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Huang Y, Osouli A, Li H, Dudaney M, Pham J, Mancino V, Khan T, Chaudhuri B, Pastor-Soler NM, Hallows KR, Chung EJ. Therapeutic potential of urinary extracellular vesicles in delivering functional proteins and modulating gene expression for genetic kidney disease. Biomaterials 2025; 321:123296. [PMID: 40158444 PMCID: PMC12048220 DOI: 10.1016/j.biomaterials.2025.123296] [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: 10/01/2024] [Revised: 03/20/2025] [Accepted: 03/26/2025] [Indexed: 04/02/2025]
Abstract
Chronic kidney disease (CKD) is a widespread health concern, impacting approximately 600 million individuals worldwide and marked by a progressive decline in kidney function. A common form of CKD is autosomal dominant polycystic kidney disease (ADPKD), which is the most inherited genetic kidney disease and affects greater than 12.5 million individuals globally. Given that there are over 400 pathogenic PKD1/PKD2 mutations in patients with ADPKD, relying solely on small molecule drugs targeting a single signaling pathway has not been effective in treating ADPKD. Urinary extracellular vesicles (uEVs) are naturally released by cells from the kidneys and the urinary tract, and uEVs isolated from non-disease sources have been reported to carry functional polycystin-1 (PC1) and polycystin-2 (PC2), the respective products of PKD1 and PKD2 genes that are mutated in ADPKD. uEVs from non-disease sources, as a result, have the potential to provide a direct solution to the root of the disease by delivering functional proteins that are mutated in ADPKD. To test our hypothesis, we first isolated uEVs from healthy mice urine and conducted a comprehensive characterization of uEVs. Then, PC1 levels and EV markers CD63 and TSG101 of uEVs were confirmed via ELISA and Western blot. Following characterization of uEVs, the in vitro cellular uptake, inhibition of cyst growth, and gene rescue ability of uEVs were demonstrated in kidney cells. Next, upon administration of uEVs in vivo, uEVs showed bioavailability and accumulation in the kidneys. Lastly, uEV treatment in ADPKD mice (Pkd1fl/fl;Pax8-rtTA;Tet-O-Cre) showed smaller kidney size, lower cyst index, and enhanced PC1 levels without affecting safety despite repeated treatment. In summary, we demonstrate the potential of uEVs as natural nanoparticles to deliver protein and gene therapies for the treatment of chronic and genetic kidney diseases such as ADPKD.
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Affiliation(s)
- Yi Huang
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Ali Osouli
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Hui Li
- Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Megan Dudaney
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Jessica Pham
- Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Valeria Mancino
- Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Taranatee Khan
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Baishali Chaudhuri
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Nuria M Pastor-Soler
- Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Kenneth R Hallows
- Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Eun Ji Chung
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA; Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA; Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Bridge Institute, University of Southern California, Los Angeles, CA, USA.
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Deng XH, Wu ZC, Sun Q, Huang LX, Xie YC, Lou DX, Li CG, Liu XQ, Zhou ZR, Tian T, Lian CL, Fu QL. The effects of Klotho delivering mesenchymal stem cell-derived small extracellular vesicles on acute kidney injury. J Nanobiotechnology 2025; 23:427. [PMID: 40481485 PMCID: PMC12144696 DOI: 10.1186/s12951-025-03499-4] [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: 02/05/2025] [Accepted: 05/27/2025] [Indexed: 06/11/2025] Open
Abstract
Acute kidney injury (AKI) is a life-threating syndrome characterized by sudden loss of kidney function, and its management is challenging and often suboptimal. Mesenchymal stem cells (MSCs) have shown promise in AKI therapy in pre-clinical and clinical trials; however, their clinical application still faces many challenges. MSC-derived small extracellular vesicles (sEV) may help overcome these challenges. In the current study, we overexpressed Klotho in MSCs and then isolated Klotho-loaded sEV (Klotho-sEV) using anion-exchange chromatography. Klotho-sEV displayed characteristics comparable to those of sEV in terms of size, morphology, conventional markers, and biosafety, as well as a higher abundance of Klotho protein. In rhabdomyolysis-induced AKI, sEV showed preferential tropism in injured kidneys. We found significantly and stably accelerated renal recovery, mitigated functional and histological abnormalities, stimulated tubular cell proliferation, reduced injury and inflammatory marker expression, and restored endogenous Klotho loss in mice after the administration of Klotho-sEV. In addition, Klotho-sEV treatment activated the mTOR and MEK1/2 signaling pathways. Proteomics and small RNA sequencing analyses of sEV and Klotho-sEV revealed abundant proteins and miRNAs involved in anti-inflammation and reno-protection, and Klotho-sEV showed characteristics that were different from those of sEV. In conclusion, Klotho-sEV may be a promising cell-free strategy for the treatment of AKI.
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Affiliation(s)
- Xiao-Hui Deng
- Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, PR China
- Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, PR China
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, PR China
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, PR China
| | - Zi-Cong Wu
- Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, PR China
- Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, PR China
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, PR China
| | - Qi Sun
- Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, PR China
| | - Long-Xin Huang
- Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, PR China
| | - Ying-Chun Xie
- Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, PR China
| | - Dong-Xiao Lou
- Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, PR China
| | - Chan-Gu Li
- Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, PR China
| | - Xiao-Qing Liu
- Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, PR China
| | - Zhi-Rou Zhou
- Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, PR China
| | - Tian Tian
- Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, PR China
| | - Chang-Lin Lian
- Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, PR China
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, PR China
| | - Qing-Ling Fu
- Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, PR China.
- Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, PR China.
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, PR China.
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Nambidi S, Pallatt S, Banerjee A, Pathak S, Chan MKS. Klotho protein: a multifaceted regulator in aging and cancer dynamics. Mol Biol Rep 2025; 52:507. [PMID: 40423846 DOI: 10.1007/s11033-025-10575-3] [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: 03/05/2025] [Accepted: 05/04/2025] [Indexed: 05/28/2025]
Abstract
Klotho, named after the youngest of the three Fates in Greek mythology daughters of Zeus and Nyx, who together spin the thread of life, allot destiny, and determine the time of passing for both mortals and immortals, is an important regulatory factor in aging and cancer dynamics. Initially described as an aging-suppressing protein, Klotho is now recognized for its more diverse role in modulating key signaling pathways like Wnt/β-catenin, IGF-1, PI3K/AKT, and TGF-β. Essentially, its various pro-cellular health functions, such as antioxidant, anti-inflammatory, and tumor-suppressive activities, are, in fact, considered that ensures the maintenance of cellular health and reduce complications related to aging. Klotho deficiency is associated with accelerated aging, chronic kidney disease, cardiovascular disorders, neurodegeneration, and various cancers. This review thus covers the twin roles of Klotho as an antiaging and tumor-suppressor protein, on their therapeutic potential, as well as advances in delivery systems and development of biomarkers and challenges for clinical translation.. Moreover, natural strategies like exercise and dietary interventions are explored that could help overcome Klotho deficiency. Further research with Klotho may offer a paradigm shift in the treatment of aging and cancer and add yet another avenue to increase survival of the patients.
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Affiliation(s)
- Sibin Nambidi
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, Tamil Nadu, India
| | - Sneha Pallatt
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, Tamil Nadu, India
| | - Antara Banerjee
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, Tamil Nadu, India.
| | - Surajit Pathak
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, Tamil Nadu, India.
| | - Mike K S Chan
- European Wellness Biomedical Group, Klosterstrasse 205, 67480, Edenkoben, Germany
- Baden R&D Laboratories GmbH, Ferdinand-Lassalle-Strasse 40, 72770, Reutlingen, Germany
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Yan Q, Liu M, Mao J, Zhao Z, Wang B. Extracellular Vesicles in Acute Kidney Injury: Mechanisms, Biomarkers, and Therapeutic Potential. Int J Nanomedicine 2025; 20:6271-6288. [PMID: 40400780 PMCID: PMC12094478 DOI: 10.2147/ijn.s519345] [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: 01/24/2025] [Accepted: 05/10/2025] [Indexed: 05/23/2025] Open
Abstract
Acute kidney injury (AKI) has a high morbidity and mortality rate but can only be treated with supportive therapy in most cases. The diagnosis of AKI is mainly based on serum creatinine level and urine volume, which cannot detect kidney injury sensitive and timely. Therefore, new diagnostic and therapeutic molecules of AKI are being actively explored. Extracellular vesicles (EVs), secreted by almost all cells, can originate from different parts of the kidney and mediate intercellular communication between various cell types of nephrons. At present, numerous successful EV-based biomarker discoveries and treatments for AKI have been made, such as the confirmed diagnostic role of urine-derived EVs in AKI and the established therapeutic role of mesenchymal stem cell-derived EVs in AKI have been confirmed; however, these related studies lack a full discussion. In this review, we summarize the latest progression in the profound understanding of the functional role of EVs in AKI caused by various etiologies in recent years and provide new insights into EVs as viable biomarkers and therapeutic molecules for AKI patients. Furthermore, the current challenges and prospects of this research area are briefly discussed, presenting a comprehensive overview of the growing foregrounds of EVs in AKI.
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Affiliation(s)
- Qianqian Yan
- Nephrology Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China
| | - Mengyuan Liu
- Department of Anesthesiology, Air Force Hospital of Western Theater Command, PLA, Chengdu, 610011, People’s Republic of China
| | - Jinyan Mao
- Department of Anesthesiology, Air Force Hospital of Western Theater Command, PLA, Chengdu, 610011, People’s Republic of China
| | - Zihao Zhao
- Nephrology Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China
- Department of Radiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China
| | - Bo Wang
- Department of Nephrology, Institute of Kidney Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
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Grange C, Deorsola L, Degiovanni B, Tomanin D, Prudente D, Peruzzi L, Pace Napoleone C, Bussolati B. Urinary Extracellular Vesicle Analysis Reveals Early Signs of Kidney Inflammation and Damage in Single Ventricle Paediatric Patients After Fontan Operation. Int J Nanomedicine 2025; 20:5907-5922. [PMID: 40356857 PMCID: PMC12067722 DOI: 10.2147/ijn.s483534] [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: 06/20/2024] [Accepted: 01/18/2025] [Indexed: 05/15/2025] Open
Abstract
Background Extracellular vesicles present in urine (uEVs) are gaining considerable interest as biomarkers, to monitor and predict kidney physio-pathological state. Patients with single ventricle defects and hemodynamic stabilization by Fontan intervention may develop kidney dysfunction as one of the most prevalent extracardiac co-morbidity. Our study aimed to characterize uEVs in children with single ventricle heart defects who underwent Fontan surgery, focusing on markers for monitoring and predicting kidney function, to get physio-pathological insights on possible mechanisms of tissue damage and progression. Methods We isolated uEVs from urine of 60 paediatric patients affected by single ventricle defects, and from 10 healthy subjects. We analysed uEVs to assess the presence of the reno-protective hormone Klotho, using super resolution microscopy of single uEVs and ELISA. Moreover, we analysed the levels of markers of kidney regeneration, such as CD133 and CD24, and of inflammation using a bead-based cytofluorimetric multiplex analysis. The markers' levels were correlated with patients' demographical, clinical and surgical data. Results uEVs from children with single ventricle defects showed reduced levels of Klotho and CD133, compared with the ones of healthy subjects. In parallel, the levels of inflammatory markers (CD3, CD56, and HLA-DR) were significantly higher. Interestingly, levels of inflammatory markers correlated with age of patients and distance from surgery. Conclusion This study demonstrates that single ventricle patients, who underwent Fontan's surgery, present altered levels of uEV biomarkers related to regeneration, inflammation and fibrosis, suggesting the presence of early signs of kidney damage and inflammation, compatible with the complexity of the pathology.
