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Background: Diabetic kidney disease (DKD), a metabolism-related syndrome characterized by abnormal glomerular filtration rate, proteinuria, and renal microangiopathy, is one of the most common forms of chronic kidney disease, whereas extracellular vesicles (EVs) have been recently evidenced as a novel cell communication player in DKD occurrence and progress via releasing various bioactive molecules, including proteins, lipids, and especially RNA, among which noncoding RNAs (including miRNAs, lncRNAs, and circRNAs) are the major regulators. However, the functional relevance of EV-derived ncRNAs in DKD is to be elucidated. Summary: Studies have reported that EV-derived ncRNAs regulate gene expression via a diverse range of regulatory mechanisms, contributing to diverse phenotypes related to DKD progression. Furthermore, there are already many potential clinical diagnostic and therapeutic studies based on these ncRNAs, which can be expected to have potential applications in clinical practice for EV-derived ncRNAs. Key Messages: In the current review, we summarized the mechanistic role of EVs in DKD according to biological function classifications, including inflammation and oxidative stress, epithelial-mesenchymal transition, cell death, and extracellular matrix deposition. In addition, we comprehensively discussed the potential applications of EV-derived ncRNAs as diagnostic biomarkers and therapeutic targets in DKD.

Diabetic Kidney Disease

Diabetic kidney disease (DKD), originating from type 1 and type 2 diabetes mellitus (DM) [1], is a major form of chronic kidney disease featuring abnormal glomerular filtration rate, proteinuria, and renal microangiopathy in China and all over the world. It is estimated that approximately 50% of DKD patients will develop end-stage renal disease that requires long-term dialysis [2, 3], and though a stable condition could be maintained with dialysis for a relatively long time period [4], renal failure-related death is an inevitable outcome for most of the DKD patients. According to the statistical data from the International Diabetes Federation (http://www.diabetesatlas.org/), the increased prevalence of DM to 10.5% in 2021 is expected to continue rising up to 11.3% and 12.2% in 2030 and 2045, respectively. In this case, a significant increase in DKD patients will also be foreseen. Although renal replacement treatment provides a management option for DKD patients in current clinical practice, a certain therapeutic gap is presented between these clinical treatment modalities and cure purposes [5]; therefore, it is particularly important to understand and clarify the mechanisms involved in DKD, and we look forward to finding more suitable treatment options.

Extracellular Vesicles

Cell-released vesicles with membranous structures, a kind of cell-released nanoscale-size microparticles (30–1,000 nm), are widely reported to be involved in cell-cell communication [6, 7]. Extracellular vesicles (EVs) encompass various subtypes classified by their synthesis and release mechanisms, including microvesicles, ectosomes, oncosomes, apoptotic bodies, and exosomes [8]. The two most recognized types are exosomes and microvesicles. In addition, some special types of EVs are released by certain types of cells or under certain conditions, such as apoptotic EVs and autophagic EVs, as well as cancer cell-secreted large oncosomes [9]. Through protecting the impacts from proteases, nucleases, and other environmental factors by their lipid double-layer membranes, EVs may directly act on neighboring or distant recipient cells in various ways, including endocytosis (Fig. 1a), protein binding (Fig. 1b), and membrane fusion (Fig. 1c), thus releasing multiple types of bioactive molecules (proteins, lipids, and RNAs) and orchestrating multiple cellular processes in recipient cells [10]. The effects of EVs on recipient cells reflect the multifactorial consequence of cell- or tissue-specific adsorption and uptake of EVs, the composition and abundance of functional EV cargo, and the degree of adaptability of recipient cells in response to certain EV cargo. Different sets of surface proteins on EVs and recipient cells are involved in different EV uptake pathways, granting a layer of specificity in the targeted delivery of EV cargo. In some other cases, EV-induced signaling in recipient cells does not require internalization of EVs or their luminal cargo but is triggered by molecular interactions at the interfaces of EVs and recipient cell membranes [11].

Fig. 1.

