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
Exosomes, a major type of extracellular vesicles (EVs), are nanoscale vesicles excreted by almost all cell types via invagination of the endosomal membrane pathway. Exosomes play a crucial role in the mediation of intercellular communication both in health and disease, which can be ascribed to their capacity to be transported to neighboring or distant cells, thus regulating the biological function of recipient cells through cargos such as DNA, mRNA, proteins and microRNA. Diabetic nephropathy (DN) is a serious microvascular complication associated with diabetes mellitus as well as a significant cause of end-stage renal disease worldwide, which has resulted in a substantial economic burden on individuals and society. However, despite extensive efforts, therapeutic approaches that prevent the progression of DN do not exist, which implies new approaches are required. An increasing number of studies suggest that exosomes are involved in the pathophysiological processes associated with DN, which may potentially provide novel biomarkers and therapeutic targets for DN. Hence, this review summarizes recent advances involving exosome mechanisms in DN and their potential as biomarkers and therapeutic targets.
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
DN, a serious microvascular complication of diabetes, is a chronic, progressive disorder and a common cause of end-stage renal disease (ESRD), which has high morbidity and mortality [
[1]
,[2]
]. Approximately 30% of people with type 1 diabetes and 40% of people with type 2 diabetes will develop DN [[3]
]. The clinical diagnosis of DN chiefly depends on the presence of proteinuria, reduction of estimated glomerular filtration rate (eGFR), and along with a long history of diabetes [[4]
,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.
[5]
], which will be enhanced by the coexistence of diabetic retinopathy and the exclusion of other chronic kidney diseases [[6]
]. In particular, microalbuminuria has been recognized as a conventional predictor for renal diseases including DN; however, in reality, renal function is damaged or even deteriorated before the microalbuminuria is detected [[7]
]. Renal biopsy, the gold standard for the diagnosis of kidney disease, is also accompanied with the disadvantages of an invasive procedure and the inability to track disease progression. Therefore, more specific and sensitive biomarkers for the diagnosis of DN are required. To date, DN therapeutic strategies rely on comprehensive control, including amelioration of albuminuria, hyperglycemia, and hypertension, administration of renin–angiotensin–aldosterone system (RAAS) inhibitors, and, new renoprotective drugs [[6]
,[8]
], such as sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1). However, there remains a high incidence of ESRD even with these treatments. All in all, it is urgent to explore new approaches to diagnose and treat DN. An increasing number of studies suggest that exosomes are involved in DN [[9]
,[10]
]. In our review, we summarize the potential roles of exosomes on the pathogenesis, biomarkers and therapies in DN.2. The biogenesis of exosomes
Exosomes were first discovered early in 1981 by Trams et al. using a transmission electron microscope; however, only minor structural features (e.g., vesicle-like) were reported at this stage [
[11]
]. Exosomes were first defined more clearly six years later by Johnstone et al. during a study of the processes associated with reticulocyte maturation in sheep [[12]
]. However, they were considered little more than “junk” excreted by cells and attracted minimal attention from researchers at the time. Currently, exosomes are widely recognized as extracellular vesicles (EVs) surrounded by lipid bilayers with diameters ranging between ~40 and 160 nm (average, ~100 nm), which are released by a variety of cell types [[13]
]. Exosomes usually originate from the endosomal system via mechanisms including internal budding and invagination of the plasma membrane, and are often accompanied with the formation of multivesicular bodies (MVBs) [- Kalluri R.
- LeBleu V.S.
The biology, function, and biomedical applications of exosomes.
Science. 2020; 367https://doi.org/10.1126/science.aau6977
[13]
] (Fig. 1). Initially, endosomes are generated by internal budding of the plasma membrane, which leads to the formation of early-sorting endosomes (ESEs) and late-sorting endosomes (LSEs). Next, after sequential or double inward invagination of the plasma membrane, MVBs are formed; this process enables MVBs containing exosome precursors known as intraluminal vesicles (ILVs). As a result, exosomes are excreted into the extracellular space following fusion of the MVBs outer membrane with the cellular plasma membrane and exocytosis [- Kalluri R.
- LeBleu V.S.
The biology, function, and biomedical applications of exosomes.
Science. 2020; 367https://doi.org/10.1126/science.aau6977
[14]
,[15]
]. Regulation of exosome formation follows a mechanism known as endosomal sorting complexes required for transport [[16]
]. Ral GTPases [[17]
], Rab GTPases [[18]
] and exosome markers (e.g., CD9, CD81, CD63, TSG101 and flotillin) also participate in exosome biogenesis [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.