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Affiliation(s)
- Cristina Grange
- Department of Medical Sciences, University of Torino, Torino, Italy
| | - Luca Deorsola
- Città della Salute e della Scienza Hospital, Torino, Italy
- Pediatric and Congenital Cardiac Surgery, Regina Margherita Children’s Hospital, Torino, Italy
| | - Beatrice Degiovanni
- Città della Salute e della Scienza Hospital, Torino, Italy
- Pediatric and Congenital Cardiac Surgery, Regina Margherita Children’s Hospital, Torino, Italy
| | - Dario Tomanin
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Diego Prudente
- Department of Medical Sciences, University of Torino, Torino, Italy
| | - Licia Peruzzi
- Città della Salute e della Scienza Hospital, Torino, Italy
- Pediatric Nephrology Dialysis and Transplant Unit, Regina Margherita Children’s Hospital, Torino, Italy
| | - Carlo Pace Napoleone
- Città della Salute e della Scienza Hospital, Torino, Italy
- Pediatric and Congenital Cardiac Surgery, Regina Margherita Children’s Hospital, Torino, Italy
| | - Benedetta Bussolati
- Department of Medical Sciences, University of Torino, Torino, Italy
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
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Zhang Z, She L, Bai M. Efficacy of exosomes in acute kidney injury treatment and the associated mechanism (Review). Mol Med Rep 2025; 31:137. [PMID: 40145555 PMCID: PMC11963750 DOI: 10.3892/mmr.2025.13503] [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: 11/23/2024] [Accepted: 01/31/2025] [Indexed: 03/28/2025] Open
Abstract
Acute kidney injury (AKI) is a syndrome characterized by rapid loss of renal function with a high morbidity and mortality. However, due to the complex pathophysiologic mechanisms of AKI, no specific treatment for this disease is currently available. Animal models have demonstrated the protective effects of exosomes on AKI; however, the underlying mechanisms require further investigation. The present review focuses on the efficacy of exosomes derived from different cell sources, including mesenchymal stem cells, endothelial progenitor cells and tubular epithelial cells, in the treatment of AKI and the associated mechanism. Furthermore, the effects of exosomal contents, including microRNAs, circular RNAs, long non‑coding RNAs, messenger RNAs and proteins, on the repair of renal tubules, protection against renal tubular epithelial cell injury, protection against fibrosis, inhibition of early endoplasmic reticulum stress and mediation of inflammation during AKI are also summarized in the present review.
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Affiliation(s)
- Zehao Zhang
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Lecheng She
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Ming Bai
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
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Wang W, Wang J, Liao D. Effects and Mechanisms of Extracellular Vesicles in Different Models of Acute Kidney Injury. Stem Cells Int 2025; 2025:1075016. [PMID: 40165854 PMCID: PMC11957863 DOI: 10.1155/sci/1075016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 02/10/2025] [Accepted: 02/20/2025] [Indexed: 04/02/2025] Open
Abstract
Acute kidney injury (AKI) is a rapid decline in renal function caused by ischemia/reperfusion (I/R), renal toxic injury, and sepsis. While the precise molecular mechanisms underlying AKI are still under investigation, current therapeutic approaches remain insufficient. In recent years, there has been growing evidence that mesenchymal stem cells (MSCs) have great potential in accelerating renal repair after AKI in various preclinical models, while there has been extensive research on extracellular vesicles (EVs) as therapeutic mediators in AKI models, and they are considered to be superior to MSCs as new regenerative therapies. EVs are nanoparticles secreted by various types of cells under physiological and pathological conditions. EVs derived from various sources possess biomarker potential and play crucial roles in mediating cellular communication between kidney cells and other tissue cells by transmitting signal molecules. These vesicles play a direct and indirect role in regulating the pathophysiological mechanisms of AKI and contribute to the occurrence, development, treatment, and repair of AKI. In this review, we briefly outline the essential characteristics of EVs, focus on the multiple molecular mechanisms currently involved in the protection of EVs against different types of AKI, and further discuss the potential targets of EVs from different sources in the treatment of AKI. Finally, we summarized the deficiencies in the production and treatment of EVs and the current strategies for improvement.
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Affiliation(s)
- Weidong Wang
- Department of Nephrology, Mianyang Central Hospital, Mianyang 621000, China
| | - Jingyu Wang
- Renal Division, Peking University First Hospital, Beijing 100080, China
| | - Dan Liao
- Department of Nephrology, Mianyang Central Hospital, Mianyang 621000, China
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Lange-Consiglio A, Tagliasacchi F, Cremonesi F, Gusmara C, Pollera C, Scarpa P, Gaspari G, Riccaboni P. Characterization of Urine-Derived Stromal/Stem Cells from Healthy Dogs and Dogs Affected by Chronic Kidney Disease (CKD). Animals (Basel) 2025; 15:242. [PMID: 39858242 PMCID: PMC11758669 DOI: 10.3390/ani15020242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/02/2025] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
Urine-derived mesenchymal stromal/stem cells (USCs) could be a valuable source of cells in regenerative medicine because urine can be easily collected non-invasively. In this paper, USCs were isolated from both healthy dogs and dogs affected by chronic kidney disease (CKD), and the efficacy of collection methods (spontaneous micturition, bladder catheterization, and cystocentesis) were compared. Isolated cells were cultured in the presence of platelet-rich plasma and studied for their proliferative capacity (growth curve, doubling time, and colony forming unit), differentiation properties, expression of mesenchymal markers, and Klotho protein. Morphologically, all cells were elongated and fibroblast-like. USCs isolated from samples collected by spontaneous micturition and bladder catheterization failed to proliferate, whilst USCs obtained by cystocentesis showed a doubling time of 2.04 days in healthy dogs and 1.7 days in dogs with CKD (p < 0.05). Cells were able to differentiate into osteogenic, chondrogenic, and adipogenic lines, showed positive expression to mesenchymal/stem markers, negative expression to hematopoietic markers, and major histocompatibility complex (MHCII) antigen. Klotho protein expression was confirmed. This study confirmed that USCs from healthy and CKD dogs can act as stem cells, with those from sick dogs having greater proliferative ability with the potential for use as autologous therapies.
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Affiliation(s)
- Anna Lange-Consiglio
- Reproduction Laboratory, Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy; (A.L.-C.); (F.C.)
| | - Filippo Tagliasacchi
- Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy; (F.T.); (C.G.); (C.P.); (P.S.); (P.R.)
| | - Fausto Cremonesi
- Reproduction Laboratory, Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy; (A.L.-C.); (F.C.)
| | - Claudia Gusmara
- Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy; (F.T.); (C.G.); (C.P.); (P.S.); (P.R.)
- Laboratorio di Malattie Infettive degli Animali (MiLab), Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy
| | - Claudia Pollera
- Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy; (F.T.); (C.G.); (C.P.); (P.S.); (P.R.)
| | - Paola Scarpa
- Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy; (F.T.); (C.G.); (C.P.); (P.S.); (P.R.)
| | - Giulia Gaspari
- Reproduction Laboratory, Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy; (A.L.-C.); (F.C.)
| | - Pietro Riccaboni
- Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy; (F.T.); (C.G.); (C.P.); (P.S.); (P.R.)
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Sun J, Shen H, Dong J, Zhang J, Yue T, Zhang R. Melanin-Deferoxamine Nanoparticles Targeting Ferroptosis Mitigate Acute Kidney Injury via RONS Scavenging and Iron Ion Chelation. ACS APPLIED MATERIALS & INTERFACES 2025; 17:282-296. [PMID: 39705095 DOI: 10.1021/acsami.4c14815] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2024]
Abstract
Rhabdomyolysis (RM)-induced acute kidney injury (AKI) involves the release of large amounts of iron ions from excess myoglobin in the kidneys, which mediates the overproduction of reactive species with the onset of iron overload via the Fenton reaction, thus inducing ferroptosis and leading to renal dysfunction. Unfortunately, there are no effective treatments for AKI other than supportive care. Herein, we developed a multifunctional nanoplatform (MPD) by covalently bonding melanin nanoparticles (MP NPs) to deferoxamine. The nanoplatform has good dispersion and physiological stability, excellent chelating performance to iron ions, and broad-spectrum reactive species scavenging activity. Furthermore, cellular experiments showed that the NPs possessed high biocompatibility, antiapoptotic activity, antioxidant properties, and strong scavenging capacity of Fe2+ to mitigate iron overload, protecting the intracellular mitochondria from oxidative stress. Meanwhile, the intrinsic photoacoustic imaging capability of melanin allows the real-time monitoring of MPD NPs' target uptake and metabolic behavior in healthy and AKI mice. Most importantly, MPD NPs led to downregulation of the antioxidant pathway by targeting ferroptosis, thus effectively rescuing renal function in vivo, mitigating oxidative stress and inflammatory responses, and inhibiting renal tubular cell apoptosis. The nanoplatform offers a novel therapeutic strategy for RM-induced AKI.
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Affiliation(s)
- Jinghua Sun
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China
| | - Hao Shen
- Shanxi Medical University, Taiyuan 030001, China
| | - Jie Dong
- Shanxi Medical University, Taiyuan 030001, China
| | - Jin Zhang
- Shanxi Medical University, Taiyuan 030001, China
| | - Tao Yue
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China
| | - Ruiping Zhang
- The Radiology Department of Shanxi Provincial People's Hospital Affiliated to Shanxi Medical University, Taiyuan 030012, China
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Zhang A, Li Q, Chen Z. Therapeutic Efficacy and Promise of Human Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles in Aging and Age-Related Disorders. Int J Mol Sci 2024; 26:225. [PMID: 39796081 PMCID: PMC11719504 DOI: 10.3390/ijms26010225] [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: 12/04/2024] [Revised: 12/24/2024] [Accepted: 12/26/2024] [Indexed: 01/13/2025] Open
Abstract
The global issue of aging populations has become increasingly prominent, thus the research and development for anti-aging therapies to assure longevity as well as to ameliorate age-related complications is put high on the agenda. The young humoral milieu has been substantiated to impart youthful characteristics to aged cells or organs. Extracellular vesicles (EVs) are a heterogeneous group of cell-derived membrane-limited structures that serve as couriers of proteins and genetic material to regulate intercellular communication. Of note, EVs appeared to be an indispensable component of young blood in prolonging lifespans, and circulating EVs have been indicated to mediate the beneficial effect of a young milieu on aging. Human umbilical cord mesenchymal stem cell-derived EVs (HUCMSC-EVs), isolated from the youngest adult stem cell source, are speculated to reproduce the function of circulating EVs in young blood and partially revitalize numerous organs in old animals. Robust evidence has suggested HUCMSC-EVs as muti-target therapeutic agents in combating aging and alleviating age-related degenerative disorders. Here, we provide a comprehensive overview of the anti-aging effects of HUCMSC-EVs in brain, heart, vasculature, kidney, muscle, bone, and other organs. Furthermore, we critically discuss the current investigation on engineering strategies of HUCMSC-EVs, intending to unveil their full potential in the field of anti-aging research.
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Affiliation(s)
- Anyuan Zhang
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
| | - Qiubai Li
- Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhichao Chen
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
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11
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Yuan F, Lerman LO. Targeted therapeutic strategies for the kidney. Expert Opin Ther Targets 2024; 28:979-989. [PMID: 39491501 PMCID: PMC11617265 DOI: 10.1080/14728222.2024.2421756] [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: 09/20/2024] [Accepted: 10/23/2024] [Indexed: 11/05/2024]
Abstract
INTRODUCTION Kidney diseases impose a significant burden with high incidence and mortality rates. Current treatment options for kidney diseases are limited, necessitating urgent development of novel and effective therapeutic strategies to delay or reverse disease progression. Targeted therapies for the kidney hold promise in significantly enhancing treatment outcomes, offering hope to patients afflicted with renal disorders. AREAS COVERED This review summarized advances in kidney-targeted therapies including genes, peptides and proteins, cell-based, nanoparticles, and localized delivery routes. We also explored the potential clinical applications, prospects, and challenges of targeted therapies for renal disorders. EXPERT OPINION Advances in targeted therapies for renal conditions have enhanced therapeutic outcomes. Clinical application of kidney-targeted therapies is currently limited by renal structure and the scarcity of robust biomarkers. Bridging the gap from basic and pre-clinical research targeting the kidney to achieving clinical translation remains a formidable challenge.
