivariable linear regression were performed. Results Urine NGAL and ACR increase with uE-WT1 quartiles (n = 146/quarter). Similarly, uE-WT1, KIM-1, and NGAL were positively associated with ACR. Furthermore, KIM-1, NGAL, and uE-WT1 correlated with ACR. uE-WT1 outperformed KMI-1 and NGAL to explain ACR variability (25% vs. 6% or 9%, respectively). Kidney injury in streptozotocin-induced diabetic rats was associated with a significant rise in uE-WT1. Moreover, the findings were confirmed by the histopathology of kidney tissues from rats. Conclusion uE-WT1 was strongly associated with kidney function in rats. In individuals without CKD, uE-WT1 outperformed NGAL as a determinant of differences in ACR.
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Affiliation(s)
- Sukhanshi Khandpur
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Medha Srivastava
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Rajni Sharma
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Shafaque Asif
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Dharmendra S. Bhadauria
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Prabhaker Mishra
- Department of Biostatistics and Health Informatics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Anil J. Purty
- Department of Community Medicine, Pondicherry Institute of Medical Sciences (A Unit of Madras Medical Mission), Puducherry, India
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Bruschi M, Candiano G, Angeletti A, Lugani F, Panfoli I. Extracellular Vesicles as Source of Biomarkers in Glomerulonephritis. Int J Mol Sci 2023; 24:13894. [PMID: 37762196 PMCID: PMC10530272 DOI: 10.3390/ijms241813894] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/31/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
Kidney disease is a global health and healthcare burden. Glomerulonephritis (Gn), both primary and secondary, is generally characterized by an inflammatory glomerular injury and may lead to end-stage renal disease. Kidney biopsy is fundamental to the diagnosis; however, kidney biopsy presents some concerns that may partly hamper the clinical process. Therefore, more accurate diagnostic tools are needed. Extracellular vesicles (EVs) are membranous vesicles released by cells and found in bodily fluids, including urine. EVs mediate intercellular signaling both in health and disease. EVs can have both harmful and cytoprotective effects in kidney diseases, especially Gn. Previous findings reported that the specific cargo of urinary EV contains an aerobic metabolic ability that may either restore the recipient cell metabolism or cause oxidative stress production. Here, we provide an overview of the most recent proteomic findings on the role of EVs in several aspects of glomerulopathies, with a focus on this metabolic and redox potential. Future studies may elucidate how the ability of EVs to interfere with aerobic metabolism and redox status can shed light on aspects of Gn etiology which have remained elusive so far.
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Affiliation(s)
- Maurizio Bruschi
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
| | - Giovanni Candiano
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
| | - Andrea Angeletti
- Division of Nephrology and Transplantation, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
| | - Francesca Lugani
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
| | - Isabella Panfoli
- Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa, 16148 Genoa, Italy
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21
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Alli AA. Extracellular Vesicles: Investigating the Pathophysiology of Diabetes-Associated Hypertension and Diabetic Nephropathy. BIOLOGY 2023; 12:1138. [PMID: 37627022 PMCID: PMC10452642 DOI: 10.3390/biology12081138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 08/03/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023]
Abstract
Extracellular vesicles (EVs) include exosomes, microvesicles, and apoptotic bodies. EVs are released by all cell types and are found in biological fluids including plasma and urine. Urinary extracellular vesicles (uEVs) are a mixed population of EVs that comprise small EVs that are filtered and excreted, EVs secreted by tubular epithelial cells, and EVs released from the bladder, urethra, and prostate. The packaged cargo within uEVs includes bioactive molecules such as metabolites, lipids, proteins, mRNAs, and miRNAs. These molecules are involved in intercellular communication, elicit changes in intracellular signaling pathways, and play a role in the pathogenesis of various diseases including diabetes-associated hypertension and diabetic nephropathy. uEVs represent a rich source of biomarkers, prognosis markers, and can be loaded with small-molecule drugs as a vehicle for delivery.
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Affiliation(s)
- Abdel A. Alli
- Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USA; ; Tel.: +1-352-273-7877
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida, Gainesville, FL 32610, USA
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA
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Sałaga-Zaleska K, Kuchta A, Bzoma B, Chyła-Danił G, Safianowska A, Płoska A, Kalinowski L, Dębska-Ślizień A, Jankowski M. Nanoparticle Tracking Analysis of Urinary Extracellular Vesicle Proteins as a New Challenge in Laboratory Medicine. Int J Mol Sci 2023; 24:12228. [PMID: 37569604 PMCID: PMC10419144 DOI: 10.3390/ijms241512228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/25/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
Urinary extracellular vesicle (uEV) proteins may be used as specific markers of kidney damage in various pathophysiological conditions. The nanoparticle-tracking analysis (NTA) appears to be the most useful method for the analysis of uEVs due to its ability to analyze particles below 300 nm. The NTA method has been used to measure the size and concentration of uEVs and also allows for a deeper analysis of uEVs based on their protein composition using fluorescence measurements. However, despite much interest in the clinical application of uEVs, their analysis using the NTA method is poorly described and requires meticulous sample preparation, experimental adjustment of instrument settings, and above all, an understanding of the limitations of the method. In the present work, we demonstrate the usefulness of an NTA. We also present problems encountered during analysis with possible solutions: the choice of sample dilution, the method of the presentation and comparison of results, photobleaching, and the adjustment of instrument settings for a specific analysis. We show that the NTA method appears to be a promising method for the determination of uEVs. However, it is important to be aware of potential problems that may affect the results.
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Affiliation(s)
- Kornelia Sałaga-Zaleska
- Department of Clinical Chemistry, Medical University of Gdansk, Debinki Street 7, 80-211 Gdansk, Poland; (K.S.-Z.)
| | - Agnieszka Kuchta
- Department of Clinical Chemistry, Medical University of Gdansk, Debinki Street 7, 80-211 Gdansk, Poland; (K.S.-Z.)
| | - Beata Bzoma
- Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdansk, Smoluchowskiego Street 17, 80-214 Gdansk, Poland
- Clinical of Nephrology, Transplantology and Internal Diseases, University Clinical Centre in Gdansk, Smoluchowskiego Street 17, 80-214 Gdansk, Poland
| | - Gabriela Chyła-Danił
- Department of Clinical Chemistry, Medical University of Gdansk, Debinki Street 7, 80-211 Gdansk, Poland; (K.S.-Z.)
| | - Anna Safianowska
- Clinical of Nephrology, Transplantology and Internal Diseases, University Clinical Centre in Gdansk, Smoluchowskiego Street 17, 80-214 Gdansk, Poland
| | - Agata Płoska
- Department of Medical Laboratory Diagnostic—Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, Debinki Street 7, 80-211 Gdansk, Poland
| | - Leszek Kalinowski
- Department of Medical Laboratory Diagnostic—Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, Debinki Street 7, 80-211 Gdansk, Poland
- BioTechMed Centre, Department of Mechanics of Materials and Structures, Gdansk University of Technology, Narutowicza Street 11/12, 80-233 Gdansk, Poland
| | - Alicja Dębska-Ślizień
- Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdansk, Smoluchowskiego Street 17, 80-214 Gdansk, Poland
- Clinical of Nephrology, Transplantology and Internal Diseases, University Clinical Centre in Gdansk, Smoluchowskiego Street 17, 80-214 Gdansk, Poland
| | - Maciej Jankowski
- Department of Clinical Chemistry, Medical University of Gdansk, Debinki Street 7, 80-211 Gdansk, Poland; (K.S.-Z.)