[13]
].- Kalluri R.
- LeBleu V.S.
The biology, function, and biomedical applications of exosomes.
Science. 2020; 367https://doi.org/10.1126/science.aau6977
Fig. 1The formation of exosomes. Exosomes originate from the endosomal system, including invagination of the plasma membrane, early-sorting endosomes (ESEs), late-sorting endosomes (LSEs), and ultimately multivesicular bodies (MVBs). Subsequently, exosomes can be released to the extracellular space by fusion of MVBs with the cellular plasma membrane.
Initially, exosomes were only considered to be responsible for the removal of unwanted cellular material such as proteins and lipids. However, the development of research in this field over recent decades has shown that exosomes are involved in the regulation of intercellular communication [
19
, 20
, 21
]. Depending on the cell from which they originate, exosomes carry complex molecular cargos such as proteins, lipids, RNA, non-coding RNA, microRNA and small RNA, which are carefully controlled by the parent cell allowing information relating to specific cellular functions to pass from parent cell to acceptor cell [[22]
]. The surface molecules of exosomes vary considerably, which results from the diverse range of cells they originate from, and endow them with high selectivity towards specific receptor cells. The general exosome uptake mechanism by acceptor cells follows three main pathways: membrane fusion with acceptor cells, internalization triggered by targeting to acceptor cells with specific molecules on the surface of exosomes, and endocytosis [[23]
].The varying sizes, content, function, and cellular origin of exosomes contributes to their heterogeneity [
[13]
]. Although our understanding of exosome biogenesis, release, uptake, and function are not completely clear [- Kalluri R.
- LeBleu V.S.
The biology, function, and biomedical applications of exosomes.
Science. 2020; 367https://doi.org/10.1126/science.aau6977
23
, 24
, 25
, 26
], exosome-focused research remains topical and extensive, which can be ascribed to the potential capability of exosomes in the diagnosis and treatment of various diseases, including neurodegeneration [[27]
], metabolic disorders [[28]
], cardiovascular dysfunction [[29]
], and cancer [[30]
]. Furthermore, exosomes have been widely used in targeted drug delivery through surface engineering techniques, which provides effective strategies for diagnosis and treatment, especially in cancer [[31]
].Exosomes are released by most cell types into the extracellular space and can be detected in various body fluids and tissues such as urine, blood, saliva and adipose tissue [
[31]
]. The foundation for research into exosome function is based on the isolation and purification of exosomes. Several advanced techniques have been reported for the isolation and purification of exosomes, including ultracentrifugation, density gradient ultracentrifugation, immunoaffinity capture, size exclusion chromatography, and polymer precipitation [[32]
]. Each technique has unique advantages and disadvantages. For example, ultracentrifugation is the most widely used and is considered the “gold standard” isolation method for exosome extraction, with the capacity to simultaneously extract large sample volumes. However, this method has disadvantages such as lengthy operational times and extensive instrument requirements. Furthermore, the exclusion of microvesicles is common using this method, which leads to impure isolated exosomes [[33]
]. Immunoaffinity capture techniques rely on specific binding between markers and antibodies and are suitable for the isolation of exosomes from specific sources; shortcomings include expensive antibodies and low productivity [[32]
]. As such, due to the heterogeneity of exosomes, thus far no exosome isolation method has been consistently recommended by researchers [[34]
]. The choice of which technique to use is driven by a multitude of factors including starting matrix (cell culture media versus biofluid), starting volume and downstream analyses and research question. Additionally, after exosome isolation, exosome characterization is required using a combination of transmission electron microscopy and protein markers, such as CD63, CD9 and CD81 [- Ludwig N.
- Whiteside T.L.
- Reichert T.E.
Challenges in exosome isolation and analysis in health and disease.
Int J Mol Sci. 2019; 20https://doi.org/10.3390/ijms20194684
[35]
]. In summary, the extraction of exosomes remains a challenge, which requires further improvement by researchers.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
The main pathological hallmarks of renal injury in diabetes include functional (such as proteinuria and glomerular filtration rate decline) and structural (extracellular matrix accumulation, glomerular basement membrane thickening, podocyte injury and depletion, tubulointerstitial inflammation, and fibrosis) changes [
[3]
]. Unfortunately, knowledge surrounding the multiple and complicated pathological mechanisms remains limited. Long-term hyperglycemia is the main contributory factor in the development of DN; however, strict glycemic management may not always slow or prevent the progression of DN [[8]
]. Other factors underlying the mechanisms of DN, including inflammation, fibrosis, mitochondrial dysfunction, impaired autophagy and oxidative stress, also play a pivotal role in the progression of DN [[8]
]. In addition, emerging evidence implicates abnormal crosstalk between renal cells in the pathogenesis of DN [[36]
].- Chen S.J.