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Affiliation(s)
- Fei Yuan
- Division of Nephrology and Hypertension, Mayo Clinic; Rochester, MN, USA
- Department of Urology, National Children’s Medical Center, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lilach O. Lerman
- Division of Nephrology and Hypertension, Mayo Clinic; Rochester, MN, USA
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
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12
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Hou J, Chen KX, He C, Li XX, Huang M, Jiang YZ, Jiao YR, Xiao QN, He WZ, Liu L, Zou NY, Huang M, Wei J, Xiao Y, Yang M, Luo XH, Zeng C, Lei GH, Li CJ. Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence. NATURE AGING 2024; 4:1562-1581. [PMID: 39266768 PMCID: PMC11564114 DOI: 10.1038/s43587-024-00694-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 07/25/2024] [Indexed: 09/14/2024]
Abstract
The accumulation and systemic propagation of senescent cells contributes to physiological aging and age-related pathology. However, which cell types are most susceptible to the aged milieu and could be responsible for the propagation of senescence has remained unclear. Here we found that physiologically aged bone marrow monocytes/macrophages (BMMs) propagate senescence to multiple tissues, through extracellular vesicles (EVs), and drive age-associated dysfunction in mice. We identified peroxisome proliferator-activated receptor α (PPARα) as a target of microRNAs within aged BMM-EVs that regulates downstream effects on senescence and age-related dysfunction. Demonstrating therapeutic potential, we report that treatment with the PPARα agonist fenofibrate effectively restores tissue homeostasis in aged mice. Suggesting conservation to humans, in a cohort study of 7,986 participants, we found that fenofibrate use is associated with a reduced risk of age-related chronic disease and higher life expectancy. Together, our findings establish that BMMs can propagate senescence to distant tissues and cause age-related dysfunction, and they provide supportive evidence for fenofibrate to extend healthy lifespan.
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Affiliation(s)
- Jing Hou
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Kai-Xuan Chen
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Chen He
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Xiao-Xiao Li
- Hunan Key Laboratory of Joint Degeneration and Injury, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
| | - Mei Huang
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Yang-Zi Jiang
- School of Biomedical Sciences, Institute for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Special Administrative Region of China, Hong Kong, China
| | - Yu-Rui Jiao
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Qiao-Ni Xiao
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Wen-Zhen He
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Ling Liu
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Nan-Yu Zou
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Min Huang
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Jie Wei
- Hunan Key Laboratory of Joint Degeneration and Injury, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Department of Orthopaedics, Xiangya Hospital of Central South University, Changsha, China
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
| | - Ye Xiao
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Mi Yang
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Xiang-Hang Luo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Chao Zeng
- Hunan Key Laboratory of Joint Degeneration and Injury, Changsha, China.
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China.
- Department of Orthopaedics, Xiangya Hospital of Central South University, Changsha, China.
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
| | - Guang-Hua Lei
- Hunan Key Laboratory of Joint Degeneration and Injury, Changsha, China.
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China.
- Department of Orthopaedics, Xiangya Hospital of Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
| | - Chang-Jun Li
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China.
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
- Laboratory Animal Center, Xiangya Hospital, Central South University, Changsha, China.
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13
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Cricri G, Gobbini A, Bruno S, Bellucci L, Tassinari S, Caicci F, Tamburello C, Nittoli T, Paraboschi I, Berrettini A, Grifantini R, Bussolati B, Morello W, Montini G, Collino F. Modeling a biofluid-derived extracellular vesicle surface signature to differentiate pediatric idiopathic nephrotic syndrome clinical subgroups. Sci Rep 2024; 14:25765. [PMID: 39468184 PMCID: PMC11519447 DOI: 10.1038/s41598-024-76727-w] [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: 04/17/2024] [Accepted: 10/16/2024] [Indexed: 10/30/2024] Open
Abstract
Idiopathic Nephrotic Syndrome (INS) is a common childhood glomerular disease requiring intense immunosuppressive drug treatments. Prediction of treatment response and the occurrence of relapses remains challenging. Biofluid-derived extracellular vesicles (EVs) may serve as novel liquid biopsies for INS classification and monitoring. Our cohort was composed of 105 INS children at different clinical time points (onset, relapse, and persistent proteinuria, remission, respectively), and 19 healthy controls. The expression of 37 surface EV surface markers was evaluated by flow cytometry in serum (n = 83) and urine (n = 74) from INS children (mean age = 10.1, 58% males) at different time points. Urine EVs (n = 7) and serum EVs (n = 11) from age-matched healthy children (mean age = 7.8, 94% males) were also analyzed. Tetraspanin expression in urine EVs was enhanced during active disease phase in respect to the remission group and positively correlates with proteinuria levels. Unsupervised clustering analysis identified an INS signature of 8 markers related to immunity and angiogenesis/adhesion processes. The CD41b, CD29, and CD105 showed the best diagnostic scores separating the INS active phase from the healthy condition. Interestingly, combining urinary and serum EV markers from the same patient improved the precision of clinical staging separation. Three urinary biomarkers (CD19, CD44, and CD8) were able to classify INS based on steroid sensitivity. Biofluid EVs offer a non-invasive tool for INS clinical subclassification and "personalized" interventions.
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Affiliation(s)
- Giulia Cricri
- Laboratory of Translational Research in Paediatric Nephro-Urology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
- Paediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - Andrea Gobbini
- Istituto Nazionale Genetica Molecolare (INGM), Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy
| | - Stefania Bruno
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Linda Bellucci
- Laboratory of Translational Research in Paediatric Nephro-Urology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
- Paediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - Sarah Tassinari
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | | | - Chiara Tamburello
- Paediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - Teresa Nittoli
- Paediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - Irene Paraboschi
- Pediatric Urology Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - Alfredo Berrettini
- Pediatric Urology Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - Renata Grifantini
- Istituto Nazionale Genetica Molecolare (INGM), Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy
| | | | - William Morello
- Paediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - Giovanni Montini
- Laboratory of Translational Research in Paediatric Nephro-Urology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
- Paediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy
| | - Federica Collino
- Laboratory of Translational Research in Paediatric Nephro-Urology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.
- Paediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.
- Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy.
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14
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Song A, Wang M, Xie K, Lu J, Zhao B, Wu W, Qian C, Hong W, Gu L. Exosomal let-7b-5p deriving from parietal epithelial cells attenuate renal fibrosis through suppression of TGFβR1 and ARID3a in obstructive kidney disease. FASEB J 2024; 38:e70085. [PMID: 39352691 DOI: 10.1096/fj.202400802rr] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 09/10/2024] [Accepted: 09/20/2024] [Indexed: 11/13/2024]
Abstract
As renal progenitor cells, parietal epithelial cells (PECs) have demonstrated multilineage differentiation potential in response to kidney injury. However, the function of exosomes derived from PECs has not been extensively explored. Immunofluorescent staining of Claudin-1 was used to identify primary PECs isolated from mouse glomeruli. Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were used to characterize the properties of PECs-derived exosomes (PEC-Exo). The therapeutic role of PEC-Exo in tubulointerstitial fibrosis was investigated in the unilateral ureteral obstruction (UUO) mouse model and TGF-β1-stimulated HK-2 cells. High-throughput miRNA sequencing was employed to profile PEC-Exo miRNAs. One of the most enriched miRNAs in PEC-Exo was knocked down by transfecting miRNA inhibitor, and then we investigated whether this candidate miRNA was involved in PEC-Exo-mediated tubular repair. The primary PECs expressed Claudin-1, PEC-Exo was homing to obstructed kidney, and TGF-β1 induced HK-2 cells. PEC-Exo significantly alleviated renal inflammation and ameliorated tubular fibrosis both in vivo and in vitro. Mechanistically, let-7b-5p, highly enriched in PEC-Exo, downregulated the protein levels of transforming growth factor beta receptor 1(TGFβR1) and AT-Rich Interaction Domain 3A(ARID3a) in tubular epithelial cells (TECs), leading to the inhibition of p21 and p27 to restoring cell cycle. Furthermore, administration of let-7b-5p agomir mitigated renal fibrosis in vivo. Our findings demonstrated that PEC-derived exosomes significantly repressed the expression of TGFβR1 and ARID3a by delivering let-7b-5p, thereby alleviating renal fibrosis. This study provides novel insights into the role of PEC-Exo in the repair of kidney injury and new ideas for renal fibrosis intervention.
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Affiliation(s)
- Ahui Song
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Minzhou Wang
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kewei Xie
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiayue Lu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bingru Zhao
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wangshu Wu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cheng Qian
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenkai Hong
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Leyi Gu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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15
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Grigore TV, Zuidscherwoude M, Olauson H, Hoenderop JG. Lessons from Klotho mouse models to understand mineral homeostasis. Acta Physiol (Oxf) 2024; 240:e14220. [PMID: 39176993 DOI: 10.1111/apha.14220] [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: 05/31/2024] [Revised: 07/30/2024] [Accepted: 08/14/2024] [Indexed: 08/24/2024]
Abstract
AIM Klotho, a key component of the endocrine fibroblast growth factor receptor-fibroblast growth factor axis, is a multi-functional protein that impacts renal electrolyte handling. The physiological significance of Klotho will be highlighted in the regulation of calcium, phosphate, and potassium metabolism. METHODS In this review, we compare several murine models with different renal targeted deletions of Klotho and the insights into the molecular and physiological function that these models offer. RESULTS In vivo, Klotho deficiency is associated with severely impaired mineral metabolism, with consequences on growth, longevity and disease development. Additionally, we explore the perspectives of Klotho in renal pathology and vascular events, as well as potential Klotho treatment options. CONCLUSION This comprehensive review emphasizes the use of Klotho to shed light on deciphering the renal molecular in vivo mechanisms in electrolyte handling, as well as novel therapeutic interventions.
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Affiliation(s)
- Teodora V Grigore
- Department of Medical BioSciences, Radboud Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Malou Zuidscherwoude
- Department of Medical BioSciences, Radboud Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Hannes Olauson
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Joost G Hoenderop
- Department of Medical BioSciences, Radboud Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
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16
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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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17
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Zhao X, Han D, Zhao C, Yang F, Wang Z, Gao Y, Jin M, Tao R. New insights into the role of Klotho in inflammation and fibrosis: molecular and cellular mechanisms. Front Immunol 2024; 15:1454142. [PMID: 39308872 PMCID: PMC11412887 DOI: 10.3389/fimmu.2024.1454142] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 08/12/2024] [Indexed: 09/25/2024] Open
Abstract
As the body's defense mechanism against damage and infection, the inflammatory response is a pathological process that involves a range of inflammatory cells and cytokines. A healthy inflammatory response helps the body repair by eliminating dangerous irritants. However, tissue fibrosis can result from an overly intense or protracted inflammatory response. The anti-aging gene Klotho suppresses oxidation, delays aging, and fosters development of various organs. Numerous investigations conducted in the last few years have discovered that Klotho expression is changed in a variety of clinical diseases and is strongly linked to the course and outcome of a disease. Klotho functions as a co-receptor for FGF and as a humoral factor that mediates intracellular signaling pathways such as transforming growth factor β (TGF-β), toll-like receptors (TLRs), nuclear factor-kappaB (NF-κB), renin -angiotensin system (RAS), and mitogen-activated protein kinase (MAPK). It also interferes with the phenotype and function of inflammatory cells, such as monocytes, macrophages, T cells, and B cells. Additionally, it regulates the production of inflammatory factors. This article aims to examine Klotho's scientific advances in terms of tissue fibrosis and the inflammatory response in order to provide novel therapy concepts for fibrotic and inflammatory disorders.
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Affiliation(s)
- Xinyue Zhao
- Chronic Disease Research Center, Medical College, Dalian University, Dalian, Liaoning, China
| | - Donghe Han
- Chronic Disease Research Center, Medical College, Dalian University, Dalian, Liaoning, China
- Department of Anatomy, Medical College, Dalian University, Dalian, Liaoning, China
| | - Chun Zhao
- Chronic Disease Research Center, Medical College, Dalian University, Dalian, Liaoning, China
| | - Fengfan Yang
- Chronic Disease Research Center, Medical College, Dalian University, Dalian, Liaoning, China
| | - Zhimei Wang
- Chronic Disease Research Center, Medical College, Dalian University, Dalian, Liaoning, China
| | - Yujiao Gao
- Chronic Disease Research Center, Medical College, Dalian University, Dalian, Liaoning, China
| | - Meihua Jin
- Chronic Disease Research Center, Medical College, Dalian University, Dalian, Liaoning, China
- Department of Immunology, Medical College, Dalian University, Dalian, Liaoning, China
| | - Ran Tao
- Department of Anatomy, Medical College, Dalian University, Dalian, Liaoning, China
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18
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Shi L, Zeng H, An Z, Chen W, Shan Y, Ji C, Qian H. Extracellular vesicles: Illuminating renal pathophysiology and therapeutic frontiers. Eur J Pharmacol 2024; 978:176720. [PMID: 38880217 DOI: 10.1016/j.ejphar.2024.176720] [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: 03/09/2024] [Revised: 05/21/2024] [Accepted: 06/05/2024] [Indexed: 06/18/2024]
Abstract
Extracellular vesicles (EVs) are minute sacs released by cells into the extracellular milieu, harboring an array of biomolecules including proteins, nucleic acids, and lipids. Notably, a large number of studies have demonstrated the important involvement of EVs in both physiological and pathological aspects of renal function. EVs can facilitate communication between different renal cells, but it is important to recognize their dual role: they can either transmit beneficial information or lead to renal damage and worsening of existing conditions. The composition of EVs in the context of the kidneys offers valuable insights into the intricate mechanisms underlying specific renal functions or disease states. In addition, mesenchymal stem cell-derived EVs have the potential to alleviate acute and chronic kidney diseases. More importantly, the innate nanoparticle properties of EVs, coupled with their engineering potential, make them effective tools for drug delivery and therapeutic intervention. In this review, we focus on the intricate biological functions of EVs in the kidney. In addition, we explore the emerging role of EVs as diagnostic tools and innovative therapeutic agents in a range of renal diseases.