Biological processes of EV genesis, release, and uptaking. In host cells, firstly, the protein components from the Golgi apparatus or internalized from the cell surface are transported onto the early endosome. Then, the maturation of early endosomes results in the formation of late endosomes and MVBs. Finally, EVs are secreted by host cells. On the side of recipient cells, EVs are uptaken by the recipient cells through the following processes: endocytosis (a), binding of surface protein (b), and membrane fusion (c). Then, multiple biological components, including proteins, lipids, and nucleic acids (e.g., noncoding RNAs), are delivered into the recipient cells. EVs, extracellular vesicles; MVBs, multivesicular bodies.

Fig. 1.

Biological processes of EV genesis, release, and uptaking. In host cells, firstly, the protein components from the Golgi apparatus or internalized from the cell surface are transported onto the early endosome. Then, the maturation of early endosomes results in the formation of late endosomes and MVBs. Finally, EVs are secreted by host cells. On the side of recipient cells, EVs are uptaken by the recipient cells through the following processes: endocytosis (a), binding of surface protein (b), and membrane fusion (c). Then, multiple biological components, including proteins, lipids, and nucleic acids (e.g., noncoding RNAs), are delivered into the recipient cells. EVs, extracellular vesicles; MVBs, multivesicular bodies.

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Noncoding RNAs

MicroRNAs (miRNAs), a type of endogenous small RNA with a length of 20–24 nucleotides (nt), have many essential adjustable functions in cells. By complementarily binding to the 3′-untranslated region of targeted mRNAs, miRNAs act as regulators of gene expression, thereby inhibiting posttranscriptional gene expression [12]. Increasing evidence has reported that miRNAs are selectively sorted into EVs and participate in intercellular communication in DKD [13]. PIWI-interacting RNAs (piRNAs), a type of small RNA with a length of 21–35 nt, specifically interact with PIWI protein to perform multifaceted functions in germline development and somatic tissues. The piRNA complex inhibits gene expression in two ways: one is by regulating the formation of heterochromatin and mediating DNA methylation modification, thereby regulating the expression of transcription-level genes; another approach is to rely on active catalytic enzymes to silence transposon mRNA, thereby inhibiting gene expression after transcription [14‒16]. In addition to small RNAs, large ncRNAs also participate in gene regulation in various biological processes. Long noncoding RNAs (lncRNAs), collectively referred to as transcripts with more than 200 nt, have limited potential to encode proteins [17]. lncRNAs perform functions through multiple molecular and cellular mechanisms, such as interacting with epigenetic factors or TFs to modulate gene transcription, sequestering miRNAs, modifying RNA, splicing and affecting mRNA stability, interacting with proteins, and encoding functional small peptides [18‒21]. In addition, lncRNAs can also be selectively sorted into EVs and participate in cell-to-cell communication in the microenvironment [22]. Circular RNAs (circRNAs), generated by a particular form of alternative splicing called back-splicing, regulate gene expression in multiple ways, including recruiting diverse epigenetic factors to orchestrate gene transcription and signal transduction, interaction with transcriptional factors and cofactors or target gene promoters, interacting with miRNAs, splicing factors, and diverse RNA-binding proteins, and orchestrating a broad repertoire of RNA or protein modifications to affect their activation and stability [23‒27]. Newly added studies have indicated that circRNAs participate in multiple diseases, including DKD. Increasing evidence has proposed that RNAs, especially noncoding RNAs (ncRNAs) [28, 29], including miRNAs [30], piRNAs [31], lncRNAs [32], and circRNAs [33], are the major cell communication function executors in EVs, and EV-derived ncRNAs have been shown to play a critical role in DKD [34‒37] via several ways, including inflammation and oxidative stress (OS), epithelial-mesenchymal transition (EMT), cell death, and extracellular matrix (ECM) deposition. Although several recent reviews emphasized the role of EV-derived ncRNAs in DKD [14, 38‒41], most studies only focus on one type of ncRNA and do not summarize their effects based on the mechanistic view. In the current review, we summarized the mechanistic role of EVs in DKD according to biology function classifications, including inflammation and OS, EMT, cell death, and ECM deposition. In addition, there is ongoing or upcoming research on potential clinical diagnosis and treatment based on these ncRNAs, which is expected to have potential applications in clinical practice.

In order to intuitively understand the role of EV-derived ncRNAs in DKD, we have illustrated these mechanistic paradigms in Figure 2 and discussed them in detail in the following table (Table 1).