- Lv L.L.
- Liu B.C.
- Tang R.N.
Crosstalk between tubular epithelial cells and glomerular endothelial cells in diabetic kidney disease.
Cell Prolif. 2020; 53e12763https://doi.org/10.1111/cpr.12763
Nevertheless, despite the currently available therapies the residual risk of DN progression remains high [
[6]
], indicating additional potential molecular mechanisms contributing to DN progression that require further investigation. The stimulation of renal cells with high concentrations of glucose alters the composition and communication, which further modifies and injures intact cells, indicating that exosomes may participate in the pathophysiological mechanisms of diabetic kidney disease [[37]
].3.1 Exosomes and intercellular communication
Exosomes are cell-derived, membrane-bound delivery vesicles, which play a crucial role in the regulation of cellular biofunction by mediating cell-to-cell communication via the transfer of cargos including microRNA, mRNA and proteins [
[38]
]. Evidence exists that these cargos are carried into neighboring or distant cells to mediate the biofunction of recipient cells [- Yang B.
- Chen Y.
- Shi J.
Exosome biochemistry and advanced nanotechnology for next-generation theranostic platforms.
Adv Mater. 2019; 31e1802896https://doi.org/10.1002/adma.201802896
[39]
]. Recent studies also indicate that exosomes transfer their cargos between the kidney cells [[40]
] (Fig. 2).
Fig. 2The mechanisms of exosomes in DN through cell-cell crosstalk. Previous studies implied that exosomes involve in cell to cell crosstalk in kidney in the context of high glucose, such as glomerular endothelial cells (GECs) to glomerular mesangial cells (GMCs),GECs to podocytes, GMCs to podocytes, tubular epithelial cells (TECs) to fibroblasts, TECs to macrophages, TECs to GECs and podocytes to TECs, which contribute to kidney injury, including epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) overproduction, cell apoptosis, inflammation, and eventually renal fibrosis.
An important component of the glomerular filtration barrier, glomerular endothelial cells (GECs) have been reported to participate in the pathogenesis of DN through crosstalk with other glomerular cells, such as glomerular mesangial cells (GMCs) and podocytes [
[41]
]. However, the delicate molecular mechanisms underlying these interactions are poorly understood. Recently, researchers have found exosomes secreted from high glucose-induced GECs delivered circRNA or mRNA to GMCs, which leads to the activation, proliferation and extracellular matrix (ECM) protein overproduction of GMCs and promotes renal fibrosis [[42]
,[43]
]. Similarly, under high glucose conditions, GECs-derived exosomes, enriched in transforming growth factor-β (TGF-β) mRNA, lead to the epithelial-mesenchymal transition (EMT) and dysfunction of podocyte via Wnt/β-catenin signaling pathway [[44]
]. Furthermore, due to a lack of proliferative capacity when confronted with injury, podocyte apoptosis and depletion is a hallmark of DN [[45]
]. A previous study demonstrated that HG-activated GMCs interact with podocytes through secreting exosomes, thus resulting in podocyte apoptosis, and that TGF-β/PI3K-AKT signaling maybe implicated in this process [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.
[46]
].In addition, tubular epithelial cells (TECs) and their interaction with fibroblasts contribute to interstitial fibrosis in kidney diseases, such as DN [
47
, 48
, 49
]. Wen et al. [[9]
] found that exosomes extracted from HG-treated renal tubular cells have the capacity to stimulate the transformation of fibroblasts into myofibroblasts in renal, suggesting that exosomes may involve in the communication between the two cell types. Likewise, dedifferentiation of renal proximal tubular epithelial cells (PTECs) also plays a crucial role in interstitial fibrosis. After treatment with high glucose, podocyte-derived EVs induced dedifferentiation of PTECs through transporting miR-221-3p via the Wnt/β-catenin signaling pathway [[10]
]. Moreover, evidence exists that implies TECs exosomal miR-19b-3p mediates the crosstalk between TECs and macrophages as well as contributes to the activation of M1 macrophages by targeting nuclear factor κB (NF-κB)/SOCS-1, which accounts for tubulointerstitial inflammation [[50]
]. TECs also secrete EVs, which stimulates an inflammatory response through NF-κB and induces GECs injury [[36]
].- Chen S.J.