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Affiliation(s)
- Linru Shi
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Houcheng Zeng
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Zhongwu An
- Department of Laboratory, Lianyungang Oriental Hospital, Lianyungang, 222042, Jiangsu, China
| | - Wenya Chen
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Yunjie Shan
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Cheng Ji
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China.
| | - Hui Qian
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China.
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19
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Rosenkrans ZT, Thickens AS, Kink JA, Aluicio-Sarduy E, Engle JW, Hematti P, Hernandez R. Investigating the In Vivo Biodistribution of Extracellular Vesicles Isolated from Various Human Cell Sources Using Positron Emission Tomography. Mol Pharm 2024; 21:4324-4335. [PMID: 39164886 PMCID: PMC11891749 DOI: 10.1021/acs.molpharmaceut.4c00298] [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] [Indexed: 08/22/2024]
Abstract
Positron emission tomography (PET) is a powerful tool for investigating the in vivo behavior of drug delivery systems. We aimed to assess the biodistribution of extracellular vesicles (EVs), nanosized vesicles secreted by cells isolated from various human cell sources using PET. EVs were isolated from mesenchymal stromal cells (MSCs) (MSC EVs), human macrophages (Mϕ EVs), and a melanoma cell line (A375 EVs) by centrifugation and were conjugated with deferoxamine for radiolabeling with Zr-89. PET using conjugated and radiolabeled EVs evaluated their in vivo biodistribution and tissue tropisms. Our study also investigated differences in mouse models, utilizing immunocompetent and immunocompromised mice and an A375 xenograft tumor model. Lastly, we investigated the impact of different labeling techniques on the observed EV biodistribution, including covalent surface modification and membrane incorporation. PET showed that all tested EVs exhibited extended in vivo circulation and generally low uptake in the liver, spleen, and lungs. However, Mϕ EVs showed high liver uptake, potentially attributable to the intrinsic tissue tropism of these EVs from the surface protein composition. MSC EV biodistribution differed between immunocompetent and immunodeficient mice, with increased spleen uptake observed in the latter. PET using A375 xenografts demonstrated efficient tumor uptake of EVs, but no preferential tissue-specific tropism of A375 EVs was found. Biodistribution differences between labeling techniques showed that surface-conjugated EVs had preferential blood circulation and low liver, spleen, and lung uptake compared to membrane integration. This study demonstrates the potential of EVs as effective drug carriers for various diseases, highlights the importance of selecting appropriate cell sources for EV-based drug delivery, and suggests that EV tropism can be harnessed to optimize therapeutic efficacy. Our findings indicate that the cellular source of EVs, labeling technique, and animal model can influence the observed biodistribution.
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Affiliation(s)
- Zachary T. Rosenkrans
- Departments of Medical Physics and Radiology, University of
Wisconsin-Madison, 1111 Highland Ave., Madison, Wisconsin, 53705, United
States
| | - Anna S. Thickens
- Departments of Medical Physics and Radiology, University of
Wisconsin-Madison, 1111 Highland Ave., Madison, Wisconsin, 53705, United
States
- Department of Medicine, University of Wisconsin-Madison
School of Medicine and Public Health, 1685 Highland Ave., Madison, Wisconsin, 53705,
United States
| | - John A. Kink
- Department of Medicine, University of Wisconsin-Madison
School of Medicine and Public Health, 1685 Highland Ave., Madison, Wisconsin, 53705,
United States
- University of Wisconsin Carbone Cancer Center, University
of Wisconsin-Madison, 600 Highland Ave., Madison, Wisconsin, 53792, United
States
| | - Eduardo Aluicio-Sarduy
- Departments of Medical Physics and Radiology, University of
Wisconsin-Madison, 1111 Highland Ave., Madison, Wisconsin, 53705, United
States
| | - Jonathan W. Engle
- Departments of Medical Physics and Radiology, University of
Wisconsin-Madison, 1111 Highland Ave., Madison, Wisconsin, 53705, United
States
- University of Wisconsin Carbone Cancer Center, University
of Wisconsin-Madison, 600 Highland Ave., Madison, Wisconsin, 53792, United
States
| | - Peiman Hematti
- Department of Medicine, University of Wisconsin-Madison
School of Medicine and Public Health, 1685 Highland Ave., Madison, Wisconsin, 53705,
United States
- University of Wisconsin Carbone Cancer Center, University
of Wisconsin-Madison, 600 Highland Ave., Madison, Wisconsin, 53792, United
States
- Division of Hematology and Oncology, Medical College of
Wisconsin, 9200 W. Wisconsin Ave., Milwaukee, Wisconsin, 53226
| | - Reinier Hernandez
- Departments of Medical Physics and Radiology, University of
Wisconsin-Madison, 1111 Highland Ave., Madison, Wisconsin, 53705, United
States
- University of Wisconsin Carbone Cancer Center, University
of Wisconsin-Madison, 600 Highland Ave., Madison, Wisconsin, 53792, United
States
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20
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Harita Y. Urinary extracellular vesicles in childhood kidney diseases. Pediatr Nephrol 2024; 39:2293-2300. [PMID: 38093081 PMCID: PMC11199279 DOI: 10.1007/s00467-023-06243-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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/21/2023] [Accepted: 11/23/2023] [Indexed: 06/26/2024]
Abstract
Most biological fluids contain extracellular vesicles (EVs). EVs are surrounded by a lipid bilayer and contain biological macromolecules such as proteins, lipids, RNA, and DNA. They lack a functioning nucleus and are incapable of replicating. The physiological characteristics and molecular composition of EVs in body fluids provide valuable information about the status of originating cells. Consequently, they could be effectively utilized for diagnostic and prognostic applications. Urine contains a heterogeneous population of EVs. To date, these urinary extracellular vesicles (uEVs) have been ignored in the standard urinalysis. In recent years, knowledge has accumulated on how uEVs should be separated and analyzed. It has become clear how uEVs reflect the expression of each molecule in cells in nephron segments and how they are altered in disease states such as glomerular/tubular disorders, rare congenital diseases, acute kidney injury (AKI), and chronic kidney disease (CKD). Significant promise exists for the molecular expression signature of uEVs detected by simple techniques such as enzyme-linked immunosorbent assay (ELISA), making them more applicable in clinical settings. This review presents the current understanding regarding uEVs, emphasizing the potential for non-invasive diagnostics, especially for childhood kidney diseases.
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Affiliation(s)
- Yutaka Harita
- Department of Pediatrics, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan.
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21
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Korecka K, Gawin M, Pastuszka A, Partyka M, Koszutski T, Pietrowska M, Hyla-Klekot L. Proteomics of urinary small extracellular vesicles in early diagnosis of kidney diseases in children-expectations and limitations. Proteomics 2024; 24:e2300168. [PMID: 38213025 DOI: 10.1002/pmic.202300168] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 12/14/2023] [Accepted: 12/20/2023] [Indexed: 01/13/2024]
Abstract
The primary function of the kidneys is to maintain systemic homeostasis (disruption of renal structure and function results in multilevel impairment of body function). Kidney diseases are characterized by a chronic, progressive course and may result in the development of chronic kidney disease (CKD). Evaluation of the composition of the proteome of urinary small extracellular vesicles (sEVs) as a so-called liquid biopsy is a promising new research direction. Knowing the composition of sEV could allow localization of cellular changes in specific sections of the nephron or the interstitial tissue before fixed changes, detectable only at an advanced stage of the disease, occur. Research is currently underway on the role of sEVs in the diagnosis and monitoring of many disease entities. Reports in the literature on the subject include: diabetic nephropathy, focal glomerulosclerosis in the course of glomerulopathies, renal fibrosis of various etiologies. Studies on pediatric patients are still few, involving piloting if small groups of patients without validation studies. Here, we review the literature addressing the use of sEV for diagnosis of the most common urinary disorders in children. We evaluate the clinical utility and define limitations of markers present in sEV as potential liquid biopsy.
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Affiliation(s)
- Klaudia Korecka
- Clinical Department of Paediatric Surgery and Urology, Medical University of Silesia in Katowice, Katowice, Poland
| | - Marta Gawin
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Agnieszka Pastuszka
- Clinical Department of Paediatric Surgery and Urology, Medical University of Silesia in Katowice, Katowice, Poland
| | - Mirosław Partyka
- Department of Laboratory Diagnostics, School of Medicine in Katowice, Medical University of Silesia in Katowice, Katowice, Poland
| | - Tomasz Koszutski
- Clinical Department of Paediatric Surgery and Urology, Medical University of Silesia in Katowice, Katowice, Poland
| | - Monika Pietrowska
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Lidia Hyla-Klekot
- Clinical Department of Paediatric Surgery and Urology, Medical University of Silesia in Katowice, Katowice, Poland
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22
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Sun Y, Zhao H, Yang S, Wang G, Zhu L, Sun C, An Y. Urine-derived stem cells: Promising advancements and applications in regenerative medicine and beyond. Heliyon 2024; 10:e27306. [PMID: 38509987 PMCID: PMC10951541 DOI: 10.1016/j.heliyon.2024.e27306] [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: 09/23/2023] [Revised: 02/27/2024] [Accepted: 02/27/2024] [Indexed: 03/22/2024] Open
Abstract
Currently, stem cells are a prominent focus of regenerative engineering research. However, due to the limitations of commonly used stem cell sources, their application in therapy is often restricted to the experimental stage and constrained by ethical considerations. In contrast, urine-derived stem cells (USCs) offer promising advantages for clinical trials and applications. The noninvasive nature of the collection process allows for repeated retrieval within a short period, making it a more feasible option. Moreover, studies have shown that USCs have a protective effect on organs, promoting vascular regeneration, inhibiting oxidative stress, and reducing inflammation in various acute and chronic organ dysfunctions. The application of USCs has also been enhanced by advancements in biomaterials technology, enabling better targeting and controlled release capabilities. This review aims to summarize the current state of research on USCs, providing insights for future applications in basic and clinical settings.
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Affiliation(s)
| | | | - Shuguang Yang
- Department of Critical Care Medicine, Peking University People's Hospital, PR China
| | - Guangjie Wang
- Department of Critical Care Medicine, Peking University People's Hospital, PR China
| | - Leijie Zhu
- Department of Critical Care Medicine, Peking University People's Hospital, PR China
| | - Chang Sun
- Department of Critical Care Medicine, Peking University People's Hospital, PR China
| | - Youzhong An
- Department of Critical Care Medicine, Peking University People's Hospital, PR China
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23
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Garcia NA, Gonzalez-King H, Mellergaard M, Nair S, Salomon C, Handberg A. Comprehensive strategy for identifying extracellular vesicle surface proteins as biomarkers for chronic kidney disease. Front Physiol 2024; 15:1328362. [PMID: 38379702 PMCID: PMC10877036 DOI: 10.3389/fphys.2024.1328362] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 01/23/2024] [Indexed: 02/22/2024] Open
Abstract
Chronic kidney disease (CKD) poses a significant health burden worldwide. Especially, obesity-induced chronic kidney disease (OCKD) is associated with a lack of accuracy in disease diagnostic methods. The identification of reliable biomarkers for the early diagnosis and monitoring of CKD and OCKD is crucial for improving patient outcomes. Extracellular vesicles (EVs) have emerged as potential biomarkers in the context of CKD. In this review, we focused on the role of EVs as potential biomarkers in CKD and OCKD and developed a comprehensive list of EV membrane proteins that could aid in the diagnosis and monitoring of the disease. To assemble our list, we employed a multi-step strategy. Initially, we conducted a thorough review of the literature on EV protein biomarkers in kidney diseases. Additionally, we explored papers investigating circulating proteins as biomarkers in kidney diseases. To further refine our list, we utilized the EV database Vesiclepedia.org to evaluate the qualifications of each identified protein. Furthermore, we consulted the Human Protein Atlas to assess the localization of these candidates, with a particular focus on membrane proteins. By integrating the information from the reviewed literature, Vesiclepedia.org, and the Human Protein Atlas, we compiled a comprehensive list of potential EV membrane protein biomarkers for CKD and OCKD. Overall, our review underscores the potential of EVs as biomarkers in the field of CKD research, providing a foundation for future studies aimed at improving CKD and OCKD diagnosis and treatment.