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Yalameha B, Reza Nejabati H. Urinary Exosomal Metabolites: Overlooked Clue for Predicting Cardiovascular Risk. Clin Chim Acta 2023:117445. [PMID: 37315726 DOI: 10.1016/j.cca.2023.117445] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/10/2023] [Accepted: 06/11/2023] [Indexed: 06/16/2023]
Abstract
Over the last decade, increasing research has focused on urinary exosomes (UEs) in biological fluids and their relationship with physiological and pathological processes. UEs are membranous vesicles with a size of 40-100 nm, containing a number of bioactive molecules such as proteins, lipids, mRNAs, and miRNAs. These vesicles are an inexpensive non-invasive source that can be used in clinical settings to differentiate healthy patients from diseased patients, thereby serving as potential biomarkers for the early identification of disease. Recent studies have reported the isolation of small molecules called exosomal metabolites from individuals' urine with different diseases. These metabolites could utilize for a variety of purposes, such as the discovery of biomarkers, investigation of mechanisms related to disease development, and importantly prediction of cardiovascular diseases (CVDs) risk factors, including thrombosis, inflammation, oxidative stress, hyperlipidemia as well as homocysteine. It has been indicated that alteration in urinary metabolites of N1-methylnicotinamide, 4-aminohippuric acid, and citric acid can be valuable in predicting cardiovascular risk factors, providing a novel approach to evaluating the pathological status of CVDs. Since the UEs metabolome has been clearly and precisely so far unexplored in CVDs, the present study has specifically addressed the role of the mentioned metabolites in the prediction of CVDs risk factors.
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Affiliation(s)
- Banafsheh Yalameha
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamid Reza Nejabati
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Mishra DD, Sahoo B, Maurya PK, Sharma R, Varughese S, Prasad N, Tiwari S. Therapeutic potential of urine exosomes derived from rats with diabetic kidney disease. Front Endocrinol (Lausanne) 2023; 14:1157194. [PMID: 37251672 PMCID: PMC10213426 DOI: 10.3389/fendo.2023.1157194] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 04/17/2023] [Indexed: 05/31/2023] Open
Abstract
Kidney disease is prevalent in diabetes. Urinary exosomes (uE) from animal models and patients with Diabetic nephropathy (DN) showed increased levels of miRs with reno-protective potential. We examined whether urinary loss of such miRs is associated with their reduced renal levels in DN patients. We also tested whether injecting uE can leverage kidney disease in rats. In this study (study-1) we performed microarray profiling of miRNA in uE and renal tissues in DN patients and subjects with diabetes without DN (controls). In study-2, diabetes was induced in Wistar rats by Streptozotocin (i.p. 50 mg/kg of body weight). Urinary exosomes were collected at 6th, 7th and 8th weeks, and injected back into the rats (100ug/biweekly, uE-treated n=7) via tail vein on weeks 9 and 10. Equal volume of vehicle was injected in controls (vehicle, n=7). uE from the human and rat showed the presence of exosome-specific proteins by immunoblotting. Microarray profiling revealed a set of 15 miRs having high levels in the uE, while lower in renal biopsies, from DN, compared to controls (n=5-9/group). Bioinformatic analysis also confirmed the Renoprotective potential of these miRs. Taqman qPCR confirmed the opposite regulation of miR-200c-3p and miR-24-3p in paired uE and renal biopsy samples from DN patients (n=15), relative to non-DN controls. A rise in 28 miRs levels, including miR-200c-3p, miR-24-3p, miR-30a-3p and miR-23a-3p were observed in the uE of DN rats, collected between 6th-8th weeks, relative to baseline (before diabetes induction). uE- treated DN rats had significantly reduced urine albumin-to-creatinine ratio, attenuated renal pathology, and lower miR-24-3p target fibrotic/inflammatory genes (TGF-beta, and Collagen IV), relative to vehicle treated DN rats. In uE treated rats, the renal expression of miR-24-3p, miR-30a-3p, let-7a-5p and miR-23a-3p was increased, relative to vehicle control. Patients with diabetic nephropathy had reduced renal levels, while higher uE abundance of miRs with reno-protective potential. Reverting the urinary loss of miRs by injecting uE attenuated renal pathology in diabetic rats.
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Affiliation(s)
- Deendayal Das Mishra
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Biswajit Sahoo
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Pramod Kumar Maurya
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Rajni Sharma
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | | | - Narayan Prasad
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Swasti Tiwari
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Sufianov A, Kostin A, Begliarzade S, Kudriashov V, Ilyasova T, Liang Y, Mukhamedzyanov A, Beylerli O. Exosomal non coding RNAs as a novel target for diabetes mellitus and its complications. Noncoding RNA Res 2023; 8:192-204. [PMID: 36818396 PMCID: PMC9929646 DOI: 10.1016/j.ncrna.2023.02.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/06/2023] [Accepted: 02/06/2023] [Indexed: 02/10/2023] Open
Abstract
Diabetes mellitus (DM) is a first-line priority among the problems facing medical science and public health in almost all countries of the world. The main problem of DM is the high incidence of damage to the cardiovascular system, which in turn leads to diseases such as myocardial infarction, stroke, gangrene of the lower extremities, blindness and chronic renal failure. As a result, the study of the molecular genetic mechanisms of the pathogenesis of DM is of critical importance for the development of new diagnostic and therapeutic strategies. Molecular genetic aspects of the etiology and pathogenesis of diabetes mellitus are intensively studied in well-known laboratories around the world. One of the strategies in this direction is to study the role of exosomes in the pathogenesis of DM. Exosomes are microscopic extracellular vesicles with a diameter of 30-100 nm, released into the intercellular space by cells of various tissues and organs. The content of exosomes depends on the cell type and includes mRNA, non-coding RNAs, DNA, and so on. Non-coding RNAs, a group of RNAs with limited transcriptional activity, have been discovered to play a significant role in regulating gene expression through epigenetic and posttranscriptional modulation, such as silencing of messenger RNA. One of the problems of usage exosomes in DM is the identification of the cellular origin of exosomes and the standardization of protocols for molecular genetic studies in clinical laboratories. In addition, the question of the target orientation of exosomes and their targeted activity requires additional study. Solving these and other problems will make it possible to use exosomes for the diagnosis and delivery of drugs directly to target cells in DM. This study presents an analysis of literature data on the role of exosomes and ncRNAs in the development and progression of DM, as well as the prospects for the use of exosomes in clinical practice in this disease.
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Affiliation(s)
- Albert Sufianov
- Educational and Scientific Institute of Neurosurgery, Рeoples’ Friendship University of Russia (RUDN University), Moscow, Russia,Department of Neurosurgery, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Andrey Kostin
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples' Friendship University of Russia, Moscow, Russia
| | - Sema Begliarzade
- Republican Clinical Perinatal Center, Ufa, Republic of Bashkortostan, 450106, Russia
| | | | - Tatiana Ilyasova
- Department of Internal Diseases, Bashkir State Medical University, Ufa, Republic of Bashkortostan, 450008, Russia
| | - Yanchao Liang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | | | - Ozal Beylerli
- Educational and Scientific Institute of Neurosurgery, Рeoples’ Friendship University of Russia (RUDN University), Moscow, Russia,Corresponding author. Рeoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, Moscow, 117198, Russian Federation.
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Urinary Extracellular Vesicles in Chronic Kidney Disease: From Bench to Bedside? Diagnostics (Basel) 2023; 13:diagnostics13030443. [PMID: 36766548 PMCID: PMC9913975 DOI: 10.3390/diagnostics13030443] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 01/21/2023] [Accepted: 01/23/2023] [Indexed: 01/28/2023] Open
Abstract
Extracellular vesicles are a diverse group of particles that include exosomes, microvesicles, and apoptotic bodies and are defined by size, composition, site of origin, and density. They incorporate various bioactive molecules from their cell of origin during formation, such as soluble proteins, membrane receptors, nucleic acids (mRNAs and miRNAs), and lipids, which can then be transferred to target cells. Extracellular vesicles/exosomes have been extensively studied as a critical factor in pathophysiological processes of human diseases. Urinary extracellular vesicles could be a promising liquid biopsy for determining the pattern and/or severity of kidney histologic injury. The signature of urinary extracellular vesicles may pave the way for noninvasive methods to supplement existing testing methods for diagnosing kidney diseases. We discuss the potential role of urinary extracellular vesicles in various chronic kidney diseases in this review, highlighting open questions and discussing the potential for future research.