- Lv L.L.
- Liu B.C.
- Tang R.N.
Crosstalk between tubular epithelial cells and glomerular endothelial cells in diabetic kidney disease.
Cell Prolif. 2020; 53e12763https://doi.org/10.1111/cpr.12763
3.2 Exosomes and inflammation
Inflammatory responses are commonly characterized by the release of proinflammatory cytokines, chemokines, adhesion molecules and inflammatory signal transduction [
[51]
]. Initially, DN was considered a non-inflammatory disease; however, mounting evidence indicates that chronic inflammatory stimulation contributes to the initiation and ongoing injury caused by DN [51
, 52
, 53
]. Specifically, macrophages, can be classified as: M1 macrophages (mainly secrete pro-inflammatory mediators) and M2 macrophages (that possess anti-inflammatory functions), and are types of immune inflammatory cells closely associated with the regulation of inflammatory processes [[54]
]. Macrophages migrate and infiltrate the kidney tissue during incipient DN [[55]
], which promotes the release of TGF-β, reactive oxygen species (ROS), vascular endothelial growth factor (VEGF) and cytokines such as IL-1 and TNF [[56]
], subsequently accelerating the progression of DN; however, the mechanisms require clarification [[57]
]. In contrast, activation of TGF-β1 and IL-1β drives macrophages activation and accumulation, thus a negative feedback loop occurs. Recent studies have also reported that EVs may also mediate these mechanisms. After treatment with high glucose, mouse macrophage-derived EVs miR-21-5p, elevated the levels of inflammasome NLRP3 and IL-1β, thereby causing podocyte pyroptosis through targeting A20, both in DN model mice and in vitro [[58]
]. NF-κB, a ubiquitous transcription factor, is one major component of inflammatory reactions [[53]
]. Research has indicated that in the context of high glucose concentrations, macrophage-related exosomes induce macrophages activation, proliferation, and the secretion of inflammatory factors and pro-fibrotic cytokines, including IL-1β, TNF-α and TGF-β1 via regulating the NF-κB p65 pathway, resulting in the kidney injury and inflammation [[59]
]. Another study conducted by the same team also reported that these exosomes can be ingested and internalized by mesangial cell and trigger mesangial cell activation, extracellular matrix (ECM) excessive deposition, and inflammatory factors release, such as IL-1β and TNF-α through TGF-β1/Smad3 signaling, indicating such alterations contribute to mesangial expansion and renal fibrosis [[60]
]. As described above [[50]
], in mice models of acute and chronic kidney injury, exosomes derived from mouse TECs also drive activating macrophage by targeting NF-κB, thus resulting in tubulointerstitial inflammation.3.3 Exosomes and autophagy
Autophagy is characterized as a cellular self-protection mechanism involving the degradation of intracellular materials such as organelles and proteins, which depends on the presence of proteolytic enzymes in lysosomes, and recycled as energy sources [
[8]
,[61]
]. As such, autophagy plays a significant role in normal cell function, survival and homeostasis [[62]
]. Autophagic activity is precisely regulated by signaling pathways that mainly include one negative regulator- mammalian target of rapamycin (mTOR), two positive regulators- adenosine monophosphate-activated protein kinase (AMPK) and sirtuins [[63]
]. Especially, under energy depletion (e.g., starvation), increased autophagy is crucial to meet cell energy demands [[8]
]. In addition, the process of autophagy is initiated from the formation of the phagophore, then requires the formation of autophagosome, which has a double membrane framework, and autophagosome-lysosome fusion, thus resulting in degradation of the materials enclosed in the autophagosome [[64]
].The essential roles of autophagy in the pathogenesis of DN have been previously reported [
[65]
]. For instance, diabetic model mice developed podocyte-specific, autophagy-deficient aggravated podocyte damage and proteinuria after receiving a high-fat diet [[65]
]. In streptozotocin (STZ)-induced mice, increased autophagy was observed in PTECs which could offset mitochondrial dysfunction and fibrosis [[66]
]. Of note, autophagic activity showed different outcomes in type 1 and type 2 diabetes [[66]
,[67]
]; that is, autophagic kidney activity was enhanced in type 1 diabetes (include STZ-induced mice and Akita mice), which exerted a protective effect, whereas, autophagic induction was suppressed in db/db mice and high-fat diet-induced rats' models (both are type 2 diabetes), which insults the kidney. Similarly, short-term exposure of podocytes in a high glucose environment may trigger autophagy and ameliorate the kidney lesions; conversely, prolonged hyperglycemia may inhibit autophagy in podocytes, thus accounting for the progression of DN [[63]
].As the key regulator of autophagy, mTORC1 activated by high glucose contributes to the kidney damage through suppressing autophagy [
[68]
]. However, exosomes secreted from mesenchymal stem cells (MSCs) induced autophagy by suppressing the mTOR pathway, thus attenuating renal injury in rats' models of diabetes [[69]
]. A similar effect was observed for exosomes extracted from adipose-derived stem cells (ADSCs) [- Ebrahim N.