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Affiliation(s)
| | - Hernan Gonzalez-King
- Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Maiken Mellergaard
- Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, The Faculty of Medicine, Aalborg University, Aalborg, Denmark
| | - Soumyalekshmi Nair
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, University of Queensland, Brisbane, QLD, Australia
| | - Carlos Salomon
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, University of Queensland, Brisbane, QLD, Australia
| | - Aase Handberg
- Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, The Faculty of Medicine, Aalborg University, Aalborg, Denmark
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24
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Miron RJ, Estrin NE, Sculean A, Zhang Y. Understanding exosomes: Part 2-Emerging leaders in regenerative medicine. Periodontol 2000 2024; 94:257-414. [PMID: 38591622 DOI: 10.1111/prd.12561] [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: 02/04/2024] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 04/10/2024]
Abstract
Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with the ability to communicate with other tissues and cell types over long distances. Their use in regenerative medicine has gained tremendous momentum recently due to their ability to be utilized as therapeutic options for a wide array of diseases/conditions. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be developed. Today exosomes have been applied in numerous contexts including neurodegenerative disorders (Alzheimer's disease, central nervous system, depression, multiple sclerosis, Parkinson's disease, post-traumatic stress disorders, traumatic brain injury, peripheral nerve injury), damaged organs (heart, kidney, liver, stroke, myocardial infarctions, myocardial infarctions, ovaries), degenerative processes (atherosclerosis, diabetes, hematology disorders, musculoskeletal degeneration, osteoradionecrosis, respiratory disease), infectious diseases (COVID-19, hepatitis), regenerative procedures (antiaging, bone regeneration, cartilage/joint regeneration, osteoarthritis, cutaneous wounds, dental regeneration, dermatology/skin regeneration, erectile dysfunction, hair regrowth, intervertebral disc repair, spinal cord injury, vascular regeneration), and cancer therapy (breast, colorectal, gastric cancer and osteosarcomas), immune function (allergy, autoimmune disorders, immune regulation, inflammatory diseases, lupus, rheumatoid arthritis). This scoping review is a first of its kind aimed at summarizing the extensive regenerative potential of exosomes over a broad range of diseases and disorders.
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Affiliation(s)
- Richard J Miron
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Nathan E Estrin
- Advanced PRF Education, Venice, Florida, USA
- School of Dental Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA
| | - Anton Sculean
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Yufeng Zhang
- Department of Oral Implantology, University of Wuhan, Wuhan, China
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25
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Dusso A, Bauerle KT, Zhang RM, Bernal-Mizrachi C. Vitamin D and renal disease. FELDMAN AND PIKE'S VITAMIN D 2024:587-618. [DOI: 10.1016/b978-0-323-91338-6.00029-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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26
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Grange C, Dalmasso A, Cortez JJ, Spokeviciute B, Bussolati B. Exploring the role of urinary extracellular vesicles in kidney physiology, aging, and disease progression. Am J Physiol Cell Physiol 2023; 325:C1439-C1450. [PMID: 37842748 PMCID: PMC10861146 DOI: 10.1152/ajpcell.00349.2023] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/10/2023] [Accepted: 10/11/2023] [Indexed: 10/17/2023]
Abstract
Extracellular vesicles (EVs), membranous vesicles present in all body fluids, are considered important messengers, carrying their information over long distance and modulating the gene expression profile of recipient cells. EVs collected in urine (uEVs) are mainly originated from the apical part of urogenital tract, following the urine flow. Moreover, bacterial-derived EVs are present within urine and may reflect the composition of microbiota. Consolidated evidence has established the involvement of uEVs in renal physiology, being responsible for glomerular and tubular cross talk and among different tubular segments. uEVs may also be involved in other physiological functions such as modulation of innate immunity, coagulation, or metabolic activities. Furthermore, it has been recently remonstrated that age, sex, endurance excise, and lifestyle may influence uEV composition and release, modifying their cargo. On the other hand, uEVs appear modulators of different urogenital pathological conditions, triggering disease progression. uEVs sustain fibrosis and inflammation processes, both involved in acute and chronic kidney diseases, aging, and stone formation. The molecular signature of uEVs collected from diseased patients can be of interest for understanding kidney physiopathology and for identifying diagnostic and prognostic biomarkers.
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Affiliation(s)
- Cristina Grange
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Alessia Dalmasso
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Judiel John Cortez
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Beatrice Spokeviciute
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Benedetta Bussolati
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
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27
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Cavaleiro C, Afonso GJM, Oliveira PJ, Valero J, Mota SI, Ferreiro E. Urine-derived stem cells in neurological diseases: current state-of-the-art and future directions. Front Mol Neurosci 2023; 16:1229728. [PMID: 37965041 PMCID: PMC10642248 DOI: 10.3389/fnmol.2023.1229728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 10/10/2023] [Indexed: 11/16/2023] Open
Abstract
Stem cells have potential applications in the field of neurological diseases, as they allow for the development of new biological models. These models can improve our understanding of the underlying pathologies and facilitate the screening of new therapeutics in the context of precision medicine. Stem cells have also been applied in clinical tests to repair tissues and improve functional recovery. Nevertheless, although promising, commonly used stem cells display some limitations that curb the scope of their applications, such as the difficulty of obtention. In that regard, urine-derived cells can be reprogrammed into induced pluripotent stem cells (iPSCs). However, their obtaining can be challenging due to the low yield and complexity of the multi-phased and typically expensive differentiation protocols. As an alternative, urine-derived stem cells (UDSCs), included within the population of urine-derived cells, present a mesenchymal-like phenotype and have shown promising properties for similar purposes. Importantly, UDSCs have been differentiated into neuronal-like cells, auspicious for disease modeling, while overcoming some of the shortcomings presented by other stem cells for these purposes. Thus, this review assesses the current state and future perspectives regarding the potential of UDSCs in the ambit of neurological diseases, both for disease modeling and therapeutic applications.
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Affiliation(s)
- Carla Cavaleiro
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- Institute for Interdisciplinary Research, University of Coimbra, Doctoral Programme in Experimental Biology and Biomedicine (PDBEB), Coimbra, Portugal
| | - Gonçalo J. M. Afonso
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- Institute for Interdisciplinary Research, University of Coimbra, Doctoral Programme in Experimental Biology and Biomedicine (PDBEB), Coimbra, Portugal
| | - Paulo J. Oliveira
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Jorge Valero
- Instituto de Neurociencias de Castilla y León, University of Salamanca, Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Department of Cell Biology and Pathology, University of Salamanca, Salamanca, Spain
| | - Sandra I. Mota
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Elisabete Ferreiro
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
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28
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Ceccotti E, Saccu G, Herrera Sanchez MB, Bruno S. Naïve or Engineered Extracellular Vesicles from Different Cell Sources: Therapeutic Tools for Kidney Diseases. Pharmaceutics 2023; 15:1715. [PMID: 37376163 DOI: 10.3390/pharmaceutics15061715] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/09/2023] [Accepted: 06/10/2023] [Indexed: 06/29/2023] Open
Abstract
Renal pathophysiology is a multifactorial process involving different kidney structures. Acute kidney injury (AKI) is a clinical condition characterized by tubular necrosis and glomerular hyperfiltration. The maladaptive repair after AKI predisposes to the onset of chronic kidney diseases (CKD). CKD is a progressive and irreversible loss of kidney function, characterized by fibrosis that could lead to end stage renal disease. In this review we provide a comprehensive overview of the most recent scientific publications analyzing the therapeutic potential of Extracellular Vesicles (EV)-based treatments in different animal models of AKI and CKD. EVs from multiple sources act as paracrine effectors involved in cell-cell communication with pro-generative and low immunogenic properties. They represent innovative and promising natural drug delivery vehicles used to treat experimental acute and chronic kidney diseases. Differently from synthetic systems, EVs can cross biological barriers and deliver biomolecules to the recipient cells inducing a physiological response. Moreover, new methods for improving the EVs as carriers have been introduced, such as the engineering of the cargo, the modification of the proteins on the external membrane, or the pre-conditioning of the cell of origin. The new nano-medicine approaches based on bioengineered EVs are an attempt to enhance their drug delivery capacity for potential clinical applications.
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Affiliation(s)
- Elena Ceccotti
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
| | - Gabriele Saccu
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
- Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy
| | - Maria Beatriz Herrera Sanchez
- Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy
- 2i3T, Società per la Gestione dell'incubatore di Imprese e per il Trasferimento Tecnologico, University of Torino, 10126 Torino, Italy
| | - Stefania Bruno
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
- Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy
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29
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Wang L, Wang D, Ye Z, Xu J. Engineering Extracellular Vesicles as Delivery Systems in Therapeutic Applications. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300552. [PMID: 37080941 PMCID: PMC10265081 DOI: 10.1002/advs.202300552] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/16/2023] [Indexed: 05/03/2023]
Abstract
Extracellular vesicles (EVs) are transport vesicles secreted by living cells and released into the extracellular environment. Recent studies have shown that EVs serve as "messengers" in intercellular and inter-organismal communication, in both normal and pathological processes. EVs, as natural nanocarriers, can deliver bioactivators in therapy with their endogenous transport properties. This review article describes the engineering EVs of sources, isolation method, cargo loading, boosting approach, and adjustable targeting of EVs. Furthermore, the review summarizes the recent progress made in EV-based delivery systems applications, including cancer, cardiovascular diseases, liver, kidney, nervous system diseases, and COVID-19 and emphasizes the obstacles and challenges of EV-based therapies and possible strategies.
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Affiliation(s)
- Liwei Wang
- Department of Orthopedic Surgerythe Second Affiliated HospitalZhejiang University School of MedicineHangzhou CityZhejiang Province310009P. R. China
- Orthopedics Research Institute of Zhejiang UniversityHangzhou CityZhejiang Province310009P. R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhou CityZhejiang Province310009P. R. China
- Clinical Research Center of Motor System Disease of Zhejiang ProvinceHangzhou CityZhejiang Province310009P. R. China
| | - Di Wang
- Department of Orthopedic Surgerythe Second Affiliated HospitalZhejiang University School of MedicineHangzhou CityZhejiang Province310009P. R. China
- Orthopedics Research Institute of Zhejiang UniversityHangzhou CityZhejiang Province310009P. R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhou CityZhejiang Province310009P. R. China
- Clinical Research Center of Motor System Disease of Zhejiang ProvinceHangzhou CityZhejiang Province310009P. R. China
| | - Zhaoming Ye
- Department of Orthopedic Surgerythe Second Affiliated HospitalZhejiang University School of MedicineHangzhou CityZhejiang Province310009P. R. China
- Orthopedics Research Institute of Zhejiang UniversityHangzhou CityZhejiang Province310009P. R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhou CityZhejiang Province310009P. R. China
- Clinical Research Center of Motor System Disease of Zhejiang ProvinceHangzhou CityZhejiang Province310009P. R. China
| | - Jianbin Xu
- Department of Orthopedic Surgerythe Second Affiliated HospitalZhejiang University School of MedicineHangzhou CityZhejiang Province310009P. R. China
- Orthopedics Research Institute of Zhejiang UniversityHangzhou CityZhejiang Province310009P. R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhou CityZhejiang Province310009P. R. China
- Clinical Research Center of Motor System Disease of Zhejiang ProvinceHangzhou CityZhejiang Province310009P. R. China
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30
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Wang C, Li SW, Zhong X, Liu BC, Lv LL. An update on renal fibrosis: from mechanisms to therapeutic strategies with a focus on extracellular vesicles. Kidney Res Clin Pract 2023; 42:174-187. [PMID: 37037480 PMCID: PMC10085720 DOI: 10.23876/j.krcp.22.159] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 09/06/2022] [Indexed: 04/03/2023] Open
Abstract
The increasing prevalence of chronic kidney disease (CKD) is a major global public health concern. Despite the complicated pathogenesis of CKD, renal fibrosis represents the most common pathological condition, comprised of progressive accumulation of extracellular matrix in the diseased kidney. Over the last several decades, tremendous progress in understanding the mechanism of renal fibrosis has been achieved, and corresponding potential therapeutic strategies targeting fibrosis-related signaling pathways are emerging. Importantly, extracellular vesicles (EVs) contribute significantly to renal inflammation and fibrosis by mediating cellular communication. Increasing evidence suggests the potential of EV-based therapy in renal inflammation and fibrosis, which may represent a future direction for CKD therapy.
