Highlights
- •Exosomes are involved in the pathophysiological processes associated with diabetic nephropathy.
- •Exosomes play an important role on the crosstalk between the kidney cells.
- •Exosomes potentially provide novel non-invasive biomarkers for diabetic nephropathy, especially urinary exosomes.
- •Currently, exosomes derived from stem cells have shown great therapeutic potential in diabetic nephropathy.
Abstract
Abbreviations:
EVs (extracellular vesicles), DN (diabetic nephropathy), SGLT2 (sodium-glucose co-transporter 2), GLP-1 (glucagon-like peptide-1), MVBs (multivesicular bodies), ESRD (end-stage renal disease), GBM (glomerular basement membrane), GECs (glomerular endothelial cells), GMCs (glomerular mesangial cells), EMT (epithelial-mesenchymal transition), PTECs (proximal tubular epithelial cells), NF-κB (nuclear factor κB), TGF-β (transforming growth factor-β), VEGF (vascular endothelial growth factor), ECM (extracellular matrix), mTOR (mammalian target of rapamycin), AMPK (adenosine monophosphate- activated protein kinase), MSCs (mesenchymal stem cells), ADSCs (adipose-derived stem cells), IR (insulin resistance), hUSCs (human urine-derived stem cells), PPARγ (peroxisome proliferator-activated receptor γ), ATM (adipose tissue macrophages), GLUT4 (glucose transporter 4)Keywords
1. Introduction
American Diabetes Association. 11. Microvascular complications and foot care: standards of medical care in diabetes-2020. Diabetes Care. 2020;43:S135-s51. https://doi.org/10.2337/dc20-S011.
2. The biogenesis of exosomes
- Kalluri R.
- LeBleu V.S.
- Kalluri R.
- LeBleu V.S.
Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12:19–30; sup pp 1–13. https://doi.org/10.1038/ncb2000.
- Kalluri R.
- LeBleu V.S.

- Kalluri R.
- LeBleu V.S.
- Ludwig N.
- Whiteside T.L.
- Reichert T.E.
Lötvall J, Hill AF, Hochberg F, Buzás EI, Di Vizio D, Gardiner C, et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles. 2014;3:26913. https://doi.org/10.3402/jev.v3.26913.
3. Exosomes in DN pathogenesis
- Chen S.J.
- Lv L.L.
- Liu B.C.
- Tang R.N.
3.1 Exosomes and intercellular communication
- Yang B.
- Chen Y.
- Shi J.

Anil Kumar P, Welsh GI, Saleem MA, Menon RK. Molecular and cellular events mediating glomerular podocyte dysfunction and depletion in diabetes mellitus. Front Endocrinol (Lausanne). 2014;5:151. https://doi.org/10.3389/fendo.2014.00151.
- Chen S.J.
- Lv L.L.
- Liu B.C.
- Tang R.N.
3.2 Exosomes and inflammation
3.3 Exosomes and autophagy
- Ebrahim N.
- Ahmed I.A.
- Hussien N.I.
- Dessouky A.A.
- Farid A.S.
- Elshazly A.M.
- et al.
3.4 Exosomes and insulin resistance
Ying W, Riopel M, Bandyopadhyay G, Dong Y, Birmingham A, Seo JB, et al. Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell. 2017;171:372–84.e12. https://doi.org/10.1016/j.cell.2017.08.035.
Ying W, Riopel M, Bandyopadhyay G, Dong Y, Birmingham A, Seo JB, et al. Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell. 2017;171:372–84.e12. https://doi.org/10.1016/j.cell.2017.08.035.
4. Exosomes as potential biomarkers of DN
- Barutta F.
- Tricarico M.
- Corbelli A.
- Annaratone L.
- Pinach S.
- Grimaldi S.
- et al.
- Delić D.
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- Singh R.S.
- Kumari M.
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- Upadhyay A.
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- et al.
