Role of Extracellular Vesicles in Renal Inflammation and Fibrosis

  • Lin-Li LvEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1165)


Extracellular vesicles (EVs) are the membrane-surrounded structures released by almost all types of cells. Accumulating evidences have suggested that EVs secretion is enhanced under stress conditions and have been associated with a large wide of cellular physiological and pathological processes. In this part, recent understanding about the generation and biological function of EVs was reviewed. Moreover, the role of EVs in renal inflammation and fibrosis and future challenges of EVs study in kidney disease were discussed.


Extracellular vesicles Renal fibrosis Renal inflammation Biomarker 



This chapter was modified from a paper reported by our group in J Cell Mol Med (Lv et al. 2019).


  1. Abdulrahman BA, Abdelaziz DH, Schatzl HM (2018) Autophagy regulates exosomal release of prions in neuronal cells. J Biol Chem 293:8956–8968CrossRefGoogle Scholar
  2. Ben-Dov IZ, Tan YC, Morozov P, Wilson PD, Rennert H, Blumenfeld JD et al (2014) Urine microRNA as potential biomarkers of autosomal dominant polycystic kidney disease progression: description of miRNA profiles at baseline. PLoS ONE 9:e86856CrossRefGoogle Scholar
  3. Borges FT, Melo SA, Ozdemir BC, Kato N, Revuelta I, Miller CA et al (2013) TGF-beta1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis. J Am Soc Nephrol 24:385–392CrossRefGoogle Scholar
  4. Cabral J, Ryan AE, Griffin MD, Ritter T (2018) Extracellular vesicles as modulators of wound healing. Adv Drug Deliv Rev 129:394–406CrossRefGoogle Scholar
  5. Caruso S, Poon IKH (2018) Apoptotic cell-derived extracellular vesicles: more than just debris. Front Immunol 9:1486CrossRefGoogle Scholar
  6. Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W et al (2018) Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560:382–386CrossRefGoogle Scholar
  7. Choo YW, Kang M, Kim HY, Han J, Kang S, Lee JR et al (2018) M1 macrophage-derived nanovesicles potentiate the anticancer efficacy of immune checkpoint inhibitors. ACS Nano 12:8977–8993CrossRefGoogle Scholar
  8. Desdin-Mico G, Mittelbrunn M (2017) Role of exosomes in the protection of cellular homeostasis. Cell Adh Migr 11:127–134CrossRefGoogle Scholar
  9. Dusso A, Colombo MI, Shanahan CM (2018) Not all vascular smooth muscle cell exosomes calcify equally in chronic kidney disease. Kidney Int 93:298–301CrossRefGoogle Scholar
  10. Escrevente C, Keller S, Altevogt P, Costa J (2011) Interaction and uptake of exosomes by ovarian cancer cells. BMC Cancer 11:108CrossRefGoogle Scholar
  11. Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R (2012) MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A 109:E2110–E2116CrossRefGoogle Scholar
  12. Fernandez-Llama P, Khositseth S, Gonzales PA, Star RA, Pisitkun T, Knepper MA (2010) Tamm-Horsfall protein and urinary exosome isolation. Kidney Int 77:736–742CrossRefGoogle Scholar
  13. Fitzgerald W, Freeman ML, Lederman MM, Vasilieva E, Romero R, Margolis L (2018) A system of cytokines encapsulated in extracellular vesicles. Sci Rep 8:8973CrossRefGoogle Scholar
  14. Fleshner M, Crane CR (2017) Exosomes, DAMPs and miRNA: features of stress physiology and immune homeostasis. Trends Immunol 38:768–776CrossRefGoogle Scholar
  15. Gheinani AH, Vogeli M, Baumgartner U, Vassella E, Draeger A, Burkhard FC et al (2018) Improved isolation strategies to increase the yield and purity of human urinary exosomes for biomarker discovery. Sci Rep 8:3945CrossRefGoogle Scholar
  16. Gieseler F, Plattfaut C, Quecke T, Freund A, Ungefroren H, Ender F (2018) Heterogeneity of microvesicles from cancer cell lines under inflammatory stimulation with TNF-alpha. Cell Biol Int 42:1533–1544CrossRefGoogle Scholar
  17. Gupta KH, Goldufsky JW, Wood SJ, Tardi NJ, Moorthy GS, Gilbert DZ (2017) Apoptosis and compensatory proliferation signaling are coupled by CrkI-containing microvesicles. Dev Cell 41(674–684):e5Google Scholar
  18. Hessvik NP, Llorente A (2018) Current knowledge on exosome biogenesis and release. Cell Mol Life Sci 75:193–208CrossRefGoogle Scholar
  19. Hough KP, Trevor JL, Strenkowski JG, Wang Y, Chacko BK, Tousif S (2018) Exosomal transfer of mitochondria from airway myeloid-derived regulatory cells to T cells. Redox Biol 18:54–64CrossRefGoogle Scholar