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Affiliation(s)
| | | | | | | | - Lin-Li Lv
- Correspondence: Lin-Li Lv Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, 87 Ding Jia Qiao Road, Nanjing 210009, China. E-mail:
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31
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Liu LL, Shannahan J, Zheng W. Choroid Plexus Modulates Subventricular Zone Adult Neurogenesis and Olfaction Through Secretion of Small Extracellular Vesicles. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.16.532966. [PMID: 36993578 PMCID: PMC10055063 DOI: 10.1101/2023.03.16.532966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
UNLABELLED The choroid plexus (CP) in brain ventricles secrete cerebrospinal fluid (CSF) that bathes the adjacent subventricular zone (SVZ); the latter is the largest neurogenic region in adult brain harboring neural stem/progenitor cells (NSPCs) and supplies newborn neurons to the olfactory bulb (OB) for normal olfaction. We discovered the presence of a CP-SVZ regulatory (CSR) axis in which the CP, by secreting small extracellular vesicles (sEVs), regulated adult neurogenesis in the SVZ and maintained olfaction. The proposed CSR axis was supported by 1) differential neurogenesis outcomes in the OB when animals treated with intracerebroventricular (ICV) infusion of sEVs collected from the CP of normal or manganese (Mn)-poisoned mice, 2) progressively diminished SVZ adult neurogenesis in mice following CP-targeted knockdown of SMPD3 to suppress CP sEV secretion, and 3) compromised olfactory performance in these CP-SMPD3-knockdown mice. Collectively, our findings demonstrate the biological and physiological presence of this sEV-dependent CSR axis in adult brains. HIGHLIGHTS CP-secreted sEVs regulate adult neurogenesis in the SVZ.CP-secreted sEVs modulate newborn neurons in the OB.Suppression of sEV secretion from the CP deteriorates olfactory performance.
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Ren JR, Wang Z, Cheng Y, He CY, Jian JM, Fan DY, Shen YY, Chen DW, Li HY, Yi X, Zeng GH, Tan CR, Shi AY, Chen LY, Mao QX, Wang YJ, Wang J. Associations Between Plasma Klotho with Renal Function and Cerebrospinal Fluid Amyloid-β Levels in Alzheimer's Disease: The Chongqing Ageing & Dementia Study. J Alzheimers Dis 2023; 92:477-485. [PMID: 36776069 DOI: 10.3233/jad-221107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
BACKGROUND The kidney-brain crosstalk has been involved in Alzheimer's disease (AD) with the mechanism remaining unclear. The anti-aging factor Klotho was reported to attenuate both kidney injury and AD pathologies. OBJECTIVE To investigate whether plasma Klotho participated in kidney-brain crosstalk in AD. METHODS We enrolled 33 PiB-PET-positive AD patients and 33 amyloid-β (Aβ)-negative age- and sex-matched cognitively normal (CN) controls from the Chongqing Ageing & Dementia Study (CADS). The levels of plasma Klotho, Aβ, and tau in the cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay. RESULTS We found higher plasma Klotho and lower estimated glomerular filtration rate (eGFR) levels in AD patients compared with CN. The eGFR were positively associated with Aβ 42, Aβ 40 levels in CSF and negatively associated with CSF T-tau levels. Plasma Klotho levels were both negatively correlated with CSF Aβ 42 and eGFR. Mediation analysis showed that plasma Klotho mediated 24.96% of the association between eGFR and CSF Aβ 42. CONCLUSION Renal function impacts brain Aβ metabolism via the kidney-brain crosstalk, in which the plasma klotho may be involved as a mediator. Targeting Klotho to regulate the kidney-brain crosstalk provides potential therapeutic approaches for AD.
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Affiliation(s)
- Jun-Rong Ren
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.,Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China.,Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Zhen Wang
- Department of Critical Care Medicine, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Yuan Cheng
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.,Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China.,Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Chen-Yang He
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.,Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China.,Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Jie-Ming Jian
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.,Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China.,Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Dong-Yu Fan
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.,Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China.,Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Ying-Ying Shen
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.,Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China.,Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Dong-Wan Chen
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.,Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China.,Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Hui-Yun Li
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.,Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China.,Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Xu Yi
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.,Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China.,Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Gui-Hua Zeng
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.,Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China.,Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Cheng-Rong Tan
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.,Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China.,Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - An-Yu Shi
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.,Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China.,Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Li-Yong Chen
- Department of Anaesthesiology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Qing-Xiang Mao
- Department of Anaesthesiology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Yan-Jiang Wang
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.,Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China.,Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China.,Chongqing Institute for Brain and Intelligence, Guangyang Bay Laboratory, Chongqing, China.,Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.,State Key Laboratory of Trauma, Burns, and Combined Injury, Third Military Medical University, Chongqing, China
| | - Jun Wang
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.,Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China.,Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
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Erdbrügger U, Hoorn EJ, Le TH, Blijdorp CJ, Burger D. Extracellular Vesicles in Kidney Diseases: Moving Forward. KIDNEY360 2023; 4:245-257. [PMID: 36821616 PMCID: PMC10103258 DOI: 10.34067/kid.0001892022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 12/18/2022] [Indexed: 12/23/2022]
Abstract
Extracellular vesicles (EVs) are evolving as novel cell mediators, biomarkers, and therapeutic targets in kidney health and disease. They are naturally derived from cells both within and outside the kidney and carry cargo which mirrors the state of the parent cell. Thus, they are potentially more sensitive and disease-specific as biomarkers and messengers in various kidney diseases. Beside their role as novel communicators within the nephron, they likely communicate between different organs affected by various kidney diseases. Study of urinary EVs (uEVs) can help to fill current knowledge gaps in kidney diseases. However, separation and characterization are challenged by their heterogeneity in size, shape, and cargo. Fortunately, more sensitive and direct EV measuring tools are in development. Many clinical syndromes in nephrology from acute to chronic kidney and glomerular to tubular diseases have been studied. Yet, validation of biomarkers in larger cohorts is warranted and simpler tools are needed. Translation from in vitro to in vivo studies is also urgently needed. The therapeutic role of uEVs in kidney diseases has been studied extensively in rodent models of AKI. On the basis of the current exponential growth of EV research, the field of EV diagnostics and therapeutics is moving forward.
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Affiliation(s)
- Uta Erdbrügger
- Division of Nephrology, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
| | - Ewout J. Hoorn
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Thu H. Le
- Division of Nephrology, Department of Medicine, University of Rochester Medical Center, Rochester, New York
| | - Charles J. Blijdorp
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Dylan Burger
- Kidney Research Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
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Liu Y, Guan X, Shao Y, Zhou J, Huang Y. The Molecular Mechanism and Therapeutic Strategy of Cardiorenal Syndrome Type 3. Rev Cardiovasc Med 2023; 24:52. [PMID: 39077418 PMCID: PMC11273121 DOI: 10.31083/j.rcm2402052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/17/2022] [Accepted: 11/22/2022] [Indexed: 07/31/2024] Open
Abstract
Cardiorenal syndrome type 3 (CRS3) is defined as acute kidney injury (AKI)-induced acute cardiac dysfunction, characterized by high morbidity and mortality. CRS3 often occurs in elderly patients with AKI who need intensive care. Approximately 70% of AKI patients develop into CRS3. CRS3 may also progress towards chronic kidney disease (CKD) and chronic cardiovascular disease (CVD). However, there is currently no effective treatment. Although the major intermediate factors that can mediate cardiac dysfunction remain elusive, recent studies have summarized the AKI biomarkers, identified direct mechanisms, including mitochondrial dysfunction, inflammation, oxidative stress, apoptosis and activation of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS), inflammasome, as well as indirect mechanisms such as fluid overload, electrolyte imbalances, acidemia and uremic toxins, which are involved in the pathophysiological changes of CRS3. This study reviews the main pathological characteristics, underlying molecular mechanisms, and potential therapeutic strategies of CRS3. Mitochondrial dysfunction and inflammatory factors have been identified as the key initiators and abnormal links between the impaired heart and kidney, which contribute to the formation of a vicious circle, ultimately accelerating the progression of CRS3. Therefore, targeting mitochondrial dysfunction, antioxidants, Klotho, melatonin, gene therapy, stem cells, exosomes, nanodrugs, intestinal microbiota and Traditional Chinese Medicine may serve as promising therapeutic approaches against CRS3.
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Affiliation(s)
- Yong Liu
- Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037 Chongqing, China
| | - Xu Guan
- Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037 Chongqing, China
| | - Yuming Shao
- Medical Division, Xinqiao Hospital, Army Medical University, 400037 Chongqing, China
| | - Jie Zhou
- Department of Oncology, Southwest Cancer Center, Southwest Hospital, Army Medical University, 400038 Chongqing, China
| | - Yinghui Huang
- Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037 Chongqing, China
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Hun M, Wen H, Han P, Vun T, Zhao M, He Q. Bibliometric analysis of scientific papers on extracellular vesicles in kidney disease published between 1999 and 2022. Front Cell Dev Biol 2023; 10:1070516. [PMID: 36684427 PMCID: PMC9849820 DOI: 10.3389/fcell.2022.1070516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 12/09/2022] [Indexed: 01/07/2023] Open
Abstract
Background: In recent years, there has been an increasing interest in using extracellular vesicles (EVs) as potential therapeutic agents or natural drug delivery systems in kidney-related diseases. However, a detailed and targeted report on the current condition of extracellular vesicle research in kidney-related diseases is lacking. Therefore, this prospective study was designed to investigate the use of bibliometric analysis to comprehensively overview the current state of research and frontier trends on extracellular vesicle research in kidney-related diseases using visualization tools. Methods: The Web of Science Core Collection (WoSCC) database was searched to identify publications related to extracellular vesicle research in kidney-related diseases since 1999. Citespace, Microsoft Excel 2019, VOSviewer software, the R Bibliometrix Package, and an online platform were used to analyze related research trends to stratify the publication data and collaborations. Results: From 1 January 1999 to 26 June 2022, a total of 1,122 EV-related articles and reviews were published, and 6,486 authors from 1,432 institutions in 63 countries or regions investigated the role of extracellular vesicles in kidney-related diseases. We found that the number of articles on extracellular vesicles in kidney-related diseases increased every year. Dozens of publications were from China and the United States. China had the most number of related publications, in which the Southeast University (China) was the most active institution in all EV-related fields. Liu Bi-cheng published the most papers on extracellular vesicles, while Clotilde Théry had the most number of co-citations. Most papers were published by The International Journal of Molecular Sciences, while Kidney International was the most co-cited journal for extracellular vesicles. We found that exosome-related keywords included exosome, exosm, expression, extracellular vesicle, microRNA, microvesicle, and liquid biopsy, while disease- and pathological-related keywords included biomarker, microRNA, apoptosis, mechanism, systemic lupus erythematosus, EGFR, acute kidney injury, and chronic kidney disease. Acute kidney disease (AKI), CKD, SLE, exosome, liquid biopsy, and extracellular vesicle were the hotspot in extracellular vesicle and kidney-related diseases research. Conclusion: The field of extracellular vesicles in kidney-related disease research is rapidly growing, and its domain is likely to expand in the next decade. The findings from this comprehensive analysis of extracellular vesicles in kidney-related disease research could help investigators to set new diagnostic, therapeutic, and prognostic ideas or methods in kidney-related diseases.