Fig. 2.

EV-derived ncRNAs play important roles in regulating DKD development and progression. A view of the cellular interaction pathways involving EV-derived ncRNAs in DKD, including (a) inflammation and OS, (b) EMT, (c) cell death, and (d) ECM deposition. ncRNAs, noncoding RNAs; OS, oxidative stress; EMT, epithelial-mesenchymal transition; ECM, extracellular matrix; MSC, mesenchymal stem cell; TEC, tubular epithelial cell; GMC, glomerular mesangial cell; GEC, glomerular endothelial cell.

Fig. 2.

EV-derived ncRNAs play important roles in regulating DKD development and progression. A view of the cellular interaction pathways involving EV-derived ncRNAs in DKD, including (a) inflammation and OS, (b) EMT, (c) cell death, and (d) ECM deposition. ncRNAs, noncoding RNAs; OS, oxidative stress; EMT, epithelial-mesenchymal transition; ECM, extracellular matrix; MSC, mesenchymal stem cell; TEC, tubular epithelial cell; GMC, glomerular mesangial cell; GEC, glomerular endothelial cell.

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Table 1.

The emerging roles of EV-derived ncRNAs in DKD

EV-derived ncRNAsSource cellTarget cellFunction and mechanismDKD progressionReference
miR-15b-5p GMCs GMCs Induces mesangial cell apoptosis by targeting BCL-2 [42
circ_0125310 GMCs GMCs Promotes cell proliferation and fibrosis by regulating the miR-422a/IGF1R/p38 axis Up [43
miR-483-5p TECs Boosts ECM deposition by lessening the restraint of cellular miR-483-5p on MAPK1 and TIMP2 mRNAs Up [44
miR-196b-5p TECs Fibroblasts Increases ECM production by inhibiting SOCS2 expression and enhancing STAT3 phosphorylation Up [45
miR-92a-1-5p TECs GMCs Induces MFT and leads to ER stress by downregulating the expression of RCN3 Up [46
circ_0008529 TECs Increases inflammation and apoptosis by regulating the miR-185-5p/SMAD2 pathway Up [47
miR-221 Podocytes TECs Induces PTEC dedifferentiation through Wnt/β-catenin signaling Up [48
miR-30a-5p GECs GECs Regulates GEC EMT and angiogenesis by modulating Notch1/VEGF signaling pathway Down [49
circTAOK1 TECs GMCs Promotes proliferation, fibrosis, and EMT by regulating the miR-520h/SMAD3 axis Up [50
miR-30e-5p BMSCs PTECs Ameliorates pyroptosis by inhibiting ELAVL1 Down [51
miR-22-3p MSCs Podocytes Increases inflammation by activating the NLRP3 signaling pathway Down [41
miR-424-5p MSCs PTECs Decreases cell apoptosis and inhibits EMT by inhibiting YAP1 activation Down [52
miR-26a-5p ADSCs Podocytes Targets TLR4, activates the NF-κB pathway, and downregulates VEGFA Down [53
miR-15b-5p MSCs Podocytes Reduces apoptosis and inflammation by targeting PDK4 and decreasing the VEGFA expression Down [40
miR-let-7a BMSCs Renal cells Suppresses apoptosis of renal cells and OS by targeting USP22 Down [54
miR-16-5p hUSCs Podocytes Suppresses podocyte apoptosis by targeting VEGFA Down [55
miR-125a adMSCs GMCs Inhibits HDAC1 and ET-1 Down [56
miR-7002-5p Macrophages PTECs Suppresses autophagy by inhibiting the expression of Atg9b Up [57
miR-21a-5p/miR-25-3p Macrophages Podocytes Increases apoptosis by regulating Tnpo1/ATXN3 axis Down [58
miR-93-5p Macrophages Podocytes Induces apoptosis by regulating the miR-93-5p/TLR4 axis Down [59
ENSMUST00000181751.1, XR_001778608.1, and XR_880236.2 Macrophages TECs Promotes EMT by regulating the MAPK pathway [60
miR-21-5p Macrophages Podocytes Promotes ROS production and activates inflammation by inhibiting the A20 expression Up [61
EV-derived ncRNAsSource cellTarget cellFunction and mechanismDKD progressionReference
miR-15b-5p GMCs GMCs Induces mesangial cell apoptosis by targeting BCL-2 [42
circ_0125310 GMCs GMCs Promotes cell proliferation and fibrosis by regulating the miR-422a/IGF1R/p38 axis Up [43
miR-483-5p TECs Boosts ECM deposition by lessening the restraint of cellular miR-483-5p on MAPK1 and TIMP2 mRNAs Up [44
miR-196b-5p TECs Fibroblasts Increases ECM production by inhibiting SOCS2 expression and enhancing STAT3 phosphorylation Up [45
miR-92a-1-5p TECs GMCs Induces MFT and leads to ER stress by downregulating the expression of RCN3 Up [46
circ_0008529 TECs Increases inflammation and apoptosis by regulating the miR-185-5p/SMAD2 pathway Up [47
miR-221 Podocytes TECs Induces PTEC dedifferentiation through Wnt/β-catenin signaling Up [48
miR-30a-5p GECs GECs Regulates GEC EMT and angiogenesis by modulating Notch1/VEGF signaling pathway Down [49
circTAOK1 TECs GMCs Promotes proliferation, fibrosis, and EMT by regulating the miR-520h/SMAD3 axis Up [50
miR-30e-5p BMSCs PTECs Ameliorates pyroptosis by inhibiting ELAVL1 Down [51
miR-22-3p MSCs Podocytes Increases inflammation by activating the NLRP3 signaling pathway Down [41
miR-424-5p MSCs PTECs Decreases cell apoptosis and inhibits EMT by inhibiting YAP1 activation Down [52
miR-26a-5p ADSCs Podocytes Targets TLR4, activates the NF-κB pathway, and downregulates VEGFA Down [53
miR-15b-5p MSCs Podocytes Reduces apoptosis and inflammation by targeting PDK4 and decreasing the VEGFA expression Down [40
miR-let-7a BMSCs Renal cells Suppresses apoptosis of renal cells and OS by targeting USP22 Down [54
miR-16-5p hUSCs Podocytes Suppresses podocyte apoptosis by targeting VEGFA Down [55
miR-125a adMSCs GMCs Inhibits HDAC1 and ET-1 Down [56
miR-7002-5p Macrophages PTECs Suppresses autophagy by inhibiting the expression of Atg9b Up [57
miR-21a-5p/miR-25-3p Macrophages Podocytes Increases apoptosis by regulating Tnpo1/ATXN3 axis Down [58
miR-93-5p Macrophages Podocytes Induces apoptosis by regulating the miR-93-5p/TLR4 axis Down [59
ENSMUST00000181751.1, XR_001778608.1, and XR_880236.2 Macrophages TECs Promotes EMT by regulating the MAPK pathway [60
miR-21-5p Macrophages Podocytes Promotes ROS production and activates inflammation by inhibiting the A20 expression Up [61

