Urinary Extracellular Vesicles for Diabetic Kidney Disease Diagnosis
Abstract
:1. Introduction
2. Extracellular Vesicles
3. Challenges in uEV and EV Separation and Characterization
4. Biological Effects of EVs on Renal Cells
5. Urinary Extracellular Vesicles (uEVs) as Potential Biomarkers in Diabetic Kidney Disease
6. Circulating EVs in Diabetic Kidney Disease
7. Conclusions/Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AGE | Advanced glycation end products |
BSA | Bovine serum albumin |
CKD | Chronic kidney disease |
CV | Cardiovascular |
DKD | Diabetic kidney disease |
DM | Diabetes mellitus |
eGFR | Estimated glomerular filtration rate |
ESRD | End stage renal disease |
(u)EVs | (urinary) Extracellular vesicles |
HbA1c | Glycated hemoglobin |
HG | High glucose |
GECs | Glomerular endothelial cells |
GFB | Glomerular filtration barrier |
GMCs | Glomerular mesangial cells |
mi(cro)RNA | Micro ribonucleic acid |
NTA | Nano particle tracking analysis |
PS | phosphatidylserine |
PTECs | Proximal tubular epithelial cells |
ROC | Receiver operating characteristic |
ROS | Reactive oxygen species |
SEC | Size exclusion chromatography |
TEM | Transmission electron microscopy |
TF | Tissue factor |
THP | Tamm Horsfall protein |
UC | Ultra centrifugation |
UF | Ultra filtration |
References
- Koye, D.N.; Magliano, D.J.; Nelson, R.G.; Pavkov, M.E. The Global Epidemiology of Diabetes and Kidney Disease. Adv. Chronic Kidney Dis. 2018, 25, 121–132. [Google Scholar] [CrossRef]
- Varghese, R.T.; Jialal, I. Diabetic Nephropathy. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2021. [Google Scholar]
- Gregg, E.W.; Li, Y.; Wang, J.; Rios Burrows, N.; Ali, M.K.; Rolka, D.; Williams, D.E.; Geiss, L. Changes in Diabetes-Related Complications in the United States, 1990–2010. N. Engl. J. Med. 2014, 370, 1514–1523. [Google Scholar] [CrossRef] [Green Version]
- Faselis, C.; Katsimardou, A.; Imprialos, K.; Deligkaris, P.; Kallistratos, M.; Dimitriadis, K. Microvascular Complications of Type 2 Diabetes Mellitus. Curr. Vasc. Pharmacol. 2019, 18, 117–124. [Google Scholar] [CrossRef] [PubMed]
- Van, J.A.D.; Scholey, J.W.; Konvalinka, A. Insights into Diabetic Kidney Disease Using Urinary Proteomics and Bioinformatics. J. Am. Soc. Nephrol. 2017, 28, 1050–1061. [Google Scholar] [CrossRef] [PubMed]
- American Diabetes Association; DeFronzo, R.A.; Reeves, W.B.; Awad, A.S. Pathophysiology of diabetic kidney disease: Impact of SGLT2 inhibitors. Nat. Rev. Nephrol. 2021, 17, 319–334. [Google Scholar] [CrossRef] [PubMed]
- Umanath, K.; Lewis, J.B. Update on Diabetic Nephropathy: Core Curriculum 2018. Am. J. Kidney Dis. 2018, 71, 884–895. [Google Scholar] [CrossRef] [PubMed]
- Glycemic targets: Standards of medical care in Diabetesd 2018. Diabetes Care 2018, 41, S55–S64. [CrossRef] [Green Version]
- La Marca, V.; Fierabracci, A. Insights into the Diagnostic Potential of Extracellular Vesicles and Their miRNA Signature from Liquid Biopsy as Early Biomarkers of Diabetic Micro/Macrovascular Complications. Int. J. Mol. Sci. 2017, 18, 1974. [Google Scholar] [CrossRef] [Green Version]
- Lu, Y.; Liu, D.; Feng, Q.; Liu, Z. Diabetic Nephropathy: Perspective on Extracellular Vesicles. Front. Immunol. 2020, 11, 943. [Google Scholar] [CrossRef]
- Prattichizzo, F.; Matacchione, G.; Giuliani, A.; Sabbatinelli, J.; Olivieri, F.; De Candia, P.; De Nigris, V.; Ceriello, A. Extracellular vesicle-shuttled miRNAs: A critical appraisal of their potential as nano-diagnostics and nano-therapeutics in type 2 diabetes mellitus and its cardiovascular complications. Theranostics 2020, 11, 1031–1045. [Google Scholar] [CrossRef]
- Zhang, W.; Zhou, X.; Zhang, H.; Yao, Q.; Liu, Y.; Dong, Z. Extracellular vesicles in diagnosis and therapy of kidney diseases. Am. J. Physiol. Physiol. 2016, 311, F844–F851. [Google Scholar] [CrossRef] [Green Version]
- Théry, C.; Witwer, K.W.; Aikawa, E.; Alcaraz, M.J.; Anderson, J.D.; Andriantsitohaina, R.; Antoniou, A.; Arab, T.; Archer, F.; Atkin-Smith, G.K.; et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracell. Vesicles 2018, 7, 1535750. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tkach, M.; Théry, C. Communication by Extracellular Vesicles: Where We Are and Where We Need to Go. Cell 2016, 164, 1226–1232. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Martins-Marques, T.; Hausenloy, D.J.; Sluijter, J.P.G.; Leybaert, L.; Girao, H. Intercellular Communication in the Heart: Therapeutic Opportunities for Cardiac Ischemia. Trends Mol. Med. 2020, 27, 248–262. [Google Scholar] [CrossRef]