- Ahmed I.A.
- Hussien N.I.
- Dessouky A.A.
- Farid A.S.
- Elshazly A.M.
- et al.
Mesenchymal stem cell-derived exosomes ameliorated diabetic nephropathy by autophagy induction through the mTOR signaling pathway.
Cells. 2018; 7https://doi.org/10.3390/cells7120226
[70]
]. Previous studies have also indicated that autophagy deficiency in adipose tissue may induce increased exosome production, which promotes the development of obesity and insulin resistance (IR) [[71]
].3.4 Exosomes and insulin resistance
A typical feature and an independent risk factor of type 2 diabetes, IR is characterized by a decreased glucose uptake and utilization efficiency accompanied with an increase in insulin concentration. Generally, IR exists long before type 2 diabetes is diagnosed. Increased insulin resistance can also be observed in type 1 diabetes, which is classically defined as an absolute insulin deficiency, when microalbuminuria is present. Therefore, it follows that the severity of IR strongly correlates with DN processes [
[72]
]. As well as the well-known insulin-targeted organs (e.g., liver, white adipose tissue, and skeletal muscle), almost all kidney cells including GMCs, podocytes, and tubular cells, respond to insulin stimulation. In the context of IR triggered by high glucose or obesity, these renal cells are affected, which results in reduced podocyte viability and tubular function [[73]
].In addition, exosomes are believed to participate in the mediation of insulin sensitivity associated with obesity or diabetes [
[74]
,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.
[75]
]. Protein kinase B (also known as Akt) and peroxisome proliferator-activated receptor γ (PPARγ) are potent insulin signaling regulators. For instance, in 2017, a study by Ying W et al. focusing on lean and obese mice showed that exosomes obtained from adipose tissue macrophages (ATM) can regulate insulin sensitivity and glucose tolerance through insulin pathway. The lean mice exhibited IR and glucose intolerance after administration of obese ATM-exosomes via alterations to the insulin signaling pathway, including decreased phosphorylation of Akt, suppressed expression of PPARγ and its target gene, glucose transporter 4 (GLUT4). Conversely, the obese mice treated with ATM-exosomes from lean mice manifested an improvement in IR and an alleviation of glucose tolerance [[74]
]. There is also evidence that suggests elevation of podocyte-derived EVs containing nephrin and podocalyxin in the urine may be considered early markers of kidney disease associated with IR [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.
[76]
]. Overall, there remains barely publications with regard to the mechanism of interaction between exosomes with IR in DN.4. Exosomes as potential biomarkers of DN
The employment of exosomes as liquid biopsies is especially promising due to their ubiquitous presence in biological fluids and potential for multicomponent analyses [
[77]
]. Lv et al. [[78]
] found exosomes was stable at 4 °C 24 h for shipping before stored at −80 °C and was stable in urine when stored at −80 °C for 12 months. Exosomal miRNA was detectable despite 5 repeat freeze-thaw cycles. An increasing body of literature is emerging that addresses urinary exosomes as potential non-invasive biomarkers for the diagnosis of DN.microRNAs (miRNAs) packaged in exosomes are considered a form of cell-to-cell communication and have received increasing attention over the past decade. miRNAs are small, stable, non-coding, single-stranded RNAs which negatively regulate gene and protein expression at a post-transcriptional level [
[79]
]. Cheng et al. [[80]
] reported that miRNAs were found to be significantly enriched and intact in urine-derived exosomes compared with cell-free urine. To date, an increasing number of differentially-expressed miRNAs have been found in exosomes extracted from urine obtained from animals' models as well as patients with DN (Table 1). Previous studies have demonstrated that in both type 1 DN(defined as persistent microalbuminuria) and type 2 diabetic patients with DN (eGFR<60 ml/min/1.73m2), the urinary exosomal miRNA content was altered and that urinary exosomal miR-145-5p [[81]
] or miR-320c [- Barutta F.