TECs, tubule epithelial cells; GECs, glomerular endothelial cells; BMSCs, bone marrow mesenchymal stem cells; ADSCs, adipose-derived stem cells; hUSCs, human urine-derived stem cells.

Regulation of Inflammation and Oxidative Stress

Inflammation is an immune response-related process that plays a vital role not only in host pathogen defense but also in tissue homeostasis [62], including tissue repair, regeneration, and remodeling through recruitment and activation of the cells involved in innate and adaptive immunity [38]. In the current opinion, DM is a chronic inflammation disease; therefore, inflammation is also critical in DM-derived DKD. Accumulating experimental and clinical evidence verified the role of inflammation in DKD [39]. Zhao et al. [40] found that mesenchymal stem cell (MSC)-derived EVs could reduce the inflammation phenotype of podocytes via the miR-15b-5p-PDK4 axis, thereby playing a protective role in DKD. Through in vitro MSC-derived EVs and high glucose (HG)-treated podocyte co-culture and in vivo EV administration into diabetic mice, Wang et al. [41] found that MSC-derived EVs could exert anti-inflammatory activity via targeting the NLRP3 inflammasome by transferring miR-22-3p into podocytes. In addition, Zhuang et al. [58] showed that γ-aminobutyric acid treatment could block podocyte injury aggravation induced by macrophage-derived EVs via regulating the miR-21a-5p-Tnpo1/miR-25-3p-ATXN3 signal axis. In addition to the protective role of EVs in DKD, recent studies have shown the pro-inflammatory role of exosomes in DKD. Jia et al. [62] found that EV-miR-199a-5p derived from human renal cortex proximal tubule epithelial cells (HK-2) induced M1 polarization by targeting the Klotho/TLR4 pathway, further accelerating the progression of DKD. This evidence suggested that EV-derived ncRNAs can influence the development of DKD by regulating inflammation.