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Affiliation(s)
- Marady Hun
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Huai Wen
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Phanna Han
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Tharith Vun
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Mingyi Zhao
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Mingyi Zhao, ; Qingnan He,
| | - Qingnan He
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Mingyi Zhao, ; Qingnan He,
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Li J, Gong X. Bibliometric and visualization analysis of kidney repair associated with acute kidney injury from 2002 to 2022. Front Pharmacol 2023; 14:1101036. [PMID: 37153766 PMCID: PMC10157647 DOI: 10.3389/fphar.2023.1101036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 04/12/2023] [Indexed: 05/10/2023] Open
Abstract
Background: Renal repair is closely related to the prognosis of acute kidney injury (AKI) and has attracted increasing attention in the research field. However, there is a lack of a comprehensive bibliometric analysis in this research area. This study aims at exploring the current status and hotspots of renal repair research in AKI from the perspective of bibliometrics. Methods: Studies published between 2002 and 2022 related to kidney repair after AKI were collected from Web of Science core collection (WoSCC) database. Bibliometric measurement and knowledge graph analysis to predict the latest research trends in the field were performed using bibliometrics software CiteSpace and VOSviewer. Results: The number of documents related to kidney repair after AKI has steadily increased over 20 years. The United States and China contribute more than 60% of documents and are the main drivers of research in this field. Harvard University is the most active academic institution that contributes the most documents. Humphreys BD and Bonventre JV are the most prolific authors and co-cited authors in the field. The American Journal of Physiology-Renal Physiology and Journal of the American Society of Nephrology are the most popular journals in the field with the greatest number of documents. "exosome", "macrophage polarization", "fibroblast", and" aki-ckd transition" are high-frequency keywords in this field in recent years. Extracellular vesicles (including exosomes), macrophage polarization, cell cycle arrest, hippo pathway, and sox9 are current research hotspots and potential targets in this field. Conclusion: This is the first comprehensive bibliometric study on the knowledge structure and development trend of AKI-related renal repair research in recent years. The results of the study comprehensively summarize and identify research frontiers in AKI-related renal repair.
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Petrosyan A, Martins PN, Solez K, Uygun BE, Gorantla VS, Orlando G. Regenerative medicine applications: An overview of clinical trials. Front Bioeng Biotechnol 2022; 10:942750. [PMID: 36507264 PMCID: PMC9732032 DOI: 10.3389/fbioe.2022.942750] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 11/11/2022] [Indexed: 11/27/2022] Open
Abstract
Insights into the use of cellular therapeutics, extracellular vesicles (EVs), and tissue engineering strategies for regenerative medicine applications are continually emerging with a focus on personalized, patient-specific treatments. Multiple pre-clinical and clinical trials have demonstrated the strong potential of cellular therapies, such as stem cells, immune cells, and EVs, to modulate inflammatory immune responses and promote neoangiogenic regeneration in diseased organs, damaged grafts, and inflammatory diseases, including COVID-19. Over 5,000 registered clinical trials on ClinicalTrials.gov involve stem cell therapies across various organs such as lung, kidney, heart, and liver, among other applications. A vast majority of stem cell clinical trials have been focused on these therapies' safety and effectiveness. Advances in our understanding of stem cell heterogeneity, dosage specificity, and ex vivo manipulation of stem cell activity have shed light on the potential benefits of cellular therapies and supported expansion into clinical indications such as optimizing organ preservation before transplantation. Standardization of manufacturing protocols of tissue-engineered grafts is a critical first step towards the ultimate goal of whole organ engineering. Although various challenges and uncertainties are present in applying cellular and tissue engineering therapies, these fields' prospect remains promising for customized patient-specific treatments. Here we will review novel regenerative medicine applications involving cellular therapies, EVs, and tissue-engineered constructs currently investigated in the clinic to mitigate diseases and possible use of cellular therapeutics for solid organ transplantation. We will discuss how these strategies may help advance the therapeutic potential of regenerative and transplant medicine.
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Affiliation(s)
- Astgik Petrosyan
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Division of Urology, Children’s Hospital Los Angeles, Saban Research Institute, Los Angeles, CA, United States
| | - Paulo N. Martins
- Department of Surgery, Transplant Division, UMass Memorial Medical Center, University of Massachusetts, Worcester, MA, United States
| | - Kim Solez
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Basak E. Uygun
- Massachusetts General Hospital, Shriners Hospitals for Children in Boston and Harvard Medical School, Boston, MA, United States
| | - Vijay S. Gorantla
- Wake Forest Baptist Medical Center and Wake Forest Institute for Regenerative Medicine, Winston Salem, NC, United States
| | - Giuseppe Orlando
- Wake Forest Baptist Medical Center and Wake Forest Institute for Regenerative Medicine, Winston Salem, NC, United States
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Cheng C, Guo F, Yang H, Ma J, Li H, Yin L, Li M, Liu S. Identification and analysis of the predictive urinary exosomal miR-195-5p in lupus nephritis based on renal miRNA-mRNA co-expression network. Lupus 2022; 31:1786-1799. [PMID: 36223498 DOI: 10.1177/09612033221133684] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Lupus nephritis (LN) is the main complication of systemic lupus erythematosus (SLE), causing huge financial burden and poor quality of life. Due to the low compliance of renal biopsy, we aim to find a non-invasive biomarker of LN to optimize its predictive, preventive, and personalized medical service or management. METHOD Herein, we provided a bioinformatic screen combined clinical validation strategy for rapidly mining exosomal miRNAs for LN diagnosis and management. We screened out differentially expressed miRNAs (DEMs) and differentially expressed mRNAs (DEGs) in LN database and performed a miRNA-mRNA integrated analysis to select out reliable changed miRNAs in LN tissues by using R and Cytoscape. Urinary exosomes were collected by ultracentrifugation and analyzed by nano-tracking analysis and western blotting. Detection of aquaporin-2 showed the tubular source of urinary exosomes. Urinary exosomal miRNAs were detected by RT-qPCR and the target of miR-195-5p was verified by using bioinformatic, dual-luciferase, and western blotting. RESULT 15 miRNAs and their 60 target mRNAs were contained in miRNA-mRNA integrated map. Bioinformatic analysis showed these miRNAs were involved in various cellular biological process. Exosomal miR-195-5p, miR-25-3p, miR-429, and miR-218-5p were verified in a small clinical group (n = 47). Urinary exosomal miR-195-5p, miR-25-3p, and miR-429 were downregulated in patients and miR-195-5p could recognize LN patients from SLE with good sensitivity and specificity, showing good potential in LN disease monitoring and diagnosis. CONCLUSION We analyzed and obtained a series of differential miRNAs in LN kidney tissues and suggested that urinary exosomal miR-195-5p could serve as a novel biomarker in LN. Further, miR-195-5p-CXCL10 axis could be a therapeutic target of LN.
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Affiliation(s)
- Chen Cheng
- Key Laboratory of Drug Metabolism Research and Evaluation of National Medical Products Administration, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, 70570Southern Medical University, Guangzhou, China
| | - Fangfang Guo
- Center of Clinical Laboratory, 162698The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Hao Yang
- Key Laboratory of Drug Metabolism Research and Evaluation of National Medical Products Administration, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, 70570Southern Medical University, Guangzhou, China
| | - Jietao Ma
- Center of Clinical Laboratory, 220741The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Honglian Li
- Key Laboratory of Drug Metabolism Research and Evaluation of National Medical Products Administration, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, 70570Southern Medical University, Guangzhou, China
| | - Lele Yin
- Center of Clinical Laboratory, 162698The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Minmin Li
- Center of Clinical Laboratory, 162698The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Shuwen Liu
- Key Laboratory of Drug Metabolism Research and Evaluation of National Medical Products Administration, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, 70570Southern Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, 70570Southern Medical University, Guangzhou, China
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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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Tailored Extracellular Vesicles: Novel Tool for Tissue Regeneration. Stem Cells Int 2022; 2022:7695078. [PMID: 35915850 PMCID: PMC9338735 DOI: 10.1155/2022/7695078] [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: 01/06/2022] [Revised: 05/10/2022] [Accepted: 07/05/2022] [Indexed: 11/18/2022] Open
Abstract
Extracellular vesicles (EVs) play an essential part in multiple pathophysiological processes including tissue injury and regeneration because of their inherent characteristics of small size, low immunogenicity and toxicity, and capability of carrying a variety of bioactive molecules and mediating intercellular communication. Nevertheless, accumulating studies have shown that the application of EVs faces many challenges such as insufficient therapeutic efficacy, a lack of targeting capability, low yield, and rapid clearance from the body. It is known that EVs can be engineered, modified, and designed to encapsulate therapeutic cargos like proteins, peptides, nucleic acids, and drugs to improve their therapeutic efficacy. Targeted peptides, antibodies, aptamers, magnetic nanoparticles, and proteins are introduced to modify various cell-derived EVs for increasing targeting ability. In addition, extracellular vesicle mimetics (EMs) and self-assembly EV-mimicking nanocomplex are applied to improve production and simplify EV purification process. The combination of EVs with biomaterials like hydrogel, and scaffolds dressing endows EVs with long-term therapeutic efficacy and synergistically enhanced regenerative outcome. Thus, we will summarize recent developments of EV modification strategies for more extraordinary regenerative effect in various tissue injury repair. Subsequently, opportunities and challenges of promoting the clinical application of engineered EVs will be discussed.
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Tang TT, Wang B, Lv LL, Dong Z, Liu BC. Extracellular vesicles for renal therapeutics: State of the art and future perspective. J Control Release 2022; 349:32-50. [PMID: 35779658 DOI: 10.1016/j.jconrel.2022.06.049] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 06/24/2022] [Accepted: 06/25/2022] [Indexed: 12/21/2022]
Abstract
With the ever-increasing burden of kidney disease, the need for developing new therapeutics to manage this disease has never been greater. Extracellular vesicles (EVs) are natural membranous nanoparticles present in virtually all organisms. Given their excellent delivery capacity in the body, EVs have emerged as a frontier technology for drug delivery and have the potential to usher in a new era of nanomedicine for kidney disease. This review is focused on why EVs are such compelling drug carriers and how to release their fullest potentiality in renal therapeutics. We discuss the unique features of EVs compared to artificial nanoparticles and outline the engineering technologies and steps in developing EV-based therapeutics, with an emphasis on the emerging approaches to target renal cells and prolong kidney retention. We also explore the applications of EVs as natural therapeutics or as drug carriers in the treatment of renal disorders and present our views on the critical challenges in manufacturing EVs as next-generation renal therapeutics.
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Affiliation(s)
- Tao-Tao Tang
- Institute of Nephrology, Zhong Da Hospital, Nanjing, China; Department of Pathology and Pathophysiology, Southeast University School of Medicine, Nanjing, China
| | - Bin Wang
- Institute of Nephrology, Zhong Da Hospital, Nanjing, China
| | - Lin-Li Lv
- Institute of Nephrology, Zhong Da Hospital, Nanjing, China.
| | - Zheng Dong
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA
| | - Bi-Cheng Liu
- Institute of Nephrology, Zhong Da Hospital, Nanjing, 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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Quaglia M, Merlotti G, Fornara L, Colombatto A, Cantaluppi V. Extracellular Vesicles Released from Stem Cells as a New Therapeutic Strategy for Primary and Secondary Glomerulonephritis. Int J Mol Sci 2022; 23:ijms23105760. [PMID: 35628570 PMCID: PMC9142886 DOI: 10.3390/ijms23105760] [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: 04/23/2022] [Revised: 05/13/2022] [Accepted: 05/20/2022] [Indexed: 12/04/2022] Open
Abstract
Current treatment of primary and secondary glomerulopathies is hampered by many limits and a significant proportion of these disorders still evolves towards end-stage renal disease. A possible answer to this unmet challenge could be represented by therapies with stem cells, which include a variety of progenitor cell types derived from embryonic or adult tissues. Stem cell self-renewal and multi-lineage differentiation ability explain their potential to protect and regenerate injured cells, including kidney tubular cells, podocytes and endothelial cells. In addition, a broad spectrum of anti-inflammatory and immunomodulatory actions appears to interfere with the pathogenic mechanisms of glomerulonephritis. Of note, mesenchymal stromal cells have been particularly investigated as therapy for Lupus Nephritis and Diabetic Nephropathy, whereas initial evidence suggest their beneficial effects in primary glomerulopathies such as IgA nephritis. Extracellular vesicles mediate a complex intercellular communication network, shuttling proteins, nucleic acids and other bioactive molecules from origin to target cells to modulate their functions. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, reparative and immunomodulatory properties of parental cells and are increasingly recognized as a cell-free alternative to stem cell-based therapies for different diseases including glomerulonephritis, also considering the low risk for potential adverse effects such as maldifferentiation and tumorigenesis. We herein summarize the renoprotective potential of therapies with stem cells and extracellular vesicles derived from progenitor cells in glomerulonephritis, with a focus on their different mechanisms of actions. Technological progress and growing knowledge are paving the way for wider clinical application of regenerative medicine to primary and secondary glomerulonephritis: this multi-level, pleiotropic therapy may open new scenarios overcoming the limits and side effects of traditional treatments, although the promising results of experimental models need to be confirmed in the clinical setting.