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Tepus M, Tonoli E, Verderio EAM. Molecular profiling of urinary extracellular vesicles in chronic kidney disease and renal fibrosis. Front Pharmacol 2023; 13:1041327. [PMID: 36712680 PMCID: PMC9877239 DOI: 10.3389/fphar.2022.1041327] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 12/21/2022] [Indexed: 01/13/2023] Open
Abstract
Chronic kidney disease (CKD) is a long-term kidney damage caused by gradual loss of essential kidney functions. A global health issue, CKD affects up to 16% of the population worldwide. Symptoms are often not apparent in the early stages, and if left untreated, CKD can progress to end-stage kidney disease (ESKD), also known as kidney failure, when the only possible treatments are dialysis and kidney transplantation. The end point of nearly all forms of CKD is kidney fibrosis, a process of unsuccessful wound-healing of kidney tissue. Detection of kidney fibrosis, therefore, often means detection of CKD. Renal biopsy remains the best test for renal scarring, despite being intrinsically limited by its invasiveness and sampling bias. Urine is a desirable source of fibrosis biomarkers as it can be easily obtained in a non-invasive way and in large volumes. Besides, urine contains biomolecules filtered through the glomeruli, mirroring the pathological state. There is, however, a problem of highly abundant urinary proteins that can mask rare disease biomarkers. Urinary extracellular vesicles (uEVs), which originate from renal cells and carry proteins, nucleic acids, and lipids, are an attractive source of potential rare CKD biomarkers. Their cargo consists of low-abundant proteins but highly concentrated in a nanosize-volume, as well as molecules too large to be filtered from plasma. Combining molecular profiling data (protein and miRNAs) of uEVs, isolated from patients affected by various forms of CKD, this review considers the possible diagnostic and prognostic value of uEVs biomarkers and their potential application in the translation of new experimental antifibrotic therapeutics.
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Affiliation(s)
- Melanie Tepus
- Centre for Health, Ageing and the Understanding of Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Elisa Tonoli
- Centre for Health, Ageing and the Understanding of Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Elisabetta A. M. Verderio
- Centre for Health, Ageing and the Understanding of Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
- Department of Biological, Geological, and Environmental Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
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Li G, Huang D, Zou Y, Kidd J, Gehr TWB, Li N, Ritter JK, Li PL. Impaired autophagic flux and dedifferentiation in podocytes lacking Asah1 gene: Role of lysosomal TRPML1 channel. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2023; 1870:119386. [PMID: 36302466 PMCID: PMC9869931 DOI: 10.1016/j.bbamcr.2022.119386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 10/15/2022] [Accepted: 10/17/2022] [Indexed: 11/05/2022]
Abstract
Podocytopathy and associated nephrotic syndrome have been reported in a mouse strain (Asah1fl/fl/Podocre) with a podocyte-specific deletion of α subunit (the main catalytic subunit) of acid ceramidase (Ac). However, the pathogenesis of podocytopathy in these mice remains unclear. The present study tested whether Ac deficiency impairs autophagic flux in podocytes through blockade of transient receptor potential mucolipin 1 (TRPML1) channel as a potential pathogenic mechanism of podocytopathy in Asah1fl/fl/Podocre mice. We first demonstrated that impairment of autophagic flux occurred in podocytes lacking Asah1 gene, which was evidenced by autophagosome accumulation and reduced lysosome-autophagosome interaction. TRPML1 channel agonists recovered lysosome-autophagosome interaction and attenuated autophagosome accumulation in podocytes from Asah1fl/fl/Podocre mice, while TRPML1 channel inhibitors impaired autophagic flux in WT/WT podocytes and worsened autophagic deficiency in podocytes lacking Asah1 gene. The effects of TRPML1 channel agonist were blocked by dynein inhibitors, indicating a critical role of dynein activity in the control of lysosome movement due to TRPML1 channel-mediated Ca2+ release. It was also found that there is an enhanced phenotypic transition to dedifferentiation status in podocytes lacking Asah1 gene in vitro and in vivo. Such podocyte phenotypic transition was inhibited by TRPML1 channel agonists but enhanced by TRPML1 channel inhibitors. Moreover, we found that TRPML1 gene silencing induced autophagosome accumulation and dedifferentiation in podocytes. Based on these results, we conclude that Ac activity is essential for autophagic flux and maintenance of differentiated status of podocytes. Dysfunction or deficiency of Ac may impair autophagic flux and induce podocyte dedifferentiation, which may be an important pathogenic mechanism of podocytopathy and associated nephrotic syndrome.
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Affiliation(s)
- Guangbi Li
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Dandan Huang
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Yao Zou
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Jason Kidd
- Division of Nephrology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Todd W B Gehr
- Division of Nephrology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Ningjun Li
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Joseph K Ritter
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Pin-Lan Li
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
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Tang H, Hu Y, Deng J. Extracellular Vesicles and Hypertension. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1418:69-80. [PMID: 37603273 DOI: 10.1007/978-981-99-1443-2_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/22/2023]
Abstract
Hypertension implicates multiple organs and systems, accounting for the majority of cardiovascular diseases and cardiac death worldwide. Extracellular vesicles derived from various types of cells could transfer a variety of substances such as proteins, lipids, and nucleic acids from cells to cells, playing essential roles in both physiological and pathological processes. Extracellular vesicles are demonstrated to be closely associated with the development of essential hypertension by mediating the renin-angiotensin-aldosterone system and crosstalk between multiple vascular cells. Extracellular vesicles also participate in various kinds of pathogenesis of secondary hypertensions including acute kidney injury, renal parenchymal diseases, kidney transplantation, secretory diseases (primary aldosteronism, pheochromocytoma and paraganglioma, Cushing's syndrome), and obstructive sleep apnea. Extracellular vesicles have been proved to have the potential to be served as new biomarkers in the diagnosis, treatment, and prognosis assessment of hypertension. In the future, large multicenter cohorts are highly in demand for further verifying the sensitivity and specificity of extracellular vesicles as biomarkers.
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Affiliation(s)
- Heng Tang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuxue Hu
- Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai, China
| | - Jiali Deng
- Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai, China.
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30
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Araújo Galdino O, de Souza Gomes I, Ferreira de Almeida Júnior R, Conceição Ferreira de Carvalho MI, Abreu BJ, Abbott Galvão Ururahy M, Cabral B, Zucolotto Langassner SM, Costa de Souza KS, Augusto de Rezende A. The nephroprotective action of Passiflora edulis in streptozotocin-induced diabetes. Sci Rep 2022; 12:17546. [PMID: 36266308 PMCID: PMC9584925 DOI: 10.1038/s41598-022-21826-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 10/04/2022] [Indexed: 01/13/2023] Open
Abstract
In the present study, we aimed to evaluate the therapeutic effect of Passiflora edulis fruit peel aqueous (AFA) extract as an adjuvant to insulin to confer nephroprotection against streptozotocin-induced diabetes. Male Wistar rats were divided into four groups based on treatment received for 60 days: diabetic (DB), control (CTL), insulin (INS), and insulin + AFA extract (INS + AFA). mRNA and protein expression levels of podocyte (nephrin, podocin, and WT1) and tubular (megalin) proteins were measured in kidney tissue specimens and urine. Biochemical parameters and kidney histopathology were also examined. Herein, the INS + AFA group showed superior glycemic control, which resulted in the reduction of urinary albumin/creatinine ratio, maintenance of baseline levels of Nphs1, Nphs2, Wt1, and Lrp2 mRNA expression, prevention of protein loss from the kidney tissue into the urinary space, along with the maintenance of glomerular basement membrane thickness, hyalinization, glomerular and tubulointerstitial fibrosis at values approximating those of the CTL group and significantly lower than those in the DB group. Therefore, these results suggest that, as an anti-diabetic agent, the AFA extract adjuvant to insulin could reduce and potentially prevent diabetic kidney disease.