- Colombo, M.; Raposo, G.; Théry, C. Biogenesis, Secretion, and Intercellular Interactions of Exosomes and Other Extracellular Vesicles. Annu. Rev. Cell Dev. Biol. 2014, 30, 255–289. [Google Scholar] [CrossRef] [PubMed]
- Taylor, J.; Azimi, I.; Monteith, G.; Bebawy, M. Ca2+ mediates extracellular vesicle biogenesis through alternate pathways in malignancy. J. Extracell. Vesicles 2020, 9, 1734326. [Google Scholar] [CrossRef] [Green Version]
- Boulanger, C.M.; Loyer, X.; Rautou, P.-E.; Amabile, N. Extracellular vesicles in coronary artery disease. Nat. Rev. Cardiol. 2017, 14, 259–272. [Google Scholar] [CrossRef] [PubMed]
- Connor, D.E.; Exner, T.; Ma, D.D.F.; Joseph, J.E. The majority of circulating platelet-derived microparticles fail to bind annexin V, lack phospholipid-dependent procoagulant activity and demonstrate greater expression of glycoprotein Ib. Thromb. Haemost. 2010, 103, 1044–1052. [Google Scholar] [CrossRef] [Green Version]
- van Niel, G.; D’Angelo, G.; Raposo, G. Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. 2018, 19, 213–228. [Google Scholar] [CrossRef]
- Russell, A.E.; Sneider, A.; Witwer, K.W.; Bergese, P.; Bhattacharyya, S.N.; Cocks, A.; Cocucci, E.; Erdbrügger, U.; Falcon-Perez, J.M.; Freeman, D.W.; et al. Biological membranes in EV biogenesis, stability, uptake, and cargo transfer: An ISEV position paper arising from the ISEV membranes and EVs workshop. J. Extracell. Vesicles 2019, 8, 1684862. [Google Scholar] [CrossRef] [Green Version]
- Momen-Heravi, F.; Getting, S.J.; Moschos, S.A. Extracellular vesicles and their nucleic acids for biomarker discovery. Pharmacol. Ther. 2018, 192, 170–187. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Słomka, A.; Urban, S.K.; Lukacs-Kornek, V.; Żekanowska, E.; Kornek, M. Large Extracellular Vesicles: Have We Found the Holy Grail of Inflammation? Front. Immunol. 2018, 9, 2723. [Google Scholar] [CrossRef] [PubMed]
- Nanbo, A.; Kawanishi, E.; Yoshida, R.; Yoshiyama, H. Exosomes Derived from Epstein-Barr Virus-Infected Cells Are Internalized via Caveola-Dependent Endocytosis and Promote Phenotypic Modulation in Target Cells. J. Virol. 2013, 87, 10334–10347. [Google Scholar] [CrossRef] [Green Version]
- Tian, T.; Zhu, Y.L.; Zhou, Y.Y.; Liang, G.F.; Wang, Y.Y.; Hu, F.H.; Xiao, Z.D. Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. J. Biol. Chem. 2014, 289, 22258–22267. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Montecalvo, A.; Larregina, A.T.; Shufesky, W.J.; Stolz, D.B.; Sullivan, M.L.G.; Karlsson, J.M.; Baty, C.J.; Gibson, G.A.; Erdos, G.; Wang, Z.; et al. Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 2012, 119, 756–766. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Morelli, A.E.; Larregina, A.T.; Shufesky, W.J.; Sullivan, M.L.G.; Stolz, D.B.; Papworth, G.D.; Zahorchak, A.F.; Logar, A.J.; Wang, Z.; Watkins, S.C.; et al. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood 2004, 104, 3257–3266. [Google Scholar] [CrossRef] [Green Version]
- Nazarenko, I.; Rana, S.; Baumann, A.; McAlear, J.; Hellwig, A.; Trendelenburg, M.; Lochnit, G.; Preissner, K.T.; Zöller, M. Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res. 2010, 70, 1668–1678. [Google Scholar] [CrossRef] [Green Version]
- Christianson, H.C.; Svensson, K.J.; Van Kuppevelt, T.H.; Li, J.P.; Belting, M. Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. Proc. Natl. Acad. Sci. USA 2013, 110, 17380–17385. [Google Scholar] [CrossRef] [Green Version]
- Fuentes, P.; Sesé, M.; Guijarro, P.J.; Emperador, M.; Sánchez-Redondo, S.; Peinado, H.; Hümmer, S.; Ramón y. Cajal, S. ITGB3-mediated uptake of small extracellular vesicles facilitates intercellular communication in breast cancer cells. Nat. Commun. 2020, 11, 1–15. [Google Scholar] [CrossRef]
- Gonda, A.; Kabagwira, J.; Senthil, G.N.; Wall, N.R. Internalization of Exosomes through Receptor-Mediated Endocytosis. Mol. Cancer Res. 2019, 17, 337–347. [Google Scholar] [CrossRef] [Green Version]
- Feng, D.; Zhao, W.L.; Ye, Y.Y.; Bai, X.C.; Liu, R.Q.; Chang, L.F.; Zhou, Q.; Sui, S.F. Cellular internalization of exosomes occurs through phagocytosis. Traffic 2010, 11, 675–687. [Google Scholar] [CrossRef]
- Ares, G.R.; Ortiz, P.A. Dynamin2, clathrin, and lipid rafts mediate endocytosis of the apical Na/K/2Cl cotransporter NKCC2 in thick ascending limbs. J. Biol. Chem. 2012, 287, 37824–37834. [Google Scholar] [CrossRef] [Green Version]