Reactive oxygen species, such as superoxide or hydroxyl, are natural by-products of oxygen metabolism that can regulate multiple biological processes, including cell proliferation, signaling transduction, and aging [63]. Kidney is particularly vulnerable to early structural and functional damage caused by OS [64]; therefore, increased OS and its related injury could affect DKD development and progression [65]. Recent studies on diabetic animal models have demonstrated that EV-derived ncRNAs can be a main determinant in OS regulation during the pathophysiological process of DKD. Gao et al. [66] demonstrated that the serum of DKD patients rich in EV-miR-4449 facilitates OS by regulating the expression of HIC1. Furthermore, Ding et al. [61] found that miR-21-5p in macrophage-derived EVs promoted podocyte injury by increasing reactive oxygen species levels. These studies indicated the OS regulatory role of EV-derived ncRNA.

Regulation of Epithelial-Mesenchymal Transition

EMT caused by HG is considered an important pathogenic factor for renal injury, disruption of glomerular filtration barrier, and proteinuria, leading to the deterioration of DKD [67]. Li et al. [50] found that exosomal circTAOK1 contributes to DKD progression by boosting proliferation, fibrosis, and EMT of glomerular endothelial cells (GECs). Mechanically, circTAOK1 regulates SMAD3 expression by sponging miR-520h. Exosomal miR-30a-5p suppresses EMT and abnormal angiogenesis of GECs by modulating the Notch1/VEGF signaling pathway [49]. Cui et al. [52] found that MSC-derived EV-miR-424-5p could inhibit HG-induced cell apoptosis and EMT by inhibiting YAP1 activation in HK2 cells. Furthermore, HG-treated macrophage-derived EV-lncRNA, including ENSMUST00000181751.1, XR_001778608.1, and XR_880236.2, could promote EMT by regulating the MAPK pathway in DKD [60]. Therefore, EV-derived ncRNAs can regulate the DKD process by modulating EMT.

Regulation of Cell Death

In DKD, cell death is considered to play a role in the depletion of the renal cells gradually [68], and several types of cell death, such as apoptosis, pyroptosis, and autophagy, have been found to be present in the kidney. Tsai et al. [42] showed that upregulated glomerular mesangial cell (GMC)-derived EV-miR-15b-5p could mediate MC apoptosis through targeting BCL-2 in DKD. Duan et al. [53] found that adipose-derived stem cell (ADSCs)-derived EV-miR-26a-5p could ameliorate the pathological symptoms of DKD in diabetic mice and inhibit HG-induced glomerular podocytes from apoptosis by targeting TLR5. Interestingly, Mao et al. [54] highlighted that bone marrow mesenchymal stem cell (BMSC)-derived EV-miR-let-7a could repress renal cell apoptosis through downregulation of USP22. Moreover, Duan et al. [55] revealed that overexpressed EV-miR-16-5p in human urine-derived stem cells (hUSCs) could suppress podocyte apoptosis. Surprisingly, MSC-derived EV-miR-125a inhibited mesangial hyperplasia and kidney fibrosis in rats through the promotion of cell apoptosis [56]. M2 macrophage-derived EV-miRNA-93-5p could improve lipopolysaccharide-induced podocyte apoptosis by targeting TLR4 in DKD [59]. Pyroptosis is a gasdermin-dependent form of pro-inflammatory necrotic cell death [69] and has been proved to be involved in DKD [70]. Gao et al. [66] demonstrated that enriched EV-miR-4449 in the serum of DKD patients could promote pyroptosis via the miR-4449/HIC1 pathway. In addition, miR-21-5p in macrophage-derived EVs can regulate pyroptosis-mediated podocyte injury by targeting A20 in DKD [61]. Lv et al. [51] found that BMSC-derived EV-miR-30e-5p inhibits caspase-1-mediated pyroptosis by targeting ELAVL1 in HG-induced HK-2 cells. Exosomal miR-7002-5p derived from HG-induced macrophages suppresses autophagy in TECs by targeting Atg9b [57]. Taken together, these studies proved that EV-ncRNAs play important roles in regulating the DKD process via mediating cell death. Numerous cell death regulators are implicated in playing a critical role in DKD, which may provide novel insight into DKD management.