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Affiliation(s)
- Ony Araújo Galdino
- grid.411233.60000 0000 9687 399XDepartment of Clinical and Toxicological Analyses, Federal University of Rio Grande do Norte, Av. General Gustavo Cordeiro de Farias, S/N, Faculty of Pharmacy, Petrópolis, Natal, RN CEP: 59012-570 Brazil
| | - Iago de Souza Gomes
- grid.411233.60000 0000 9687 399XDepartment of Clinical and Toxicological Analyses, Federal University of Rio Grande do Norte, Av. General Gustavo Cordeiro de Farias, S/N, Faculty of Pharmacy, Petrópolis, Natal, RN CEP: 59012-570 Brazil
| | - Renato Ferreira de Almeida Júnior
- grid.411233.60000 0000 9687 399XDepartment of Clinical and Toxicological Analyses, Federal University of Rio Grande do Norte, Av. General Gustavo Cordeiro de Farias, S/N, Faculty of Pharmacy, Petrópolis, Natal, RN CEP: 59012-570 Brazil
| | - Maria Imaculada Conceição Ferreira de Carvalho
- grid.411233.60000 0000 9687 399XDepartment of Clinical and Toxicological Analyses, Federal University of Rio Grande do Norte, Av. General Gustavo Cordeiro de Farias, S/N, Faculty of Pharmacy, Petrópolis, Natal, RN CEP: 59012-570 Brazil
| | - Bento João Abreu
- grid.411233.60000 0000 9687 399XDepartment of Morphology, Federal University of Rio Grande do Norte, Natal, RN Brazil
| | - Marcela Abbott Galvão Ururahy
- grid.411233.60000 0000 9687 399XDepartment of Clinical and Toxicological Analyses, Federal University of Rio Grande do Norte, Av. General Gustavo Cordeiro de Farias, S/N, Faculty of Pharmacy, Petrópolis, Natal, RN CEP: 59012-570 Brazil
| | - Barbara Cabral
- grid.411233.60000 0000 9687 399XDepartment of Pharmacy, Federal University of Rio Grande do Norte, Natal, RN Brazil
| | | | - Karla Simone Costa de Souza
- grid.411233.60000 0000 9687 399XDepartment of Clinical and Toxicological Analyses, Federal University of Rio Grande do Norte, Av. General Gustavo Cordeiro de Farias, S/N, Faculty of Pharmacy, Petrópolis, Natal, RN CEP: 59012-570 Brazil
| | - Adriana Augusto de Rezende
- grid.411233.60000 0000 9687 399XDepartment of Clinical and Toxicological Analyses, Federal University of Rio Grande do Norte, Av. General Gustavo Cordeiro de Farias, S/N, Faculty of Pharmacy, Petrópolis, Natal, RN CEP: 59012-570 Brazil
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31
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Xiang H, Zhang C, Xiong J. Emerging role of extracellular vesicles in kidney diseases. Front Pharmacol 2022; 13:985030. [PMID: 36172178 PMCID: PMC9510773 DOI: 10.3389/fphar.2022.985030] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 08/24/2022] [Indexed: 11/17/2022] Open
Abstract
Many types of renal disease eventually progress to end-stage renal disease, which can only be maintained by renal replacement therapy. Therefore, kidney diseases now contribute significantly to the health care burden in many countries. Many new advances and strategies have been found in the research involving kidney diseases; however, there is still no efficient treatment. Extracellular vesicles (EVs) are cell-derived membrane structures, which contains proteins, lipids, and nucleic acids. After internalization by downstream cells, these components can still maintain functional activity and regulate the phenotype of downstream cells. EVs drive the information exchange between cells and tissues. Majority of the cells can produce EVs; however, its production, contents, and transportation may be affected by various factors. EVs have been proved to play an important role in the occurrence, development, and treatment of renal diseases. However, the mechanism and potential applications of EVs in kidney diseases remain unclear. This review summarizes the latest research of EVs in renal diseases, and provides new therapeutic targets and strategies for renal diseases.
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Wu HHL, Goldys EM, Pollock CA, Saad S. Exfoliated Kidney Cells from Urine for Early Diagnosis and Prognostication of CKD: The Way of the Future? Int J Mol Sci 2022; 23:7610. [PMID: 35886957 PMCID: PMC9324667 DOI: 10.3390/ijms23147610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/07/2022] [Accepted: 07/08/2022] [Indexed: 11/17/2022] Open
Abstract
Chronic kidney disease (CKD) is a global health issue, affecting more than 10% of the worldwide population. The current approach for formal diagnosis and prognostication of CKD typically relies on non-invasive serum and urine biomarkers such as serum creatinine and albuminuria. However, histological evidence of tubulointerstitial fibrosis is the 'gold standard' marker of the likelihood of disease progression. The development of novel biomedical technologies to evaluate exfoliated kidney cells from urine for non-invasive diagnosis and prognostication of CKD presents opportunities to avoid kidney biopsy for the purpose of prognostication. Efforts to apply these technologies more widely in clinical practice are encouraged, given their potential as a cost-effective approach, and no risk of post-biopsy complications such as bleeding, pain and hospitalization. The identification of biomarkers in exfoliated kidney cells from urine via western blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence techniques, measurement of cell and protein-specific messenger ribonucleic acid (mRNA)/micro-RNA and other techniques have been reported. Recent innovations such as multispectral autofluorescence imaging and single-cell RNA sequencing (scRNA-seq) have brought additional dimensions to the clinical application of exfoliated kidney cells from urine. In this review, we discuss the current evidence regarding the utility of exfoliated proximal tubule cells (PTC), podocytes, mesangial cells, extracellular vesicles and stem/progenitor cells as surrogate markers for the early diagnosis and prognostication of CKD. Future directions for development within this research area are also identified.
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Affiliation(s)
- Henry H. L. Wu
- Renal Research Laboratory, Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW 2065, Australia; (H.H.L.W.); (C.A.P.)
- School of Biomedical Engineering, The University of New South Wales, Sydney, NSW 2052, Australia;
| | - Ewa M. Goldys
- School of Biomedical Engineering, The University of New South Wales, Sydney, NSW 2052, Australia;
| | - Carol A. Pollock
- Renal Research Laboratory, Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW 2065, Australia; (H.H.L.W.); (C.A.P.)
| | - Sonia Saad
- Renal Research Laboratory, Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW 2065, Australia; (H.H.L.W.); (C.A.P.)
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Li X, Yang L. Urinary exosomes: Emerging therapy delivery tools and biomarkers for urinary system diseases. Biomed Pharmacother 2022; 150:113055. [PMID: 35658226 DOI: 10.1016/j.biopha.2022.113055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/25/2022] [Accepted: 04/26/2022] [Indexed: 11/29/2022] Open
Abstract
Urinary exosomes (UE) are small circular membranous vesicles with a lipid bilayer with a diameter of 40-160 nm secreted by epithelial cells of the kidney and genitourinary system, which can reflect the physiological and functional status of secretory cells. Protein and RNA in exosomes can be used as markers for diseases diagnosis. Urine specimens are available and non-invasive. The protein and RNA in UE are more stable than the soluble protein and RNA in urine, which have broad application prospects in the diagnosis of urinary system diseases. This article reviews the recent advances in the application of protein or RNA in UE as markers to the diagnosis of urinary system diseases.
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Affiliation(s)
- Xin Li
- Departments of Infectious Disease, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Lina Yang
- Departments of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang, China.
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Abstract
Extracellular vesicles are released by the majority of cell types and circulate in body fluids. They function as a long-distance cell-to-cell communication mechanism that modulates the gene expression profile and fate of target cells. Increasing evidence has established a central role of extracellular vesicles in kidney physiology and pathology. Urinary extracellular vesicles mediate crosstalk between glomerular and tubular cells and between different segments of the tubule, whereas circulating extracellular vesicles mediate organ crosstalk and are involved in the amplification of kidney damage and inflammation. The molecular profile of extracellular vesicles reflects the type and pathophysiological status of the originating cell so could potentially be exploited for diagnostic and prognostic purposes. In addition, robust preclinical data suggest that administration of exogenous extracellular vesicles could promote kidney regeneration and reduce inflammation and fibrosis in acute and chronic kidney diseases. Stem cells are thought to be the most promising source of extracellular vesicles with regenerative activity. Extracellular vesicles are also attractive candidates for drug delivery and various engineering strategies are being investigated to alter their cargo and increase their efficacy. However, rigorous standardization and scalable production strategies will be necessary to enable the clinical application of extracellular vesicles as potential therapeutics. In this Review, the authors discuss the roles of extracellular vesicles in kidney physiology and disease as well as the beneficial effects of stem cell-derived extracellular vesicles in preclinical models of acute kidney injury and chronic kidney disease. They also highlight current and future clinical applications of extracellular vesicles in kidney diseases.