miRNAs | Level | Type of DN | Species | Reference |
---|---|---|---|---|
miR-145-5p | ↑ | Type 1 DN | Human, mice, cell | [ [81] ]
Urinary exosomal microRNAs in incipient diabetic nephropathy. PLoS One. 2013; 8e73798https://doi.org/10.1371/journal.pone.0073798 |
miR-320c | ↑ | Type 2 DN | Human | [ [82] ]
Urinary exosomal miRNA signature in type II diabetic nephropathy patients. PLoS One. 2016; 11e0150154https://doi.org/10.1371/journal.pone.0150154 |
miR-133b-3p, miR-342-3p, miR-30a-5p | ↑ | Type 2 DN | Human | [ [83] ] |
miR-362-3p, miR-877-3p, miR-150-5p | ↑ | Type 2 DN | Human | [ [84] ] |
miR-15a-5p | ↓ | Type 2 DN | Human | [ [84] ] |
miR-21-5p, let-7e-5p, miR-23b-3p | ↑ | Type 2 DN | Human | [ [85] ] |
miR-30b-5p, miR-125b-5p | ↓ | Type 2 DN | Human | [ [85] ] |
miR-188-5p, miR-150-3p | ↑ | – | Human | [ [86] ]
Urinary exosomal microRNA signatures in nephrotic, biopsy-proven diabetic nephropathy. J Clin Med. 2020; 9https://doi.org/10.3390/jcm9041220 |
miR-153-3p | ↓ | – | Human | [ [86] ]
Urinary exosomal microRNA signatures in nephrotic, biopsy-proven diabetic nephropathy. J Clin Med. 2020; 9https://doi.org/10.3390/jcm9041220 |
miR-15b-5p | ↑ | Type 2 DN | Human, cell, rat | [ [87] ] |
miR-451-5p | ↑ | Type 1 DN | Rat | [ [88] ]
Urinary exosomal microRNA-451-5p is a potential early biomarker of diabetic nephropathy in rats. PLoS One. 2016; 11e0154055https://doi.org/10.1371/journal.pone.0154055 |
- Kalani A.
- Mohan A.
- Godbole M.M.
- Bhatia E.
- Gupta A.
- Sharma R.K.
- et al.
Zubiri I, Posada-Ayala M, Benito-Martin A, Maroto AS, Martin-Lorenzo M, Cannata-Ortiz P, et al. Kidney tissue proteomics reveals regucalcin downregulation in response to diabetic nephropathy with reflection in urinary exosomes. Transl Res. 2015;166:474–84.e4. https://doi.org/10.1016/j.trsl.2015.05.007.
- Sakurai A.
- Ono H.
- Ochi A.
- Matsuura M.
- Yoshimoto S.
- Kishi S.
- et al.
5. Therapeutic perspectives of exosomes in DN
Origin of exosomes | Cargo | Mechanism | Organism | Reference |
---|---|---|---|---|
ADSCs | miR-486-5p | Facilitating autophagy flux through Smad1/mTOR signaling pathway | Mice | [ [69] ]
Mesenchymal stem cell-derived exosomes ameliorated diabetic nephropathy by autophagy induction through the mTOR signaling pathway. Cells. 2018; 7https://doi.org/10.3390/cells7120226 |
ADSCs | miR-215-5p | Relieving EMT of podocyte through downregulating ZEB2 | Cells | [ [97] ] |
hUSCs | – | Inhibiting podocyte apoptosis by suppressing caspase-3 overexpression and promoting vascular regeneration and cell survival | Rats, cells | [ [98] ] |
hUSCs | miR-16-5p | Alleviating podocyte injury via suppressing VEGFA expression | Rats, cells | [ [99] ] |
MSCs | – | Suppressing proinflammatory cytokine, epithelial damage in proximal tubules, tubular EMT, apoptosis and degeneration of TECs | Mice | [ [102] ]
Exosomal microRNA-16-5p from human urine-derived stem cells ameliorates diabetic nephropathy through protection of podocyte. J Cell Mol Med. 2019; https://doi.org/10.1111/jcmm.14558 |
MSCs | – | Activating autophagy through suppressing mTOR signaling pathway | Rats | [ [68] ] |
BMSCs | miR-let-7a-3p | Inhibiting oxidative stress and represses renal cell apoptosis via downregulating USP22 | Rats | [ [103] ] |
M2 macrophage | miR-25-3p | Protecting podocytes injury through activating autophagy of the cells by suppressing DUSP1 expression | Cells | [ [104] ]
Mesenchymal stem cells-potential applications in kidney diseases. Int J Mol Sci. 2019; 20https://doi.org/10.3390/ijms20102462 |
Muscle | miR-23a-3p/27a-3p | Attenuating renal fibrosis through muscle-kidney crosstalk | Mice | [ [105] ] |
- Duan Y.R.
- Chen B.P.
- Chen F.
- Yang S.X.
- Zhu C.Y.
- Ma Y.L.
- et al.
- Bochon B.
- Kozubska M.
- Surygała G.
- Witkowska A.
- Kuźniewicz R.
- Grzeszczak W.
- et al.
- Ebrahim N.
- Ahmed I.A.
- Hussien N.I.
- Dessouky A.A.
- Farid A.S.
- Elshazly A.M.
- et al.
- Mao R.
- Shen J.
- Hu X.
6. Summary
Funding
CRediT authorship contribution statement
Declaration of competing interest
Acknowledgements
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