  20. Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C (1987) Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 262:9412–9420PubMedGoogle Scholar
  21. Kudo S, Mizuno K, Hirai Y, Shimizu T (1990) Clearance and tissue distribution of recombinant human interleukin 1 beta in rats. Cancer Res 50:5751–5755PubMedGoogle Scholar
  22. Lasser C, Jang SC, Lotvall J (2018) Subpopulations of extracellular vesicles and their therapeutic potential. Mol Aspects Med 60:1–14CrossRefGoogle Scholar
  23. Leoni G, Neumann PA, Kamaly N, Quiros M, Nishio H, Jones HR et al (2015) Annexin A1-containing extracellular vesicles and polymeric nanoparticles promote epithelial wound repair. J Clin Invest 125:1215–1227CrossRefGoogle Scholar
  24. Li ZL, Lv LL, Tang TT, Wang B, Feng Y, Zhou LT et al (2019) HIF-1alpha inducing exosomal microRNA-23a expression mediates the cross-talk between tubular epithelial cells and macrophages in tubulointerstitial inflammation. Kidney Int 95:388–404CrossRefGoogle Scholar
  25. Liu BC, Tang TT, Lv LL, Lan HY (2018) Renal tubule injury: a driving force toward chronic kidney disease. Kidney Int 93:568–579CrossRefGoogle Scholar
  26. Lopez-Castejon G, Brough D (2011) Understanding the mechanism of IL-1beta secretion. Cytokine Growth Factor Rev 22:189–195CrossRefGoogle Scholar
  27. Lotvall J, Hill AF, Hochberg F, Buzas EI, Di Vizio D, Gardiner C et al (2014) Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles 3:26913CrossRefGoogle Scholar
  28. Lv LL, Cao Y, Liu D, Xu M, Liu H, Tang RN et al (2013a) Isolation and quantification of microRNAs from urinary exosomes/microvesicles for biomarker discovery. Int J Biol Sci 9:1021–1031CrossRefGoogle Scholar
  29. Lv LL, Cao YH, Ni HF, Xu M, Liu D, Liu H et al (2013b) MicroRNA-29c in urinary exosome/microvesicle as a biomarker of renal fibrosis. Am J Physiol Renal Physiol 305:F1220–F1227CrossRefGoogle Scholar
  30. Lv LL, Cao YH, Pan MM, Liu H, Tang RN, Ma KL et al (2014) CD2AP mRNA in urinary exosome as biomarker of kidney disease. Clin Chim Acta 428:26–31CrossRefGoogle Scholar
  31. Lv LL, Feng Y, Tang TT, Liu BC (2019) New insight into the role of extracellular vesicles in kidney disease. J Cell Mol Med 23:731–739CrossRefGoogle Scholar
  32. Lv LL, Feng Y, Wen Y, Wu WJ, Ni HF, Li ZL (2018) Exosomal CCL2 from tubular epithelial cells is critical for albumin-induced tubulointerstitial inflammation. J Am Soc Nephrol 29:919–935CrossRefGoogle Scholar
  33. MacKenzie A, Wilson HL, Kiss-Toth E, Dower SK, North RA, Surprenant A (2001) Rapid secretion of interleukin-1beta by microvesicle shedding. Immunity 15:825–835CrossRefGoogle Scholar
  34. Mathieu M, Martin-Jaular L, Lavieu G, Thery C (2019) Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol 21:9–17CrossRefGoogle Scholar
  35. Miao Y, Li G, Zhang X, Xu H, Abraham SN (2015) A TRP channel senses lysosome neutralization by pathogens to trigger their expulsion. Cell 161:1306–1319CrossRefGoogle Scholar
  36. Mohan A, Singh RS, Kumari M, Garg D, Upadhyay A, Ecelbarger CM et al (2016) Urinary exosomal microRNA-451-5p is a potential early biomarker of diabetic nephropathy in rats. PLoS ONE 11:e0154055CrossRefGoogle Scholar
  37. Munkonda MN, Akbari S, Landry C, Sun S, Xiao F, Turner M et al (2018) Podocyte-derived microparticles promote proximal tubule fibrotic signaling via p38 MAPK and CD36. J Extracell Vesicles 7:1432206CrossRefGoogle Scholar
  38. Nabet BY, Qiu Y, Shabason JE, Wu TJ, Yoon T, Kim BC (2017) Exosome RNA unshielding couples stromal activation to pattern recognition receptor signaling in cancer. Cell 170:352–366 (e13)CrossRefGoogle Scholar
  39. Nair RR, Mazza D, Brambilla F, Gorzanelli A, Agresti A, Bianchi ME (2018) LPS-challenged macrophages release microvesicles coated with histones. Front Immunol 9:1463CrossRefGoogle Scholar
  40. Park JE, Dutta B, Tse SW, Gupta N, Tan CF, Low JK (2019) Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift. OncogeneGoogle Scholar
  41. Perez-Hernandez J, Olivares D, Forner MJ, Ortega A, Solaz E, Martinez F et al (2018) Urinary exosome miR-146a is a potential marker of albuminuria in essential hypertension. J Transl Med 16:228CrossRefGoogle Scholar
  42. Phinney DG, Di Giuseppe M, Njah J, Sala E, Shiva S, St Croix CM (2015) Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun 6:8472CrossRefGoogle Scholar