- Shimoda, M. Extracellular vesicle-associated MMPs: A modulator of the tissue microenvironment. In Advances in Clinical Chemistry; Academic Press Inc.: Cambridge, MA, USA, 2019; Volume 88, pp. 35–66. ISBN 9780128171431. [Google Scholar]
- Saenz-Pipaon, G.; San Martín, P.; Planell, N.; Maillo, A.; Ravassa, S.; Vilas-Zornoza, A.; Martinez-Aguilar, E.; Rodriguez, J.A.; Alameda, D.; Lara-Astiaso, D.; et al. Functional and transcriptomic analysis of extracellular vesicles identifies calprotectin as a new prognostic marker in peripheral arterial disease (PAD). J. Extracell. Vesicles 2020, 9, 1729646. [Google Scholar] [CrossRef]
- Xu, W.-C.; Qian, G.; Liu, A.-Q.; Li, Y.-Q.; Zou, H.-Q. Urinary Extracellular Vesicle. Chin. Med. J. 2018, 131, 1357–1364. [Google Scholar] [CrossRef]
- Doyle, L.; Wang, M. Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells 2019, 8, 727. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lourenço, C.; Constâncio, V.; Henrique, R.; Carvalho, Â.; Jerónimo, C. Urinary Extracellular Vesicles as Potential Biomarkers for Urologic Cancers: An Overview of Current Methods and Advances. Cancers 2021, 13, 1529. [Google Scholar] [CrossRef] [PubMed]
- Simonsen, J.B. What Are We Looking At? Extracellular Vesicles, Lipoproteins, or Both? Circ. Res. 2017, 121, 920–922. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Barreiro, K.; Huber, T.B.; Holthofer, H. Isolating Urinary Extracellular Vesicles as Biomarkers for Diabetic Disease. In Methods in Molecular Biology; Humana: New York, NY, USA, 2020; pp. 175–188. [Google Scholar]
- Zhou, H.; Yuen, P.S.T.; Pisitkun, T.; Gonzales, P.A.; Yasuda, H.; Dear, J.W.; Gross, P.; Knepper, M.A.; Star, R.A. Collection, storage, preservation, and normalization of human urinary exosomes for biomarker discovery. Kidney Int. 2006, 69, 1471–1476. [Google Scholar] [CrossRef] [Green Version]
- Svenningsen, P.; Sabaratnam, R.; Jensen, B.L. Urinary extracellular vesicles: Origin, role as intercellular messengers and biomarkers; efficient sorting and potential treatment options. Acta Physiol. 2020, 228, e13346. [Google Scholar] [CrossRef]
- Witwer, K.W.; Buzás, E.I.; Bemis, L.T.; Bora, A.; Lässer, C.; Lötvall, J.; Nolte-‘t Hoen, E.N.; Piper, M.G.; Sivaraman, S.; Skog, J.; et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J. Extracell. Vesicles 2013, 2, 20360. [Google Scholar] [CrossRef] [PubMed]
- György, B.; Pálóczi, K.; Kovács, A.; Barabás, E.; Bekő, G.; Várnai, K.; Pállinger, É.; Szabó-Taylor, K.; Szabó, T.G.; Kiss, A.A.; et al. Improved circulating microparticle analysis in acid-citrate dextrose (ACD) anticoagulant tube. Thromb. Res. 2014, 133, 285–292. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lacroix, R.; Judicone, C.; Mooberry, M.; Boucekine, M.; Key, N.S.; Dignat-George, F. Standardization of pre-analytical variables in plasma microparticle determination: Results of the International Society on Thrombosis and Haemostasis SSC Collaborative workshop. J. Thromb. Haemost. 2013, 11, 1190–1193. [Google Scholar] [CrossRef] [PubMed]
- Merchant, M.L.; Rood, I.M.; Deegens, J.K.J.; Klein, J.B. Isolation and characterization of urinary extracellular vesicles: Implications for biomarker discovery. Nat. Rev. Nephrol. 2017, 13, 731–749. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fernández-Llama, P.; Khositseth, S.; Gonzales, P.A.; Star, R.A.; Pisitkun, T.; Knepper, M.A. Tamm-Horsfall protein and urinary exosome isolation. Kidney Int. 2010, 77, 736–742. [Google Scholar] [CrossRef] [Green Version]
- Musante, L.; Saraswat, M.; Duriez, E.; Byrne, B.; Ravidà, A.; Domon, B.; Holthofer, H. Biochemical and physical characterisation of urinary nanovesicles following CHAPS treatment. PLoS ONE 2012, 7, e37279. [Google Scholar] [CrossRef] [Green Version]
- Cheruvanky, A.; Zhou, H.; Pisitkun, T.; Kopp, J.B.; Knepper, M.A.; Yuen, P.S.T.; Star, R.A. Rapid isolation of urinary exosomal biomarkers using a nanomembrane ultrafiltration concentrator. Am. J. Physiol. Ren. Physiol. 2007, 292, F1657–F1661. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rood, I.M.; Deegens, J.K.J.; Merchant, M.L.; Tamboer, W.P.M.; Wilkey, D.W.; Wetzels, J.F.M.; Klein, J.B. Comparison of three methods for isolation of urinary microvesicles to identify biomarkers of nephrotic syndrome. Kidney Int. 2010, 78, 810–816. [Google Scholar] [CrossRef] [Green Version]
- Musante, L.; Tataruch, D.; Gu, D.; Benito-Martin, A.; Calzaferri, G.; Aherne, S.; Holthofer, H. A simplified method to recover urinary vesicles for clinical applications, and sample banking. Sci. Rep. 2014, 4, 7532. [Google Scholar] [CrossRef]