- Tricarico M.
- Corbelli A.
- Annaratone L.
- Pinach S.
- Grimaldi S.
- et al.
Urinary exosomal microRNAs in incipient diabetic nephropathy.
PLoS One. 2013; 8e73798https://doi.org/10.1371/journal.pone.0073798
[82]
] levels were higher, thus indicating their potential as novel biomarkers in the diagnosis of DN. Eissa et al. [- Delić D.
- Eisele C.
- Schmid R.
- Baum P.
- Wiech F.
- Gerl M.
- et al.
Urinary exosomal miRNA signature in type II diabetic nephropathy patients.
PLoS One. 2016; 11e0150154https://doi.org/10.1371/journal.pone.0150154
[83]
] observed significantly increased levels of urinary exosomal miR-133b-3p, miR-342-3p, and miR-30a-5p in patients of type 2 diabetes with micro- or macro- albuminuria. Meanwhile, these miRNAs were also altered in diabetic patients with normoalbuminuria, indicating their potential as early biomarkers in diagnosis of DN. Another study found three miRNAs isolated from urinary exosomes (miR-362-3p, miR-877-3p, and miR-150-5p) were increased and one (miR-15a-5p) was decreased in diabetic patients with macroalbuminuria compared to that of patients with type 2 diabetes. Furthermore, these miRNAs might mediate DN processes via the p53, mTOR, and AMPK pathways, indicating their potential capability in the early diagnosis of DN [[84]
]. In a recent study, when compared to patients with type 2 diabetes, a notable upregulation in miR-21-5p, let-7e-5p and miR-23b-3p was observed in urinary samples from patients with type 2 DN (eGFR <60 ml/min/1.73m2); in contrast, miR-30b-5p and miR-125b-5p expression was significantly decreased in type 2 DN [[85]
]. Similarly, two of the most prevalent upregulation miRNAs, namely miR-188-5p and miR-150-3p, were found in the urinary exosomes of DN patients who underwent a renal biopsy, in contrast, the miR-153-3p levels were downregulated [[86]
]. Last year, Tsai et al. [- Lee W.C.
- Li L.C.
- Ng H.Y.
- Lin P.T.
- Chiou T.T.
- Kuo W.H.
- et al.
Urinary exosomal microRNA signatures in nephrotic, biopsy-proven diabetic nephropathy.
J Clin Med. 2020; 9https://doi.org/10.3390/jcm9041220
[87]
] also investigated that miR-15b-5p harvested from EVs in urine was higher in type 2 diabetic patients; moreover, the levels were correlated with the urinary albumin-to-creatinine ratio, enabling it to be used as a novel indicator to forecast the severity of kidney damage in DN. Significantly, another study reported that levels of miR-451-5p in urinary exosomes were increased in diabetic rats while they were decreased in the kidneys of diabetic rats, implying this change is involved in kidney damage; moreover, the detection of increased miR-451-5p in urinary exosomes may offer a sensitive biomarker for incipient diabetic kidney disease instead of monitoring albumin excretion levels [[88]
]. In addition to the analysis of urine, reports relating to serum exosome analysis also exist. In 2019, Kim and his team reported that in comparison to healthy controls, circulating miRNAs (e.g. miR-1246, miR-642a-3p, let-7c-5p, miR-1255b-5p, miR-5010-5p, miR-150-3p, let-7i-3p) were significantly up-regulated in DN patients with micro- or macro-albuminuria compared to patients without DN, suggesting the potential of these miRNAs in the diagnosis and treatment of DN [- Mohan A.
- Singh R.S.
- Kumari M.
- Garg D.
- Upadhyay A.
- Ecelbarger C.M.
- et al.
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
[89]
].Table 1miRNAs in urinary exosomes as potential biomarkers of DN.
| 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 |
Abbreviation: DN: Diabetic nephropathy; ↑: Increased; ↓: Decreased.
Proteomic studies of urinary exosomes have suggested that proteins carried within exosomes may also be candidate biomarkers for DN. For instance, the levels of Xaa-Pro dipeptidase (or Prolidase, PEPD) were found to be substantially increased in the urinary exosomes of diabetic patients, which appeared to correlate with the severity of DN [
[90]
]. similarly, reports concerning Wilm's tumor 1 (WT1) protein indicated that WT1 participated in the homeostasis of mature podocytes, and could be detected in the urinary exosomes of diabetic patients to reflect renal function damage [[91]
,[92]
]. Zubiri et al. [- Kalani A.