Urinary extracellular vesicles have roles in intra-glomerular, glomerulo-tubular and intra-tubular crosstalk, whereas circulating extracellular vesicles might mediate organ crosstalk; these mechanisms could amplify kidney damage and contribute to disease progression. Urinary extracellular vesicles could potentially be analysed using multiplex diagnostic platforms to identify pathological processes and the originating cell types; technological advances including single extracellular vesicle analysis might increase the specificity of bulk analysis of extracellular vesicle preparations. Robust standardization and validation in large patient cohorts are required to enable clinical application of extracellular vesicle-based biomarkers. Stem cell-derived extracellular vesicles have been shown to improve renal recovery, limit progression of injury and reduce fibrosis in animal models of acute kidney injury and chronic kidney disease. Various engineering approaches can be used to load extracellular vesicles with therapeutic molecules and increase their delivery to the kidney. A small clinical trial that tested the efficacy of mesenchymal stem cell extracellular vesicle administration in patients with chronic kidney disease reported promising results; however, therapeutic application of extracellular vesicles is limited by a lack of scalable manufacturing protocols and clear criteria for standardization.
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Sharma R, Sahoo B, Srivastava A, Tiwari S. Reduced insulin signaling and high glucagon in early insulin resistance impaired fast-fed regulation of renal gluconeogenesis via insulin receptor substrate. J Cell Biochem 2022; 123:1327-1339. [PMID: 35644013 DOI: 10.1002/jcb.30294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 05/11/2022] [Accepted: 05/18/2022] [Indexed: 11/08/2022]
Abstract
Gluconeogenesis is one of the key processes through which the kidney contributes to glucose homeostasis. Urinary exosomes (uE) have been used to study renal gene regulation noninvasively in humans and rodents. Recently, we demonstrated fast-fed regulation of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme for gluconeogenesis, in human uE. The regulation was impaired in subjects with early insulin resistance. Here, we studied primary human proximal tubule cells (hPT) and human uE to elucidate a potential link between insulin resistance and fast-fed regulation of renal PEPCK. We demonstrate that fasted hPTs had higher PEPCK and insulin receptor substrate-2 (IRS2) mRNA and protein levels, relative to fed cells. The fast-fed regulation was, however, attenuated in insulin receptor knockdown (IRKO) hPTs. The IRKO was confirmed by the blunted insulin-induced response on PEPCK, PGC1α, p-IR, and p-AKT expression in IRKO cells. Exosomes secreted by the wild-type or IRKO hPT showed similar regulation to the respective hPT. Similarly, in human uE, the relative abundance of IRS-2 mRNA (to IRS1) was higher in the fasted state relative to the fed condition. However, the fast-fed difference was absent in subjects with early insulin resistance. These subjects had higher circulating glucagon levels relative to subjects with optimal insulin sensitivity. Furthermore, in hPT cells, glucagon significantly induced PEPCK and IRS2 gene, and gluconeogenesis. IR knockdown in hPT cells further increased the gene expression levels. Together the data suggest that reduced insulin sensitivity and high glucagon in early insulin resistance may impair renal gluconeogenesis via IRS2 regulation.
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Affiliation(s)
- Rajni Sharma
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Biswajit Sahoo
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Aneesh Srivastava
- Department of Urology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Swasti Tiwari
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Kanakalakshmi ST, Swaminathan SM, Basthi Mohan P, Nagaraju SP, Bhojaraja MV, Koulmane Laxminarayana SL. Microparticles in Diabetic Kidney Disease. Clin Chim Acta 2022; 531:418-425. [PMID: 35568209 DOI: 10.1016/j.cca.2022.05.001] [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: 11/05/2021] [Revised: 04/29/2022] [Accepted: 05/02/2022] [Indexed: 11/17/2022]
Abstract
Diabetickidneydisease(DKD)isthemostcommoncauseofrenal failure and a major contributor to the socioeconomic burden in chronic kidney disease (CKD) patients worldwide. The pathogenesis of DKD involves all the structures in the nephron, and it is indicated by proteinuria, hypertension, and progressive decline in renal function, leading tosubstantialmorbidityandmortality. Due to the limitations of currently available standard markers (albuminuria and glomerular filtration rate) in the diagnosis and clinical grading of DKD, it's time to have novel biomarkers for early detection, targeted and effective therapy to prevent the progression. Microparticles (MPs) are extracellular vesicles measuring 0.1 to 1 micron derived by cytoskeletal reorganization in the form of cytoplasmic blebs which alters the phospholipid cytochemistry of the cell membrane. They are shed during cell activation and apoptosis as well as plays an important role in cell-to-cell communication. Over the last few decades, both plasma and urinary MPs have been investigated, validated and the preliminary research looks promising. With alterations in their number and composition documented in clinical situations involving both Type1 and 2 diabetes mellitus, microparticles assay appears to be promising in early diagnosis and prognostication of DKD. WecoverthebasicsofmicroparticlesandtheirinvolvementinDKDinthisreviewarticle.
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Affiliation(s)
- Sushma Thimmaiah Kanakalakshmi
- Department of Anaesthesiology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Shilna Muttickal Swaminathan
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Pooja Basthi Mohan
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Shankar Prasad Nagaraju
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Mohan V Bhojaraja
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
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Janouskova O, Herma R, Semeradtova A, Poustka D, Liegertova M, Malinska HA, Maly J. Conventional and Nonconventional Sources of Exosomes-Isolation Methods and Influence on Their Downstream Biomedical Application. Front Mol Biosci 2022; 9:846650. [PMID: 35586196 PMCID: PMC9110031 DOI: 10.3389/fmolb.2022.846650] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 03/28/2022] [Indexed: 11/13/2022] Open
Abstract
Despite extensive study of extracellular vesicles (EVs), specifically exosomes (EXs) as biomarkers, important modulators of physiological or pathological processes, or therapeutic agents, relatively little is known about nonconventional sources of EXs, such as invertebrate or plant EXs, and their uses. Likewise, there is no clear information on the overview of storage conditions and currently used isolation methods, including new ones, such as microfluidics, which fundamentally affect the characterization of EXs and their other biomedical applications. The purpose of this review is to briefly summarize conventional and nonconventional sources of EXs, storage conditions and typical isolation methods, widely used kits and new "smart" technologies with emphasis on the influence of isolation techniques on EX content, protein detection, RNA, mRNA and others. At the same time, attention is paid to a brief overview of the direction of biomedical application of EXs, especially in diagnostics, therapy, senescence and aging and, with regard to the current situation, in issues related to Covid-19.
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Affiliation(s)
- Olga Janouskova
- Centre of Nanomaterials and Biotechnology, Faculty of Science, Jan Evangelista University in Ústí Nad Labem, Ústí Nad Labem, Czech Republic
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Hu M, Ma Q, Liu B, Wang Q, Zhang T, Huang T, Lv Z. Long Non-Coding RNAs in the Pathogenesis of Diabetic Kidney Disease. Front Cell Dev Biol 2022; 10:845371. [PMID: 35517509 PMCID: PMC9065414 DOI: 10.3389/fcell.2022.845371] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 03/08/2022] [Indexed: 01/09/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes mellitus, with relatively high morbidity and mortality globally but still in short therapeutic options. Over the decades, a large body of data has demonstrated that oxidative stress, inflammatory responses, and hemodynamic disorders might exert critical influence in the initiation and development of DKD, whereas the delicate pathogenesis of DKD remains profoundly elusive. Recently, long non-coding RNAs (lncRNAs), extensively studied in the field of cancer, are attracting increasing attentions on the development of diabetes mellitus and its complications including DKD, diabetic retinopathy, and diabetic cardiomyopathy. In this review, we chiefly focused on abnormal expression and function of lncRNAs in major resident cells (mesangial cell, endothelial cell, podocyte, and tubular epithelial cell) in the kidney, summarized the critical roles of lncRNAs in the pathogenesis of DKD, and elaborated their potential therapeutic significance, in order to advance our knowledge in this field, which might help in future research and clinical treatment for the disease.