- Nakai, W.; Yoshida, T.; Diez, D.; Miyatake, Y.; Nishibu, T.; Imawaka, N.; Naruse, K.; Sadamura, Y.; Hanayama, R. A novel affinity-based method for the isolation of highly purified extracellular vesicles. Sci. Rep. 2016, 6, 33935. [Google Scholar] [CrossRef] [Green Version]
- Ghosh, A.; Davey, M.; Chute, I.C.; Griffiths, S.G.; Lewis, S.; Chacko, S.; Barnett, D.; Crapoulet, N.; Fournier, S.; Joy, A.; et al. Rapid isolation of extracellular vesicles from cell culture and biological fluids using a synthetic peptide with specific affinity for heat shock proteins. PLoS ONE 2014, 9, e110443. [Google Scholar] [CrossRef] [Green Version]
- Dong, L.; Zieren, R.C.; Horie, K.; Kim, C.J.; Mallick, E.; Jing, Y.; Feng, M.; Kuczler, M.D.; Green, J.; Amend, S.R.; et al. Comprehensive evaluation of methods for small extracellular vesicles separation from human plasma, urine and cell culture medium. J. Extracell. Vesicles 2020, 10, e12044. [Google Scholar] [CrossRef]
- Dragovic, R.A.; Gardiner, C.; Brooks, A.S.; Tannetta, D.S.; Ferguson, D.J.P.; Hole, P.; Carr, B.; Redman, C.W.G.; Harris, A.L.; Dobson, P.J.; et al. Sizing and phenotyping of cellular vesicles using Nanoparticle Tracking Analysis. Nanomed. Nanotechnol. Biol. Med. 2011, 7, 780–788. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brittain, G.C.; Chen, Y.Q.; Martinez, E.; Tang, V.A.; Renner, T.M.; Langlois, M.A.; Gulnik, S. A Novel Semiconductor-Based Flow Cytometer with Enhanced Light-Scatter Sensitivity for the Analysis of Biological Nanoparticles. Sci. Rep. 2019, 9, 16039. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- De Rond, L.; Van Der Pol, E.; Hau, C.M.; Varga, Z.; Sturk, A.; Van Leeuwen, T.G.; Nieuwland, R.; Coumans, F.A.W. Comparison of generic fluorescent markers for detection of extracellular vesicles by flow cytometry. Clin. Chem. 2018, 64, 680–689. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chuo, S.T.-Y.; Chien, J.C.-Y.; Lai, C.P.-K. Imaging extracellular vesicles: Current and emerging methods. J. Biomed. Sci. 2018, 25, 91. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Huang, Y.; Li, R.; Zhang, L.; Chen, Y.; Dong, W.; Zhao, X.; Yang, H.; Zhang, S.; Xie, Z.; Ye, Z.; et al. Extracellular Vesicles From High Glucose-Treated Podocytes Induce Apoptosis of Proximal Tubular Epithelial Cells. Front. Physiol. 2020, 11, 579296. [Google Scholar] [CrossRef]
- Li, M.; Zhang, T.; Wu, X.; Chen, Y.; Sun, L. High glucose provokes microvesicles generation from glomerular podocytes via NOX4/ROS pathway. Biosci. Rep. 2019, 39, BSR20192554. [Google Scholar] [CrossRef]
- Wu, X.; Gao, Y.; Xu, L.; Dang, W.; Yan, H.; Zou, D.; Zhu, Z.; Luo, L.; Tian, N.; Wang, X.; et al. Exosomes from high glucose-treated glomerular endothelial cells trigger the epithelial-mesenchymal transition and dysfunction of podocytes. Sci. Rep. 2017, 7, 9371. [Google Scholar] [CrossRef] [Green Version]
- Wu, X.M.; Gao, Y.B.; Cui, F.Q.; Zhang, N. Exosomes from high glucose-treated glomerular endothelial cells activate mesangial cells to promote renal fibrosis. Biol. Open 2016, 5, 484–491. [Google Scholar] [CrossRef] [Green Version]
- Barutta, F.; Tricarico, M.; Corbelli, A.; Annaratone, L.; Pinach, S.; Grimaldi, S.; Bruno, G.; Cimino, D.; Taverna, D.; Deregibus, M.C.; et al. Urinary exosomal MicroRNAs in incipient diabetic nephropathy. PLoS ONE 2013, 8, e73798. [Google Scholar] [CrossRef] [Green Version]
- da Silva Novaes, A.; Borges, F.T.; Maquigussa, E.; Varela, V.A.; Dias, M.V.S.; Boim, M.A. Influence of high glucose on mesangial cell-derived exosome composition, secretion and cell communication. Sci. Rep. 2019, 9, 6270. [Google Scholar] [CrossRef] [PubMed]
- Wen, J.; Ma, Z.; Livingston, M.J.; Zhang, W.; Yuan, Y.; Guo, C.; Liu, Y.; Fu, P.; Dong, Z. Decreased secretion and profibrotic activity of tubular exosomes in diabetic kidney disease. Am. J. Physiol. Ren. Physiol. 2020, 319, F664–F673. [Google Scholar] [CrossRef]
- Abe, H.; Sakurai, A.; Ono, H.; Hayashi, S.; Yoshimoto, S.; Ochi, A.; Ueda, S.; Nishimura, K.; Shibata, E.; Tamaki, M.; et al. Urinary exosomal mRNA of WT1 as diagnostic and prognostic biomarker for diabetic nephropathy. J. Med. Investig. 2018, 65, 208–215. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Su, H.; Qiao, J.; Hu, J.; Li, Y.; Lin, J.; Yu, Q.; Zhen, J.; Ma, Q.; Wang, Q.; Lv, Z.; et al. Podocyte-derived extracellular vesicles mediate renal proximal tubule cells dedifferentiation via microRNA-221 in diabetic nephropathy. Mol. Cell. Endocrinol. 2020, 518, 111034. [Google Scholar] [CrossRef] [PubMed]