- Mohan A.
- Godbole M.M.
- Bhatia E.
- Gupta A.
- Sharma R.K.
- et al.
Wilm’s tumor-1 protein levels in urinary exosomes from diabetic patients with or without proteinuria.
PLoS One. 2013; 8e60177https://doi.org/10.1371/journal.pone.0060177
[93]
] revealed that urinary exosomal regucalcin was downregulated in a rat model of early DN versus healthy individuals, indicating that regucalcin may represent a novel tool to diagnose and monitor the progression of diabetic kidney diseases. Epithelium-specific transcription factor-Elf3 from urinary exosomes was only found in patients with T2DN, reflecting the podocyte injury associated with DN [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.
[94]
]. Against a background of high urinary albumin, another three proteins were found to be expressed to differing levels in urinary exosomes of patients with DN, these were: α-microglobulin/bikunin precursor (increased); histone-lysine N-methyltransferase (observed only in patients with DN); and, voltage-dependent anion-selective channel protein 1(decreased) [- Sakurai A.
- Ono H.
- Ochi A.
- Matsuura M.
- Yoshimoto S.
- Kishi S.
- et al.
Involvement of Elf3 on Smad3 activation-dependent injuries in podocytes and excretion of urinary exosome in diabetic nephropathy.
PLoS One. 2019; 14e0216788https://doi.org/10.1371/journal.pone.0216788
[95]
].Taken together, there is accumulating evidence to support the theory that cargos carried in urinary exosomes, such as miRNA and proteins, can be used as early markers of DN and have the potential to predict disease progression. However, the origin and mechanism concerning these cargos are not fully understood and further in-depth investigations are required to explore and verify the clinical value of these new biomarkers.
5. Therapeutic perspectives of exosomes in DN
Although current remedies have a significant effect on the progression of DN, the incidence of ESRD associated with diabetes remains high and effective tools to halt (or even reverse) the progression of DN are lacking [
[96]
,[97]
]. Therefore, there is a pressing need to explore and recognize emerging, potent renoprotective therapeutic strategies to slow the progression of DN. Recently, several studies have confirmed that exosomes offer potential as therapeutic delivery vehicles for the treatment of DN (Table 2).Table 2Potential therapeutic roles 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] ] |
Abbreviation: ADSCs: adipose-derived stem cells; EMT: epithelial-mesenchymal transition; ZEB2: zinc finger E-box-binding homeobox-2; hUSCs: human urine-derived stem cells; VEGFA: vascular endothelial growth factor A; MSCs: mesenchymal stem cells; TECs: tubular epithelial cells; BMSCs: bone marrow mesenchymal stem cells; USP22: ubiquitin-specific protease 22; DUSP1: dual specificity protein phosphatase1.
Stem cells, which can self-renew and develop into a wide variety of functional cells, have been considered as potential therapeutic agents for DN due to their beneficial effects being mainly exerted through paracrine mechanisms. There is a growing mount of strong evidence that demonstrates exosomes derived from stem cells, which can transport exogenous miRNAs to recipient cells [
[98]
], are efficacious and safe for the treatment of renal diseases in rat and mouse models [[99]
]. One report indicated that exosomal miR-486-5p produced from ADSCs mitigates podocyte damage in db/db mice by facilitating autophagy flux through the Smad1/mTOR signaling pathway [[70]
]. In a follow-up study, the same team also found that miR-215-5p in ADSC exosomes may relieve podocyte EMT when treated with high concentrations of glucose via inhibiting zinc finger E-box-binding homeobox-2, which is the target gene of miR-215-5p [[100]
]. Moreover, human urine-derived stem cells (hUSCs)-extracted exosomes may have the potential to inhibit podocyte apoptosis by suppression of caspase-3 overexpression and promotion of vascular regeneration and cell survival, which resulted in protection from kidney damage in type 1 diabetic rats [[101]
]. A similar study also showed that exosomal miR-16-5p secreted by hUSCs effectively alleviated high glucose-induced podocyte injury via suppression of vascular endothelial growth factor A (VEGFA) expression [[102]
]. MSCs have recently attracted increasing interest as a novel regenerative therapy against kidney injury [- Duan Y.R.
- Chen B.P.
- Chen F.
- Yang S.X.
- Zhu C.Y.