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Affiliation(s)
- Mengsi Hu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qiqi Ma
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Bing Liu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qianhui Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Tingwei Zhang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Tongtong Huang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhimei Lv
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- *Correspondence: Zhimei Lv,
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Garavelli S, Prattichizzo F, Ceriello A, Galgani M, de Candia P. Type 1 Diabetes and Associated Cardiovascular Damage: Contribution of Extracellular Vesicles in Tissue Crosstalk. Antioxid Redox Signal 2022; 36:631-651. [PMID: 34407376 DOI: 10.1089/ars.2021.0053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Significance: Type 1 diabetes (T1D) is characterized by the autoimmune destruction of the insulin secreting β-cells, with consequent aberrant blood glucose levels. Hyperglycemia is the common denominator for most of the chronic diabetic vascular complications, which represent the main cause of life reduction in T1D patients. For this disease, three interlaced medical needs remain: understanding the underlying mechanisms involved in pancreatic β-cell loss; identifying biomarkers able to predict T1D progression and its related complications; recognizing novel therapeutic targets. Recent Advances: Extracellular vesicles (EVs), released by most cell types, were discovered to contain a plethora of different molecules (including microRNAs) with regulatory properties, which are emerging as mediators of cell-to-cell communication at the paracrine and endocrine level. Recent knowledge suggests that EVs may act as pathogenic factors, and be developed into disease biomarkers and therapeutic targets in the context of several human diseases. Critical Issues: EVs have been recently shown to sustain a dysregulated cellular crosstalk able to exacerbate the autoimmune response in the pancreatic islets of T1D; moreover, EVs were shown to be able to monitor and/or predict the progression of T1D and the insurgence of vasculopathies. Future Directions: More mechanistic studies are needed to investigate whether the dysregulation of EVs in T1D patients is solely reflecting the progression of diabetes and related complications, or EVs also directly participate in the disease process, thus pointing to a potential use of EVs as therapeutic targets/tools in T1D. Antioxid. Redox Signal. 36, 631-651.
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Affiliation(s)
- Silvia Garavelli
- Institute for Endocrinology and Experimental Oncology "G. Salvatore," Consiglio Nazionale delle Ricerche (C.N.R.), Naples, Italy
| | | | | | - Mario Galgani
- Institute for Endocrinology and Experimental Oncology "G. Salvatore," Consiglio Nazionale delle Ricerche (C.N.R.), Naples, Italy.,Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II," Italy
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Dehghanbanadaki H, Forouzanfar K, Kakaei A, Zeidi S, Salehi N, Arjmand B, Razi F, Hashemi E. The role of CDH2 and MCP-1 mRNAs of blood extracellular vesicles in predicting early-stage diabetic nephropathy. PLoS One 2022; 17:e0265619. [PMID: 35363774 PMCID: PMC8975111 DOI: 10.1371/journal.pone.0265619] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 03/04/2022] [Indexed: 11/25/2022] Open
Abstract
Background Extracellular vesicles (EVs), including exosomes and microvesicles, are involved in intercellular communication by transferring biomolecules such as mRNA, which has been shown to be as essential biomarkers for many physiological and pathological conditions such as diabetic nephropathy (DN). This study aimed to investigate the expression of CDH1, CDH2, MCP-1, and PAI-1 mRNAs in blood EVs of DN patients and to determine their accuracy in predicting early-stage DN. Methods We recruited 196 participants, including 35 overt DN patients, 53 incipient DN patients, 62 diabetic patients (DM), and 46 healthy individuals. Quantification of the mRNA profile of blood EVs was performed using the qRT-PCR method. The diagnostic performance of mRNA was evaluated using receiver operating characteristic analysis. Results The mRNA expression of CDH2 and MCP-1 was downregulated in overt DN group (0.22-fold change and 0.15-fold change, respectively) and incipient DN group (0.60-fold change and 0.43-fold change, respectively) compared to DM group (1.72-fold change and 2.77-fold change, respectively), while PAI-1 mRNA expression decreased in incipient DN group (0.70-fold change) and DM group (0.58-fold change) compared to control. However, the expression level of CDH1 mRNA was not significantly different among the four groups (p = 0.408). Moreover, CDH2 and MCP-1 mRNAs inversely correlated with creatinine (r = -0.370 and r = -0.361, p<0.001) and Alb/Cr ratio (r = -0.355 and r = -0.297, p<0.001). 1/CDH2 mRNA also predicted overt DN with an accuracy of 0.75 (95%CI: 0.65–0.85) and incipient DN with an accuracy of 0.61 (95%CI: 0.50–0.71) while 1/MCP-1 mRNA had an accuracy of 0.66 (95%CI: 0.55–0.77) for overt DN prediction and an accuracy of 0.61 (95%CI: 0.51–0.71) for incipient DN prediction. Conclusion CDH2 and MCP-1 mRNAs expression in blood EVs was decreased with the development of DN, suggesting the renoprotective effect of these mRNAs in diabetic individuals. Moreover, their quantifications could serve as diagnostic biomarkers for early-stage DN.
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Affiliation(s)
- Hojat Dehghanbanadaki
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular–Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Katayoon Forouzanfar
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ardeshir Kakaei
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular–Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Samaneh Zeidi
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Negar Salehi
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Babak Arjmand
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular–Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Farideh Razi
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- * E-mail: (FR); (EH)
| | - Ehsan Hashemi
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
- * E-mail: (FR); (EH)
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Suire CN, Hade MD. Extracellular Vesicles in Type 1 Diabetes: A Versatile Tool. Bioengineering (Basel) 2022; 9:105. [PMID: 35324794 PMCID: PMC8945706 DOI: 10.3390/bioengineering9030105] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 12/15/2022] Open
Abstract
Type 1 diabetes is a chronic autoimmune disease affecting nearly 35 million people. This disease develops as T-cells continually attack the β-cells of the islets of Langerhans in the pancreas, which leads to β-cell death, and steadily decreasing secretion of insulin. Lowered levels of insulin minimize the uptake of glucose into cells, thus putting the body in a hyperglycemic state. Despite significant progress in the understanding of the pathophysiology of this disease, there is a need for novel developments in the diagnostics and management of type 1 diabetes. Extracellular vesicles (EVs) are lipid-bound nanoparticles that contain diverse content from their cell of origin and can be used as a biomarker for both the onset of diabetes and transplantation rejection. Furthermore, vesicles can be loaded with therapeutic cargo and delivered in conjunction with a transplant to increase cell survival and long-term outcomes. Crucially, several studies have linked EVs and their cargos to the progression of type 1 diabetes. As a result, gaining a better understanding of EVs would help researchers better comprehend the utility of EVs in regulating and understanding type 1 diabetes. EVs are a composition of biologically active components such as nucleic acids, proteins, metabolites, and lipids that can be transported to particular cells/tissues through the blood system. Through their varied content, EVs can serve as a flexible aid in the diagnosis and management of type 1 diabetes. In this review, we provide an overview of existing knowledge about EVs. We also cover the role of EVs in the pathogenesis, detection, and treatment of type 1 diabetes and the function of EVs in pancreas and islet β-cell transplantation.
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N V Lakshmi Kavya A, Subramanian S, Ramakrishna S. Therapeutic applications of exosomes in various diseases: A review. BIOMATERIALS ADVANCES 2022; 134:112579. [PMID: 35525729 DOI: 10.1016/j.msec.2021.112579] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 11/10/2021] [Accepted: 11/25/2021] [Indexed: 06/14/2023]
Abstract
Exosomes (30-150 nm in diameter) a subset of extracellular vesicles, secreted by mostly all cells, have been gaining enormous recognition from the last decade. In recent times, several studies have included exosomes to design novel therapeutic applications along with their contribution to diagnostic evaluations and pathophysiological processes. Based on cell origin, they show diverse functions and characteristics. This article is classified into several sections that include exosomes biogenesis, isolation methods, and application as therapeutic tools, commercialized exosome products, clinical trials, benefits, and challenges faced in the progress of exosome-dependent therapeutics. This work aims to give a thorough review of the numerous studies where exosomes act as therapeutic tools in the treatment of various disorders including heart, kidney, liver, and lung illnesses. The clinical trials involving exosomes, their advantages, and hazards, and difficulties involved during storage and large-scale production, applications of nanotechnology in exosome research while applying for therapeutic applications, and future directions are summarized.
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Affiliation(s)
| | - Sundarrajan Subramanian
- Center for Nanofibers and Nanotechnology Lab, Mechanical Engineering, National University of Singapore, Blk E3 05-12, 2 Engineering Drive 3, Singapore 117581, Singapore.
| | - Seeram Ramakrishna
- Center for Nanofibers and Nanotechnology Lab, Mechanical Engineering, National University of Singapore, Blk E3 05-12, 2 Engineering Drive 3, Singapore 117581, Singapore.