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Quaglia M, Merlotti G, Colombatto A, Bruno S, Stasi A, Franzin R, Castellano G, Grossini E, Fanelli V, Cantaluppi V. Stem Cell-Derived Extracellular Vesicles as Potential Therapeutic Approach for Acute Kidney Injury. Front Immunol 2022; 13:849891. [PMID: 35359949 PMCID: PMC8960117 DOI: 10.3389/fimmu.2022.849891] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 02/15/2022] [Indexed: 12/12/2022] Open
Abstract
Acute kidney injury is a frequent complication of hospitalized patients and significantly increases morbidity and mortality, worsening costs and length of hospital stay. Despite this impact on healthcare system, treatment still remains only supportive (dialysis). Stem cell-derived extracellular vesicles are a promising option as they recapitulate stem cells properties, overcoming safety issues related to risks or rejection or aberrant differentiation. A growing body of evidence based on pre-clinical studies suggests that extracellular vesicles may be effective to treat acute kidney injury and to limit fibrosis through direct interference with pathogenic mechanisms of vascular and tubular epithelial cell damage. We herein analyze the state-of-the-art knowledge of therapeutic approaches with stem cell-derived extracellular vesicles for different forms of acute kidney injury (toxic, ischemic or septic) dissecting their cytoprotective, regenerative and immunomodulatory properties. We also analyze the potential impact of extracellular vesicles on the mechanisms of transition from acute kidney injury to chronic kidney disease, with a focus on the pivotal role of the inhibition of complement cascade in this setting. Despite some technical limits, nowadays the development of therapies based on stem cell-derived extracellular vesicles holds promise as a new frontier to limit acute kidney injury onset and progression.
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Affiliation(s)
- Marco Quaglia
- Nephrology and Kidney Transplantation Unit, "Maggiore della Carità" University Hospital, Department of Translational Medicine, Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale (UPO), Novara, Italy
| | - Guido Merlotti
- Nephrology and Kidney Transplantation Unit, "Maggiore della Carità" University Hospital, Department of Translational Medicine, Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale (UPO), Novara, Italy
| | - Andrea Colombatto
- Nephrology and Kidney Transplantation Unit, "Maggiore della Carità" University Hospital, Department of Translational Medicine, Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale (UPO), Novara, Italy
| | - Stefania Bruno
- Department of Medical Sciences, University of Torino, Torino, Italy
| | - Alessandra Stasi
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Rossana Franzin
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Kidney Transplantation Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Elena Grossini
- Laboratory of Physiology, Department of Translational Medicine, Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale, Novara, Italy
| | - Vito Fanelli
- Department of Anesthesiology and Intensive Care, University of Torino, Torino, Italy
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplantation Unit, "Maggiore della Carità" University Hospital, Department of Translational Medicine, Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale (UPO), Novara, Italy
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Kosanović M, Milutinovic B, Glamočlija S, Morlans IM, Ortiz A, Bozic M. Extracellular Vesicles and Acute Kidney Injury: Potential Therapeutic Avenue for Renal Repair and Regeneration. Int J Mol Sci 2022; 23:ijms23073792. [PMID: 35409151 PMCID: PMC8998560 DOI: 10.3390/ijms23073792] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 03/27/2022] [Accepted: 03/28/2022] [Indexed: 12/10/2022] Open
Abstract
Acute kidney injury (AKI) is a sudden decline of renal function and represents a global clinical problem due to an elevated morbidity and mortality. Despite many efforts, currently there are no treatments to halt this devastating condition. Extracellular vesicles (EVs) are nanoparticles secreted by various cell types in both physiological and pathological conditions. EVs can arise from distinct parts of the kidney and can mediate intercellular communication between various cell types along the nephron. Besides their potential as diagnostic tools, EVs have been proposed as powerful new tools for regenerative medicine and have been broadly studied as therapeutic mediators in different models of experimental AKI. In this review, we present an overview of the basic features and biological relevance of EVs, with an emphasis on their functional role in cell-to-cell communication in the kidney. We explore versatile roles of EVs in crucial pathophysiological mechanisms contributing to AKI and give a detailed description of the renoprotective effects of EVs from different origins in AKI. Finally, we explain known mechanisms of action of EVs in AKI and provide an outlook on the potential clinical translation of EVs in the setting of AKI.
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Affiliation(s)
- Maja Kosanović
- Institute for the Application of Nuclear Energy, INEP, University of Belgrade, 11080 Belgrade, Serbia; (M.K.); (S.G.)
| | - Bojana Milutinovic
- Department of Neurosurgery, MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA;
| | - Sofija Glamočlija
- Institute for the Application of Nuclear Energy, INEP, University of Belgrade, 11080 Belgrade, Serbia; (M.K.); (S.G.)
| | - Ingrid Mena Morlans
- Vascular and Renal Translational Research Group, Biomedical Research Institute of Lleida Dr. Pifarré Foundation (IRBLleida), 25196 Lleida, Spain;
| | - Alberto Ortiz
- Department of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28040 Madrid, Spain;
| | - Milica Bozic
- Vascular and Renal Translational Research Group, Biomedical Research Institute of Lleida Dr. Pifarré Foundation (IRBLleida), 25196 Lleida, Spain;
- Correspondence:
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46
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Blijdorp CJ, Burger D, Llorente A, Martens-Uzunova ES, Erdbrügger U. Extracellular Vesicles as Novel Players in Kidney Disease. J Am Soc Nephrol 2022; 33:467-471. [PMID: 35131841 PMCID: PMC8975061 DOI: 10.1681/asn.2021091232] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Affiliation(s)
- Charles J. Blijdorp
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Dylan Burger
- Kidney Research Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Alicia Llorente
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway,Department for Mechanical Electronics and Chemical Engineering, Oslo Metropolitan University, Oslo, Norway
| | - Elena S. Martens-Uzunova
- Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Uta Erdbrügger
- Department of Medicine, Division of Nephrology, University of Virginia Health System, Charlottesville, Virginia
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Namestnikov M, Dekel B. Moving To A New Dimension: 3D Kidney Cultures For Kidney Regeneration. CURRENT OPINION IN BIOMEDICAL ENGINEERING 2022. [DOI: 10.1016/j.cobme.2022.100379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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48
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Lee SA, Yoo TH. Therapeutic application of extracellular vesicles for various kidney diseases: a brief review. BMB Rep 2022. [PMID: 34903318 PMCID: PMC8810552 DOI: 10.5483/bmbrep.2022.55.1.141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Sul A Lee
- Department of Medicine, MetroWest Medical Center/Tufts University School of Medicine, Framingham, MA 01702, USA
| | - Tae Hyun Yoo
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul 03722, Korea
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49
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Lee SA, Yoo TH. Therapeutic application of extracellular vesicles for various kidney diseases: a brief review. BMB Rep 2022; 55:3-10. [PMID: 34903318 PMCID: PMC8810552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 11/17/2021] [Accepted: 12/10/2021] [Indexed: 02/21/2025] Open
Abstract
Extracellular vesicles (EVs) released from different types of kidney cells under physiologic conditions contribute to homeostasis maintenance, immune-modulation, and cell-to-cell communications. EVs can also negatively affect the progression of renal diseases through their pro-inflammatory, pro-fibrotic, and tumorigenic potential. Inhibiting EVs by blocking their production, release, and uptake has been suggested as a potential therapeutic mechanism based on the significant implication of exosomes in various renal diseases. On the other hand, stem cell-derived EVs can ameliorate tissue injury and mediate tissue repair by ameliorating apoptosis, inflammation, and fibrosis while promoting angiogenesis and tubular cell proliferation. Recent advancement in biomedical engineering technique has made it feasible to modulate the composition of exosomes with diverse biologic functions, making EV one of the most popular drug delivery tools. The objective of this review was to provide updates of recent clinical and experimental findings on the therapeutic potential of EVs in renal diseases and discuss the clinical applicability of EVs in various renal diseases. [BMB Reports 2022; 55(1): 3-10].
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Affiliation(s)
- Sul A Lee
- Department of Medicine, MetroWest Medical Center/Tufts University School of Medicine, Framingham, MA 01702, USA
| | - Tae Hyun Yoo
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul 03722, Korea
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Ma M, Luo Q, Fan L, Li W, Li Q, Meng Y, Yun C, Wu H, Lu Y, Cui S, Liu F, Hu B, Guan B, Liu H, Huang S, Liang W, Morgera S, Krämer B, Luan S, Yin L, Hocher B. The urinary exosomes derived from premature infants attenuate cisplatin-induced acute kidney injury in mice via microRNA-30a-5p/ mitogen-activated protein kinase 8 (MAPK8). Bioengineered 2022; 13:1650-1665. [PMID: 35001794 PMCID: PMC8805886 DOI: 10.1080/21655979.2021.2021686] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 12/03/2021] [Indexed: 11/24/2022] Open
Abstract
Acute kidney injury (AKI) is a susceptible factor for chronic kidney disease (CKD). There is still a lack of effective prevention methods in clinical practice. This study investigated the protective effect of the urinary exosomes from premature infants on cisplatin-induced acute kidney injury. Here we isolated exosomes from the fresh urine of premature infants. A C57BL/6 mice model of cisplatin-induced acute kidney injury was given 100 ug urinary exosomes 24 hours after model establishment. The kidneys were collected for pathological examination and the evaluation of renal tubular damage and apoptosis. In the in vitro experiment, human renal cortex/proximal tubular cells (HK-2) were induced by cisplatin to assess the effect of the urine exosomes from premature infants. Exosome microRNA (miRNA) sequencing technology was applied to investigate the miRNAs enriched in exosomes and the dual-luciferase gene reporter system to examine the targeting relationship of the miRNA with target genes. The results indicated that the urinary exosomes could decrease the serum creatinine level and the apoptosis of renal tubular cells, and reduce mice mortality. In addition, miR-30a-5p was the most abundant miRNA in the exosomes. It protected HK-2 cells from cisplatin-induced apoptosis by targeting and down-regulating the mitogen-activated protein kinase 8 (MAPK8). Together, our findings identified that the urinary exosomes derived from premature infants alleviated cisplatin-induced acute kidney injury and inhibited the apoptosis of HK-2 via miR-30a-5p, which could target MAPK8. These findings implied that urinary exosomes from premature infants riched in miR-30a-5p might become a potential treatment for AKI.
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Affiliation(s)
- Mingming Ma
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Qiao Luo
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Lijing Fan
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Weilong Li
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- Department of Nephrology, Shenzhen Longhua District Central Hospital, Guangdong, China
| | - Qiang Li
- Department of Nephrology, Dongguan Hospital of Traditional Chinese Medicine, Dongguan, China
| | - Yu Meng
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Chen Yun
- Charité -Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
| | - Hongwei Wu
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- Charité -Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
| | - Yongping Lu
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- Charité -Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
| | - Shuang Cui
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Fanna Liu
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Bo Hu
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Baozhang Guan
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Huanhuan Liu
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Shengling Huang
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Wenxue Liang
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | | | - Bernhard Krämer
- Fifth Department of Medicine (Nephrology/endocrinology/rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Shaodong Luan
- Department of Nephrology, Shenzhen Longhua District Central Hospital, Guangdong, China
| | - Lianghong Yin
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Berthold Hocher
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- Charité -Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
- Fifth Department of Medicine (Nephrology/endocrinology/rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
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