- Ma Y.L.
- et al.
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
[103]
,[104]
]. Nagaishi and his colleagues found that MSCs suppressed proinflammatory cytokines (such as TNF-α) expression, epithelial damage in the proximal tubules, tubular EMT, apoptosis and degeneration of TECs in the kidneys of diabetic mice, which may contribute to the level of exosomes found in the MSCs [- Bochon B.
- Kozubska M.
- Surygała G.
- Witkowska A.
- Kuźniewicz R.
- Grzeszczak W.
- et al.
Mesenchymal stem cells-potential applications in kidney diseases.
Int J Mol Sci. 2019; 20https://doi.org/10.3390/ijms20102462
[105]
]. Another study concluded that exosomes derived from MSCs may activate autophagy through suppression of the mTOR signaling pathway, thus exerting their nephroprotective and antifibrotic effect in rats' models of diabetic nephropathy [[69]
]. A more recent report suggested that bone marrow mesenchymal stem cells (BMSCs)-derived exosomal miR-let-7a-3p inhibited oxidative stress and repressed renal cell apoptosis in the renal tissues of diabetic rats via downregulation of ubiquitin-specific protease 22 [- Ebrahim N.
- Ahmed I.A.
- Hussien N.I.
- Dessouky A.A.
- Farid A.S.
- Elshazly A.M.
- et al.
Mesenchymal stem cell-derived exosomes ameliorated diabetic nephropathy by autophagy induction through the mTOR signaling pathway.
Cells. 2018; 7https://doi.org/10.3390/cells7120226
[106]
].- Mao R.
- Shen J.
- Hu X.
BMSCs-derived exosomal microRNA-let-7a plays a protective role in diabetic nephropathy via inhibition of USP22 expression.
Life Sci. 2020; 118937https://doi.org/10.1016/j.lfs.2020.118937
In addition to exosomes from various stem cells, there are also several reports concerning exosomes secreted from other cell types as potential therapies for DN. Huang et al. suggested that exosomal miR-25-3p derived from M2 macrophages may protect podocytes against high glucose-induced injury via activation of cell autophagy through suppression of dual specificity protein phosphatase 1 expression [
[107]
]. Another report demonstrated that exosomal miRNA-23a-3p/27a-3p shed from muscle is involved in crosstalk between muscle and kidney cells, thus attenuating renal fibrosis in diabetic mice [[108]
]. Taken together, these findings suggest that exosomes secreted from stem cells, M2 macrophages and tissues offer the capacity to suppress the vitro and in vivo progression of DN through various mechanisms, which provides the basis for future applications of exosomes as a novel biological therapeutic approach for the treatment of DN. However, more detailed studies on the protective mechanism of exosomes for DN are required and further basic and clinical trials are required to validate the promising results described above.6. Summary
In conclusion, DN is a global public health problem due to its high incidence and substantial economic burden. Despite decades of effort, effective, targeted therapeutic strategies for DN remain elusive. Nephrologists and endocrinologists are continually searching for new tools to improve their ability to rapidly and accurately diagnose renal disease caused by diabetes via noninvasive methodologies as well as for novel therapeutic approaches via exploration of the molecular mechanisms of DN. As explained in this review, exosomes possess various properties including modulation of cell-to-cell crosstalk, cargo transfer to specific target cells, and alteration of the biofunction of acceptor cells, which has exhibited an important influence on the pathogenesis, diagnosis and treatment of DN. Therefore, exosomes provide considerable promise for the future development of DN treatments, although some potential exosome biomarkers and therapeutic strategies for renal diseases associated with diabetes remain limited and require further validation in comprehensive basic and clinical trials. In the near future, we believe that the intrinsic properties of exosomes will be fully revealed and utilized, allowing more patients suffering from diabetic kidney disease to benefit.
Funding
This study was supported by National Science and Technology Major Project of China (Grant No. 2020ZX09201-009 ).
CRediT authorship contribution statement
LZS and LDW conceived the idea. CJF and ZQ prepared the figures and tables. LDW and CJF drafted the manuscript. LZS and LDW edited and revised the manuscript. All authors read and approved the final manuscript.
Declaration of competing interest
The authors have no conflict of interest to declare.
Acknowledgements
We thank the Research Institute of Nephrology personnel for their guidance and help.
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Article Info
Publication History
Published online: July 01, 2021
Accepted:
June 14,
2021
Received:
May 14,
2021
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© 2021 The Authors. Published by Elsevier Inc.
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