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Ding X, Wang X, Du J, Han Q, Zhang D, Zhu H. A systematic review and Meta-analysis of urinary extracellular vesicles proteome in diabetic nephropathy. Front Endocrinol (Lausanne) 2022; 13:866252. [PMID: 36034457 PMCID: PMC9405893 DOI: 10.3389/fendo.2022.866252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 07/04/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetic nephropathy (DN) is a major microvascular complication of both type 1 and type 2 diabetes mellitus and is the most frequent cause of end-stage renal disease with an increasing prevalence. Presently there is no non-invasive method for differential diagnosis, and an efficient target therapy is lacking. Extracellular vesicles (EV), including exosomes, microvesicles, and apoptotic bodies, are present in various body fluids such as blood, cerebrospinal fluid, and urine. Proteins in EV are speculated to be involved in various processes of disease and reflect the original cells' physiological states and pathological conditions. This systematic review is based on urinary extracellular vesicles studies, which enrolled patients with DN and investigated the proteins in urinary EV. We systematically reviewed articles from the PubMed, Embase, Web of Science databases, and China National Knowledge Infrastructure (CNKI) database until January 4, 2022. The article quality was appraised according to the Newcastle-Ottawa Quality Assessment Scale (NOS). The methodology of samples, isolation and purification techniques of urinary EV, and characterization methods are summarized. Molecular functions, biological processes, and pathways were enriched in all retrievable urinary EV proteins. Protein-protein interaction analysis (PPI) revealed pathways of potential biomarkers. A total of 539 articles were retrieved, and 13 eligible records were enrolled in this systematic review and meta-analysis. And two studies performed mass spectrometry to obtain the proteome profile. Two of them enrolled only T1DM patients, two studies enrolled both patients with T1DM and T2DM, and other the nine studies focused on T2DM patients. In total 988 participants were enrolled, and DN was diagnosed according to UACR, UAER, or decreased GFR. Totally 579 urinary EV proteins were detected and 28 of them showed a potential value to be biomarkers. The results of bioinformatics analysis revealed that urinary EV may participate in DN through various pathways such as angiogenesis, biogenesis of EV, renin-angiotensin system, fluid shear stress and atherosclerosis, collagen degradation, and immune system. Besides that, it is necessary to report results compliant with the guideline of ISEV, in orderto assure repeatability and help for further studies. This systematic review concordance with previous studies and the results of meta-analysis may help to value the methodology details when urinary EV proteins were reported, and also help to deepen the understanding of urinary EV proteins in DN.
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Affiliation(s)
- Xiaonan Ding
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- Department of Nephrology, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Chinese People’s Liberation Army (PLA) Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
| | - Xiaochen Wang
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- Department of Nephrology, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Chinese People’s Liberation Army (PLA) Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
| | - Junxia Du
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- Department of Nephrology, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Chinese People’s Liberation Army (PLA) Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
| | - Qiuxia Han
- Department of Nephrology, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Chinese People’s Liberation Army (PLA) Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
| | - Dong Zhang
- Department of Nephrology, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Chinese People’s Liberation Army (PLA) Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
- *Correspondence: Hanyu Zhu, ; Dong Zhang,
| | - Hanyu Zhu
- Department of Nephrology, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Chinese People’s Liberation Army (PLA) Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
- *Correspondence: Hanyu Zhu, ; Dong Zhang,
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Yang M, Chen J, Chen L. The roles of mesenchymal stem cell-derived exosomes in diabetes mellitus and its related complications. Front Endocrinol (Lausanne) 2022; 13:1027686. [PMID: 36339446 PMCID: PMC9633677 DOI: 10.3389/fendo.2022.1027686] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetes mellitus is a type of metabolic disease characterized by hyperglycemia, primarily caused by defects in insulin secretion, insulin action, or both. Long-term chronic hyperglycemia can lead to diabetes-related complications, causing damage, dysfunction, and failure of different organs. However, traditional insulin and oral drug therapy can only treat the symptoms but not delay the progressive failure of pancreatic beta cells or prevent the emergence of diabetic complications. Mesenchymal stem cells have received extensive attention due to their strong immunoregulatory functions and regeneration effects. Mesenchymal stem cell-derived exosomes (MSC-Exos) have been proposed as a novel treatment for diabetic patients as they have demonstrated superior efficiency to mesenchymal stem cells. This review summarizes the therapeutic effects, mechanisms, challenges, and future prospects of MSC-Exos in treating diabetes mellitus and its related complications. This review supports the potential use of MSC-Exos in future regenerative medicine to overcome the current difficulties in clinical treatment, particularly in treating diabetes.
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Affiliation(s)
- Mengmeng Yang
- Department of Endocrinology, Qilu Hospital, Shandong University, Jinan, China
| | - Jun Chen
- Department of Endocrinology, Qilu Hospital, Shandong University, Jinan, China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
- Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
- *Correspondence: Jun Chen, ; Li Chen,
| | - Li Chen
- Department of Endocrinology, Qilu Hospital, Shandong University, Jinan, China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
- Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
- *Correspondence: Jun Chen, ; Li Chen,
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Parveen A, Mishra S, Srivastava M, Chaudhary DK, Kapoor D, Gupta A, Tiwari S. Circulating Placental Alkaline Phosphatase Expressing Exosomes in Maternal Blood Showed Temporal Regulation of Placental Genes. Front Med (Lausanne) 2021; 8:758971. [PMID: 35004728 PMCID: PMC8739800 DOI: 10.3389/fmed.2021.758971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 12/02/2021] [Indexed: 11/16/2022] Open
Abstract
Background: Analysis of placental genes could unravel maternal-fetal complications. However, inaccessibility to placental tissue during early pregnancy has limited this effort. We tested if exosomes (Exo) released by human placenta in the maternal circulation harbor crucial placental genes. Methods: Placental alkaline phosphate positive exosomes (ExoPLAP) were enriched from maternal blood collected at the following gestational weeks; 6-8th (T1), 12-14th (T2), 20-24th (T3), and 28th-32nd (T4). Nanotracking analysis, electron microscopy, dynamic light scattering, and immunoblotting were used for characterization. We used microarray for transcriptome and quantitative PCR (qPCR) for gene analysis in ExoPLAP. Results: Physical characterization and presence of CD63 and CD9 proteins confirmed the successful ExoPLAP enrichment. Four of the selected 36 placental genes did not amplify in ExoPLAP, while 32 showed regulations (n = 3-8/time point). Most genes in ExoPLAP showed significantly lower expression at T2-T4, relative to T1 (p < 0.05), such as NOS3, TNFSF10, OR5H6, APOL3, and NEDD4L. In contrast, genes, such as ATF6, NEDD1, and IGF2, had significantly higher expression at T2-T4 relative to T1. Unbiased gene profiling by microarray also confirmed expression of above genes in ExoPLAP-transcriptome. In addition, repeated measure ANOVA showed a significant change in the ExoPLAP transcriptome from T2 to T4 (n = 5/time point). Conclusion: Placental alkaline phosphate positive exosomes transcriptome changed with gestational age advancement in healthy women. The transcriptome expressed crucial placental genes involved in early embryonic development, such as actin cytoskeleton organization, appropriate cell positioning, DNA replication, and B-cell regulation for protecting mammalian fetuses from rejection. Thus, ExoPLAP in maternal blood could be a promising source to study the placental genes regulation for non-invasive monitoring of placental health.