- Munkonda, M.N.; Akbari, S.; Landry, C.; Sun, S.; Xiao, F.; Turner, M.; Holterman, C.E.; Nasrallah, R.; Hébert, R.L.; Kennedy, C.R.J.; et al. Podocyte-derived microparticles promote proximal tubule fibrotic signaling via p38 MAPK and CD36. J. Extracell. Vesicles 2018, 7, 1432206. [Google Scholar] [CrossRef]
- Wang, Y.Y.; Tang, L.Q.; Wei, W. Berberine attenuates podocytes injury caused by exosomes derived from high glucose-induced mesangial cells through TGFβ1-PI3K/AKT pathway. Eur. J. Pharmacol. 2018, 824, 185–192. [Google Scholar] [CrossRef]
- Jia, Y.; Guan, M.; Zheng, Z.; Zhang, Q.; Tang, C.; Xu, W.; Xiao, Z.; Wang, L.; Xue, Y. MiRNAs in Urine Extracellular Vesicles as Predictors of Early-Stage Diabetic Nephropathy. J. Diabetes Res. 2016, 2016, 7932765. [Google Scholar] [CrossRef] [Green Version]
- Ravindran, S.; Pasha, M.; Agouni, A.; Munusamy, S. Microparticles as potential mediators of high glucose-induced renal cell injury. Biomolecules 2019, 9, 348. [Google Scholar] [CrossRef] [Green Version]
- Zhu, M.; Sun, X.; Qi, X.; Xia, L.; Wu, Y. Exosomes from high glucose-treated macrophages activate macrophages and induce inflammatory responses via NF-κB signaling pathway in vitro and in vivo. Int. Immunopharmacol. 2020, 84, 106551. [Google Scholar] [CrossRef]
- Zhu, Q.J.; Zhu, M.; Xu, X.X.; Meng, X.M.; Wu, Y.G. Exosomes from high glucose–treated macrophages activate glomerular mesangial cells via TGF-β1/Smad3 pathway in vivo and in vitro. FASEB J. 2019, 33, 9279–9290. [Google Scholar] [CrossRef]
- Anders, H.-J.; Huber, T.B.; Isermann, B.; Schiffer, M. CKD in diabetes: Diabetic kidney disease versus nondiabetic kidney disease. Nat. Rev. Nephrol. 2018, 14, 361–377. [Google Scholar] [CrossRef]
- Kalani, A.; Mohan, A.; Godbole, M.M.; Bhatia, E.; Gupta, A.; Sharma, R.K.; Tiwari, S. Wilm’s Tumor-1 Protein Levels in Urinary Exosomes from Diabetic Patients with or without Proteinuria. PLoS ONE 2013, 8, e60177. [Google Scholar] [CrossRef]
- Raimondo, F.; Corbetta, S.; Morosi, L.; Chinello, C.; Gianazza, E.; Castoldi, G.; Di Gioia, C.; Bombardi, C.; Stella, A.; Battaglia, C.; et al. Urinary exosomes and diabetic nephropathy: A proteomic approach. Mol. Biosyst. 2013, 9, 1139–1146. [Google Scholar] [CrossRef]
- Gu, D.; Chen, Y.; Masucci, M.; Xiong, C.; Zou, H.; Holthofer, H. Potential urine biomarkers for the diagnosis of prediabetes and early diabetic nephropathy based on ISN CKHDP program. Clin. Nephrol. 2021, 93, S129–S133. [Google Scholar] [CrossRef] [PubMed]
- Musante, L.; Tataruch, D.; Gu, D.; Liu, X.; Forsblom, C.; Groop, P.H.; Holthofer, H. Proteases and protease inhibitors of urinary extracellular vesicles in diabetic nephropathy. J. Diabetes Res. 2015, 2015, 289734. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ning, J.; Xiang, Z.; Xiong, C.; Zhou, Q.; Wang, X.; Zou, H. Alpha1-antitrypsin in urinary extracellular vesicles: A potential biomarker of diabetic kidney disease prior to microalbuminuria. Diabetes, Metab. Syndr. Obes. Targets Ther. 2020, 13, 2037–2048. [Google Scholar] [CrossRef] [PubMed]
- Yamamoto, C.M.; Murakami, T.; Oakes, M.L.; Mitsuhashi, M.; Kelly, C.; Henry, R.R.; Sharma, K. Uromodulin mRNA from Urinary Extracellular Vesicles Correlate to Kidney Function Decline in Type 2 Diabetes Mellitus. Am. J. Nephrol. 2018, 47, 283–291. [Google Scholar] [CrossRef] [PubMed]
- Lytvyn, Y.; Xiao, F.; Kennedy, C.R.J.; Perkins, B.A.; Reich, H.N.; Scholey, J.W.; Cherney, D.Z.; Burger, D. Assessment of urinary microparticles in normotensive patients with type 1 diabetes. Diabetologia 2017, 60, 581–584. [Google Scholar] [CrossRef] [Green Version]
- Sakurai, A.; Ono, H.; Ochi, A.; Matsuura, M.; Yoshimoto, S.; Kishi, S.; Murakami, T.; Tominaga, T.; Nagai, K.; Abe, H.; et al. Involvement of Elf3 on Smad3 activation-dependent injuries in podocytes and excretion of urinary exosome in diabetic nephropathy. PLoS ONE 2019, 14, e0216788. [Google Scholar] [CrossRef]
- Cappelli, C.; Tellez, A.; Jara, C.; Alarcón, S.; Torres, A.; Mendoza, P.; Podestá, L.; Flores, C.; Quezada, C.; Oyarzún, C.; et al. The TGF-β profibrotic cascade targets ecto-5′-nucleotidase gene in proximal tubule epithelial cells and is a traceable marker of progressive diabetic kidney disease. Biochim. Biophys. Acta Mol. Basis Dis. 2020, 1866, 165796. [Google Scholar] [CrossRef]