  43. Prunotto M, Farina A, Lane L, Pernin A, Schifferli J, Hochstrasser DF et al (2013) Proteomic analysis of podocyte exosome-enriched fraction from normal human urine. J Proteomics 82:193–229CrossRefGoogle Scholar
  44. Ramezani A, Devaney JM, Cohen S, Wing MR, Scott R, Knoblach S et al (2015) Circulating and urinary microRNA profile in focal segmental glomerulosclerosis: a pilot study. Eur J Clin Invest 45:394–404CrossRefGoogle Scholar
  45. Sanderson RD, Bandari SK, Vlodavsky I (2017) Proteases and glycosidases on the surface of exosomes: newly discovered mechanisms for extracellular remodeling. Matrix Biol 75–76:160–169PubMedGoogle Scholar
  46. Shah R, Patel T, Freedman JE (2018) Circulating extracellular vesicles in human disease. N Engl J Med 379:958–966CrossRefGoogle Scholar
  47. Shimoda M, Khokha R (2017) Metalloproteinases in extracellular vesicles. Biochim Biophys Acta 1864:1989–2000CrossRefGoogle Scholar
  48. Sun Y, Shi H, Yin S, Ji C, Zhang X, Zhang B (2018) Human mesenchymal stem cell derived exosomes alleviate type 2 diabetes mellitus through reversing peripheral insulin resistance and relieving beta-cell destruction. ACS Nano 12:7613–7628CrossRefGoogle Scholar
  49. Sung BH, Ketova T, Hoshino D, Zijlstra A, Weaver AM (2015) Directional cell movement through tissues is controlled by exosome secretion. Nat Commun 6:7164CrossRefGoogle Scholar
  50. Svensson KJ, Christianson HC, Wittrup A, Bourseau-Guilmain E, Lindqvist E, Svensson LM (2013) Exosome uptake depends on ERK1/2-heat shock protein 27 signaling and lipid Raft-mediated endocytosis negatively regulated by caveolin-1. J Biol Chem 288:17713–17724CrossRefGoogle Scholar
  51. Takahashi A, Okada R, Nagao K, Kawamata Y, Hanyu A, Yoshimoto S (2017) Exosomes maintain cellular homeostasis by excreting harmful DNA from cells. Nat Commun 8:15287CrossRefGoogle Scholar
  52. Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R et al (2018) 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 7:1535750CrossRefGoogle Scholar
  53. Torralba D, Baixauli F, Villarroya-Beltri C, Fernandez-Delgado I, Latorre-Pellicer A, Acin-Perez R (2018) Priming of dendritic cells by DNA-containing extracellular vesicles from activated T cells through antigen-driven contacts. Nat Commun 9:2658CrossRefGoogle Scholar
  54. Turchinovich A, Drapkina O, Tonevitsky A (2019) Transcriptome of extracellular vesicles: state-of-the-art. Front Immunol 10:202CrossRefGoogle Scholar
  55. Vagner T, Spinelli C (2018) Large extracellular vesicles carry most of the tumour DNA circulating in prostate cancer patient plasma 7:1505403Google Scholar
  56. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659CrossRefGoogle Scholar
  57. van Balkom BW, Pisitkun T, Verhaar MC, Knepper MA (2011) Exosomes and the kidney: prospects for diagnosis and therapy of renal diseases. Kidney Int 80:1138–1145CrossRefGoogle Scholar
  58. Wang Q, Liang Y, Qiao Y, Zhao X, Yang Y, Yang S (2018) Expression of soluble epoxide hydrolase in renal tubular epithelial cells regulates macrophage infiltration and polarization in IgA nephropathy. Am J Physiol Renal Physiol 315:F915–F926CrossRefGoogle Scholar
  59. Xu J, Camfield R, Gorski SM (2018) The interplay between exosomes and autophagy—partners in crime. J Cell Sci 131CrossRefGoogle Scholar
  60. Yamamoto CM, Murakami T, Oakes ML, Mitsuhashi M, Kelly C, Henry RR et al (2018) Uromodulin mRNA from urinary extracellular vesicles correlate to kidney function decline in type 2 diabetes mellitus. Am J Nephrol 47:283–291CrossRefGoogle Scholar
  61. Ying W, Riopel M, Bandyopadhyay G, Dong Y, Birmingham A, Seo JB (2017) Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell 171:372–384CrossRefGoogle Scholar
  62. Zhang W, Zhou X, Yao Q, Liu Y, Zhang H, Dong Z (2017) HIF-1-mediated production of exosomes during hypoxia is protective in renal tubular cells. Am J Physiol Renal Physiol 313:F906–F913CrossRefGoogle Scholar
  63. Zhou Y, Xiong M, Fang L, Jiang L, Wen P, Dai C et al (2013) miR-21-containing microvesicles from injured tubular epithelial cells promote tubular phenotype transition by targeting PTEN protein. Am J Pathol 183:1183–1196CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Institute of Nephrology, Zhong Da HospitalSoutheast University School of MedicineNanjingChina

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