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Affiliation(s)
- Arshiya Parveen
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Suman Mishra
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Medha Srivastava
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Dharmendra K. Chaudhary
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Deepa Kapoor
- General Hospital, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Amrit Gupta
- Department of Maternal & Reproductive Health, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Swasti Tiwari
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
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Sharma R, Kumari M, Mishra S, Chaudhary DK, Kumar A, Avni B, Tiwari S. Exosomes Secreted by Umbilical Cord Blood-Derived Mesenchymal Stem Cell Attenuate Diabetes in Mice. J Diabetes Res 2021; 2021:9534574. [PMID: 34926699 PMCID: PMC8683199 DOI: 10.1155/2021/9534574] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 10/21/2021] [Accepted: 11/22/2021] [Indexed: 12/20/2022] Open
Abstract
Mesenchymal stem cell (MSC) therapy is an innovative approach in diabetes due to its capacity to modulate tissue microenvironment and regeneration of glucose-responsive insulin-producing cells. In this study, we investigated the role of MSC-derived exosomes in pancreatic regeneration and insulin secretion in mice with streptozotocin-induced diabetes. Mesenchymal stem cells (MSCs) were isolated and characterized from umbilical cord blood (UCB). Exosomes were isolated and characterized from these MSCs. Diabetes was induced in male C57Bl/6 mice by streptozotocin (STZ; 40 mg/kg body weight, i.p.) for five consecutive days. The diabetic mice were administered (i.v.) with MSC (1 × 105 umbilical cord blood MSC cells/mice/day), their derived exosomes (the MSC-Exo group that received exosomes derived from 1 × 105 MSC cells/mice/day), or the same volume of PBS. Before administration, the potency of MSCs and their exosomes was evaluated in vitro by T cell activation experiments. After day 7 of the treatments, blood samples and pancreatic tissues were collected. Histochemistry was performed to check cellular architecture and β cell regeneration. In body weight, blood glucose level, and insulin level, cell proliferation assay was done to confirm regeneration of cells after MSC and MSC-Exo treatments. Hyperglycemia was also attenuated in these mice with a concomitant increase in insulin production and an improved histological structure compared to mice in the PBS-treated group. We found increased expression of genes associated with tissue regeneration pathways, including Reg2, Reg3, and Amy2b in the pancreatic tissue of mice treated with MSC or MSC-Exo relative to PBS-treated mice. MicroRNA profiling of MSC-derived exosomes showed the presence of miRs that may facilitate pancreatic regeneration by regulating the Extl3-Reg-cyclinD1 pathway. These results demonstrate a potential therapeutic role of umbilical cord blood MSC-derived exosomes in attenuating insulin deficiency by activating pancreatic islets' regenerative abilities.
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Affiliation(s)
- Rajni Sharma
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India
| | - Manju Kumari
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India
| | - Suman Mishra
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India
| | - Dharmendra K. Chaudhary
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India
| | - Alok Kumar
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India
| | - Batia Avni
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel
- Faculty of Medicine, Hebrew University of Jerusalem, Israel
| | - Swasti Tiwari
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India
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Urinary podocyte markers in kidney diseases. Clin Chim Acta 2021; 523:315-324. [PMID: 34666027 DOI: 10.1016/j.cca.2021.10.017] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/17/2021] [Accepted: 10/13/2021] [Indexed: 01/19/2023]
Abstract
Podocytes play an important role in the maintenance of kidney function, and they are the primary focus of many kidney diseases. Podocyte injury results in the shedding of podocyte-derived cellular fragments and podocyte-specific molecular targets into the urine, which may serve as biomarkers of kidney diseases. Intact podocytes, either viable or dead, and podocyte-derived microvesicles could be quantified in the urine by various centrifugation, visualization and culture methods. Podocyte-specific protein targets from the nucleus, cytoplasm, slit-diaphragm, glomerular capillary basement membrane, and cytoskeleton, as well as their corresponding messenger RNA (mRNA), in the urine could be quantified by western blotting, ELISA, or quantitative polymerase chain reaction. Although some of these techniques may be expensive or labor-intensive at present, they may become widely available in the future because of the improvement in technology and automation. The application of urinary podocyte markers for the diagnosis and monitoring of various kidney diseases have been explored but the published data in this area are not sufficiently systematic and lack external validation. Further research should focus on standardizing, comparing, and automizing laboratory methods, as well as defining their added value to the routine clinical tests.
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Ardalan M, Hosseiniyan Khatibi SM, Rahbar Saadat Y, Bastami M, Nariman-Saleh-Fam Z, Abediazar S, Khalilov R, Zununi Vahed S. Migrasomes and exosomes; different types of messaging vesicles in podocytes. Cell Biol Int 2021; 46:52-62. [PMID: 34647672 DOI: 10.1002/cbin.11711] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/01/2021] [Accepted: 10/11/2021] [Indexed: 01/08/2023]
Abstract
Podocytes, highly specified kidney epithelial cells, live under several pathological stimuli and stresses during which they adapt themselves to keep homeostasis. Nevertheless, under extreme stress, a complex scenario of podocyte damage and its consequences occur. Podocyte damage causes foot process effacement and their detachment from the glomerular basement membrane, leading to proteinuria. Podocyte-derived extracellular vesicles (pEVs), mainly microparticles and exosomes are considered as signaling mediators of intercellular communication. Recently, it has been shown that throughout the injury-related migration procedure, podocytes are capable of releasing the injury-related migrasomes. Evidence indicates that at the early stages of glomerular disorders, increased levels of pEVs are observed in urine. At the early stage of nephropathy, pEVs especially migrasomes seem to be more sensitive and reliable indicators of podocyte stress and/or damage than proteinuria. This review highlights the current knowledge of pEVs and their values for the diagnosis of different kidney diseases.
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Affiliation(s)
| | | | | | - Milad Bastami
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Ziba Nariman-Saleh-Fam
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sima Abediazar
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rovshan Khalilov
- Department of Biophysics and Molecular Biology, Baku State University, Baku, Azerbaijan.,Joint Ukraine-Azerbaijan International Research and Education Center of Nanobiotechnology and Functional Nanosystems, Drohobych, Ukraine
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Chen J, Zhang Q, Liu D, Liu Z. Exosomes: Advances, development and potential therapeutic strategies in diabetic nephropathy. Metabolism 2021; 122:154834. [PMID: 34217734 DOI: 10.1016/j.metabol.2021.154834] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/11/2021] [Accepted: 06/14/2021] [Indexed: 02/06/2023]
Abstract
Exosomes, a major type of extracellular vesicles (EVs), are nanoscale vesicles excreted by almost all cell types via invagination of the endosomal membrane pathway. Exosomes play a crucial role in the mediation of intercellular communication both in health and disease, which can be ascribed to their capacity to be transported to neighboring or distant cells, thus regulating the biological function of recipient cells through cargos such as DNA, mRNA, proteins and microRNA. Diabetic nephropathy (DN) is a serious microvascular complication associated with diabetes mellitus as well as a significant cause of end-stage renal disease worldwide, which has resulted in a substantial economic burden on individuals and society. However, despite extensive efforts, therapeutic approaches that prevent the progression of DN do not exist, which implies new approaches are required. An increasing number of studies suggest that exosomes are involved in the pathophysiological processes associated with DN, which may potentially provide novel biomarkers and therapeutic targets for DN. Hence, this review summarizes recent advances involving exosome mechanisms in DN and their potential as biomarkers and therapeutic targets.
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Affiliation(s)
- Jingfang Chen
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, China; Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, China
| | - Qing Zhang
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, China; Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, China
| | - Dongwei Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, China; Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, China.
| | - Zhangsuo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, China; Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, China.
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Urinary Extracellular Vesicles: Uncovering the Basis of the Pathological Processes in Kidney-Related Diseases. Int J Mol Sci 2021; 22:ijms22126507. [PMID: 34204452 PMCID: PMC8234687 DOI: 10.3390/ijms22126507] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/27/2021] [Accepted: 06/11/2021] [Indexed: 12/29/2022] Open
Abstract
Intercellular communication governs multicellular interactions in complex organisms. A variety of mechanisms exist through which cells can communicate, e.g., cell-cell contact, the release of paracrine/autocrine soluble molecules, or the transfer of extracellular vesicles (EVs). EVs are membrane-surrounded structures released by almost all cell types, acting both nearby and distant from their tissue/organ of origin. In the kidney, EVs are potent intercellular messengers released by all urinary system cells and are involved in cell crosstalk, contributing to physiology and pathogenesis. Moreover, urine is a reservoir of EVs coming from the circulation after crossing the glomerular filtration barrier—or originating in the kidney. Thus, urine represents an alternative source for biomarkers in kidney-related diseases, potentially replacing standard diagnostic techniques, including kidney biopsy. This review will present an overview of EV biogenesis and classification and the leading procedures for isolating EVs from body fluids. Furthermore, their role in intra-nephron communication and their use as a diagnostic tool for precision medicine in kidney-related disorders will be discussed.
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