- De, S.; Kuwahara, S.; Hosojima, M.; Ishikawa, T.; Kaseda, R.; Sarkar, P.; Yoshioka, Y.; Kabasawa, H.; Iida, T.; Goto, S.; et al. Exocytosis-mediated urinary full-length megalin excretion is linked with the pathogenesis of diabetic nephropathy. Diabetes 2017, 66, 1391–1404. [Google Scholar] [CrossRef] [Green Version]
- Dimuccio, V.; Peruzzi, L.; Brizzi, M.F.; Cocchi, E.; Fop, F.; Boido, A.; Gili, M.; Gallo, S.; Biancone, L.; Camussi, G.; et al. Acute and chronic glomerular damage is associated with reduced CD133 expression in urinary extracellular vesicles. Am. J. Physiol. Ren. Physiol. 2020, 312, F486–F495. [Google Scholar] [CrossRef]
- Ghai, V.; Wu, X.; Bheda-Malge, A.; Argyropoulos, C.P.; Bernardo, J.F.; Orchard, T.; Galas, D.; Wang, K. Genome-wide Profiling of Urinary Extracellular Vesicle microRNAs Associated With Diabetic Nephropathy in Type 1 Diabetes. Kidney Int. Reports 2018, 3, 555–572. [Google Scholar] [CrossRef] [Green Version]
- Prabu, P.; Rome, S.; Sathishkumar, C.; Gastebois, C.; Meugnier, E.; Mohan, V.; Balasubramanyam, M. MicroRNAs from urinary extracellular vesicles are non-invasive early biomarkers of diabetic nephropathy in type 2 diabetes patients with the ‘Asian Indian phenotype’. Diabetes Metab. 2019, 45, 276–285. [Google Scholar] [CrossRef]
- Xie, Y.; Jia, Y.; Cuihua, X.; Hu, F.; Xue, M.; Xue, Y. Urinary Exosomal MicroRNA Profiling in Incipient Type 2 Diabetic Kidney Disease. J. Diabetes Res. 2017, 2017. [Google Scholar] [CrossRef]
- Zang, J.; Maxwell, A.P.; Simpson, D.A.; McKay, G.J. Differential Expression of Urinary Exosomal MicroRNAs miR-21-5p and miR-30b-5p in Individuals with Diabetic Kidney Disease. Sci. Rep. 2019, 9, 10900. [Google Scholar] [CrossRef]
- Zheng, Z.; Guan, M.; Jia, Y.; Wang, D.; Pang, R.; Lv, F.; Xiao, Z.; Wang, L.; Zhang, H.; Xue, Y. The coordinated roles of miR-26a and miR-30c in regulating TGFβ1-induced epithelial-to-mesenchymal transition in diabetic nephropathy. Sci. Rep. 2016, 6, 37492. [Google Scholar] [CrossRef]
- Burger, D.; Thibodeau, J.F.; Holterman, C.E.; Burns, K.D.; Touyz, R.M.; Kennedy, C.R.J. Urinary podocyte microparticles identify prealbuminuric diabetic glomerular injury. J. Am. Soc. Nephrol. 2014, 25, 1401–1407. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Park, S.; Lee, K.; Park, I.B.; Kim, N.H.; Cho, S.; Rhee, W.J.; Oh, Y.; Choi, J.; Nam, S.; Lee, D.H. The profiles of microRNAs from urinary extracellular vesicles (EVs) prepared by various isolation methods and their correlation with serum EV microRNAs. Diabetes Res. Clin. Pract. 2020, 160, 108010. [Google Scholar] [CrossRef] [PubMed]
- Rodrigues, K.F.; Pietrani, N.T.; Fernandes, A.P.; Bosco, A.A.; de Sousa, M.C.R.; de Fátima Oliveira Silva, I.; Silveira, J.N.; Campos, F.M.F.; Gomes, K.B. Circulating microparticles levels are increased in patients with diabetic kidney disease: A case-control research. Clin. Chim. Acta 2018, 479, 48–55. [Google Scholar] [CrossRef] [PubMed]
- Yu, M.; Xie, R.; Zhang, Y.; Liang, H.; Hou, L.; Yu, C.; Zhang, J.; Dong, Z.; Tian, Y.; Bi, Y.; et al. Phosphatidylserine on microparticles and associated cells contributes to the hypercoagulable state in diabetic kidney disease. Nephrol. Dial. Transplant. 2018, 33, 2215–2227. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Uil, M.; Hau, C.M.; Ahdi, M.; Mills, J.D.; Kers, J.; Saleem, M.A.; Florquin, S.; Gerdes, V.E.A.; Nieuwland, R.; Roelofs, J.J.T.H. Cellular origin and microRNA profiles of circulating extracellular vesicles in different stages of diabetic nephropathy. Clin. Kidney J. 2021, 14, 358–365. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Ma, K.L.; Gong, Y.X.; Wang, G.H.; Hu, Z.B.; Liu, L.; Lu, J.; Chen, P.P.; Lu, C.C.; Ruan, X.Z.; et al. Platelet microparticles mediate glomerular endothelial injury in early diabetic nephropathy. J. Am. Soc. Nephrol. 2018, 29, 2671–2695. [Google Scholar] [CrossRef] [PubMed]
- Florijn, B.W.; Duijs, J.M.G.J.; Levels, J.H.; Dallinga-Thie, G.M.; Wang, Y.; Boing, A.N.; Yuana, Y.; Stam, W.; Limpens, R.W.A.L.; Au, Y.W.; et al. Diabetic nephropathy alters the distribution of circulating angiogenic MicroRNAs among extracellular vesicles, HDL, and Ago-2. Diabetes 2019, 68, 2287–2300. [Google Scholar] [CrossRef]
- Kim, H.; Bae, Y.U.; Jeon, J.S.; Noh, H.; Park, H.K.; Byun, D.W.; Han, D.C.; Ryu, S.; Kwon, S.H. The circulating exosomal microRNAs related to albuminuria in patients with diabetic nephropathy. J. Transl. Med. 2019, 17, 236. [Google Scholar] [CrossRef] [Green Version]
EV Source | Target Cells/ Organ | Study Type | Observation | Biological Activity | Ref. |
---|---|---|---|---|---|
Mouse podocytes | - | In vitro | High glucose (HG) increased Wilm’s tumor-1 (WT1) mRNA in podocyte-derived EVs. | Specific EV subpopulations as early podocyte injury biomarker | [66] |
Mouse podocytes | - | In vitro | In HG conditions, release of podocyte EVs was reduced upon silencing of NOX4 pathway. | Characterization of EV release mechanisms | [60] |
Human podocytes | PTECs | In vitro | HG-podocyte EVs, enriched in miR-221, induced PTECs dedifferentiation through Wnt/β-catenin signaling. | Intercellular communication. Dedifferentiation and fibrosis signaling activation in target cells | [67] |
Human podocytes | PTECs | In vitro | Podocyte EVs increased the expression of fibronectin, collagen type IV, p38, and phosphorylated Smad3 in PTECs. | Intercellular communication. Fibrosis signaling activation in target cells | [68] |
Mouse podocytes | PTECs | In vitro | HG-podocyte EVs induced apoptosis of PTECs and showed differential loading of miR-1981, -3474, -7224, -6538, and let-7f-2. | Intercellular communication. Transcriptional regulation through miRNA transport. Apoptosis signal transduction in target cells | [59] |
Mouse glomerular endothelial cells (GECs) | Podocytes | In vitro | EVs from HG-GECs were enriched in TGF-β1 and promoted podocyte epithelial-mesenchymal transition (EMT) and dysfunction. | Intercellular communication. Induced podocyte EMT and dysfunction. | [61] |
Mouse GECs | GMCs | In vitro In vivo | HG-GEC-EVs were enriched in TGF-β1 and induced mesangial expansion, GMC proliferation and ECM protein overproduction in vivo and in vitro. | Intercellular communication. Tissue remodeling. Induced proliferation and fibrosis in target cells. | [62] |
Human GMCs | GMCs | In vitro | The exposure of GMCs to HG-GMC-EVs increased the expression of fibronectin, angiotensinogen, renin, AT1 and AT2 receptors. | Intercellular communication. Induced fibrosis activation in target cells | [64] |
Human GMCs | - | In vitro | HG reduced the release of GMC-EVs but increased their miR-145 loading. | Transcriptional regulation through specific miRNA encapsulation | [63] |
Rat primary GMCs | Podocytes | In vitro | HG-GMC-EVs impaired podocyte cell adhesion and promoted apoptosis via TGF-β1 signaling. | Intercellular communication. Induced fibrosis and apoptosis in target cells | [69] |
Human PTEC and GMC | - | In vitro | HG increased the expression of miR-192, -194 and -215 in PTEC-EVs but not in GMCs-EVs. | Transcriptional regulation through specific miRNA encapsulation in PTECs | [70] |
Rat PTC | PTCs | In vitro | HG-PTC-EVs activated TGF-β, mTOR, ERK and endoplasmic reticulum stress pathways in naïve PTCs. | Intercellular communication. Fibrosis signaling activation in PTCs | [71] |
Mouse PTCs | Fibroblast | In vitro | HG reduced PTC-EV release. HG-PTC-EVs promoted fibroblast proliferation and protein expression of fibronectin, collagen type I and α-SMA. | Intercellular communication. Fibrosis signaling activation in fibroblast. | [65] |
Mouse macrophages | GMCs C57BL/6 WT mice | In vitro In vivo | HG-macrophage-EVs were enriched in iNOS, IL-1β, and TGF-β1 and induced ECM production and inflammatory factor secretion from GMCs in vitro and in vivo through NF-κB/p65 and TGF-β1/SMAD3 signaling pathways. | Intercellular communication. Tissue remodeling. Inflammation and fibrosis activation | [72,73] |
Patient Groups (n = Number) | Observation | Application of uEVs | Refs. |
---|---|---|---|
uEV protein and mRNA content | |||
Healthy controls (n = 15), pre-DM (n = 15), diabetes with normal proteinuria (NA) levels (n = 15), DM with microalbuminuria (MIC, n = 15), and DM with macroproteinuria (MAC, n = 15) | Protein concentration was higher in uEVs of DM vs. controls. MASP2, CALB1, S100A8 and S100A9 identified as potential biomarkers of DKD by proteomics analysis. | uEV proteomics for the identification of novel biomarkers and/or therapeutic targets | [77] |
Healthy volunteers (n = 12), T1DM with different degrees of albuminuria (n = 37) | Myeloblastin and elafin increased in the T1DM-NA and T1DM-MIC uEVs. Cystatin B, natural inhibitor of cathepsins L, H, and B, and NGAL increased in the T1DM-NA group. | uEV proteomics for the identification of novel biomarkers and/or therapeutic targets | [78] |
Healthy people (n = 40), prediabetic patients (n = 40), diabetics with: NA (n = 28), MIC (n = 28) and MAC (n = 11) | No expression of α1- AT protein in uEVs of healthy or prediabetic patients. uEV α1-AT content gradually increased in diabetic patients according to DKD degree. | α1-AT+ uEVs; biomarkers of DKD severity | [79] |
DKD with heavy proteinuria (n = 10), MCNS (n = 10), healthy subjects (n = 5) | WT1 mRNA expression increased in uEVs of DKD vs. controls. Low expression of WT1 in uEVs was associated with lesser progression to ESRD. | WT1+uEVs; biomarkers of DKD diagnosis and progression | [66] |
Healthy (n = 18), obese (n = 18), T2DM (n = 161), mild DKD (n = 19) and severe DKD (n = 15) | Uromodulin mRNA in uEVs was elevated in DKD vs. healthy, obese, and T2DM subjects. | Uromodulin+uEVs; biomarkers of DKD diagnosis | [80] |
uEV subpopulations | |||
Healthy controls (n = 20), T1DM (n = 25) | Podoplanin+uEVs were elevated in T1DM vs. control, and further increased after hyperglycemic clamp. | Podoplaning+uEVs; podocyte injury biomarkers | [81] |
Healthy subjects (n = 5), DKD with heavy proteinuria (n = 25) or MCNS (n = 25) | Elf3+uEVs undetected in healthy subjects. Elf3+uEVs associated with a decline in eGFR in DKD. | Elf3+uEVs; podocyte injury and DKD severity biomarkers | [82] |
Nondiabetic (n = 10), diabetic (n = 48) and DKD (n = 10) | CD73 was enriched in uEVs of DKD vs. control and diabetes. | CD73+uEVs; DKD diagnosis and tubular fibrosis biomarkers. | [83] |
Controls (n = 19), T2DM-NA (n = 20); T2DM-MIC (n = 17); and T2DM-MAC (n = 19) | The levels of total uEVs and C-megalin+uEVs increased according to albuminuria in patients with T2DM. | C-megalin+uEVs; biomarkers of DKD diagnosis and tubular fibrosis | [84] |
Controls (n = 13), T2DM-NA (n = 17), T2DM-MIC (n = 15) and T2DM-MAC (n = 15) | CD133+uEVs decreased in T2DM vs. control and within diabetic according to MIC or MAC. | CD133+EVs; biomarkers of tissue regeneration and DKD diagnosis and severity | [85] |
uEVs miRNA content | |||
T1DM patients with a follow-up of 25 years that developed: overt nephropathy (n = 8), intermittent MIC (n = 9), persistent MIC (n = 10) and with no evolution (NA, n = 5) | uEVs of T1DM patients were enriched in miRNAs compared to urine. Overt patients presented 21 differential miRNAs in uEVs vs. NA | uEVs miRNA profile associated with DKD progression | [86] |
Nondiabetic subjects (n = 10), and T1DM: T1DM-NA (n = 12), T1DM-MIC (n = 12) | uEVs were reduced in T1DM-MIC patients. miR-155 and miR-424 were lower, while miR-130a and miR-145 were higher in T1DM-MIC than in T1DM-NA patients. | uEVs miRNA profile associated with DKD severity | [63] |
TD2M-NA (n = 30), T2DM-MIC (n = 30), T2DM-MAC (n = 20) and healthy controls (n = 10) | The levels of miRNA-192, -194 and -215 increases gradually among controls, NA, and MIC-T2DM, but decreases in the MAC group. uEVs content in TGF-𝛽1 correlated with that of miR-192 and -215. | uEVs miRNA profile associated with DKD severity and fibrosis | [70] |
Subjects (n = 40 each) with normal glucose tolerance (NGT), T2DM-NA (n = 40), T2DM-MIC (n = 40) and T2DM-MAC (n = 40) | Let-7i-5p, miR-135b-5p, miR-15b-3p, miR-197-3p, miR-24-3p and miR-27b-3p discriminate T2DM-NA patients from those with T2DM-MIC and T2DM-MAC. | uEVs miRNA profile associated with DKD diagnosis | [87] |
T2DM (n = 20) and T2DM-MAC (n = 20) | miR-362-3p, miR-877-3p, and miR-150-5p were upregulated and miR-15a-5p was downregulated in T2DM-MAC. | uEVs miRNA profile associated with DKD diagnosis | [88] |
T2DM-DKD (n = 22), T2DM normal renal function (n = 15) and CKD without diabetes (n = 18) | miR-21-5p increased in uEVs of T2DM-DKD and CKD vs. T2DM, while miR-30b-5p was downregulated in both diabetic DKD and in CKD patients. | uEVs miRNA profile associated with DKD and CKD diagnosis | [89] |
T2DM (n = 30) and T2DM-DKD (n = 20) | Expression of miR-26a was elevated in uEVs from DKD patients. | miRNA-26a associated with DKD diagnosis | [90] |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Saenz-Pipaon, G.; Echeverria, S.; Orbe, J.; Roncal, C. Urinary Extracellular Vesicles for Diabetic Kidney Disease Diagnosis. J. Clin. Med. 2021, 10, 2046. https://doi.org/10.3390/jcm10102046
Saenz-Pipaon G, Echeverria S, Orbe J, Roncal C. Urinary Extracellular Vesicles for Diabetic Kidney Disease Diagnosis. Journal of Clinical Medicine. 2021; 10(10):2046. https://doi.org/10.3390/jcm10102046
Chicago/Turabian StyleSaenz-Pipaon, Goren, Saioa Echeverria, Josune Orbe, and Carmen Roncal. 2021. "Urinary Extracellular Vesicles for Diabetic Kidney Disease Diagnosis" Journal of Clinical Medicine 10, no. 10: 2046. https://doi.org/10.3390/jcm10102046