Regulation of ECM Deposition

Fibrosis, defined by the formation and accumulation of ECM mainly by tissue-resident parenchymal cells and interstitial cells, is essential for wound healing, which is a secondary response to tissue injury, providing a scaffold for regeneration after or concomitant to the cessation of the inflammatory response [71]. In the kidney, no virtual data could accurately define the pros or cons of the physiological role of fibrosis. Recently, increasing evidence has indicated that EV-derived ncRNAs can modulate the process of DKD by regulating renal fibrosis. Zhu et al. [43] demonstrated that the HG-induced EV-circ_012531 sponged miR-422a and targeted the IGF1R/p38 axis, thereby leading to ECM deposition in DKD. Moreover, Liu et al. [44] showed that EVs containing lncRNA HNRNPA1 were delivered to urine to lessen the inhibition of miR-483-5p on MAPK1 and TIMP2, eventually boosting ECM deposition and promoting renal interstitial fibrosis in DKD. In addition, EV-circ_0008529 was found to contribute to ECM accumulation via the miR-185-5p/SMAD2 pathway in DKD [47]. The proliferation of myofibroblasts also plays an important role in ECM deposition and renal interstitial fibrosis formation. Tsai et al. [46] found that the exosomal miR-92a-1-5p secreted by HG-stimulated PTECs is absorbed by GMCs, inducing myofibroblast transdifferentiation in vitro and in vivo, ultimately leading to GMC injury. These studies suggested the influence of ECM deposition and renal fibrosis on DKD occurrence and progression.

According to previous studies, several signaling pathways have been found to be involved in the process of DKD, including Wnt/β-catenin, TGF-β, MAPK, PI3K, Notch, and JAK/STAT signal pathway [72‒78]. Su et al. [48] found that miR-221 in EVs can regulate Wnt/β-catenin signaling by directly targeting DKK2 to mediate PTEC dedifferentiation, thereby inducing PTEC injury in DKD. Bai et al. [79] illuminated that circ_DLGAP4 in EVs could promote DKD progression by sponging miR-143 and further regulating the ERBB3/NF-κB/MMP-2 axis. Additionally, Hu et al. [45] proved that miR-196b-5p in EVs could modulate the crosstalk between PTECs and fibroblasts during the development of renal fibrosis via regulating the STAT3/SOCO2 signaling pathway. Additional DKD modulating related signaling pathways might be identified in the future. Nevertheless, more studies are required to elucidate the precise molecular mechanisms involved in EV-derived ncRNA-regulated signal pathways in DKD, thereby offering possible intervention modalities via targeting these pathways for DKD management.

Mounting evidence suggested that EV-derived ncRNAs have the potential to serve as diagnostic biomarkers based on their high specificity and sensitivity and their easy accessibility via noninvasive collection [80, 81]. Kim et al. [82] found that 7 EV-derived miRNAs (miR-1246, miR-642a-3p, let-7c-5p, miR-1255b-5p, let-7i-3p, miR-5010-5p, and miR-150-3p) were specifically increased in DKD patients compared to healthy volunteers, among which miR-4449 was remarkably upregulated in DKD patients. Compared with healthy controls and DM patients, the expression of 14 urine EV-derived miRNAs (miR-4491, miR-2117, miR-4507, miR-5088-5P, miR-1587, miR-219a-3p, miR-5091, miR-498, miR-4687-3p, miR-516b-5p, miR-4534, miR-1275, miR-5007-3p, and miR-4516) was upregulated (>2-fold) in DKD patients according to the study by Zhao et al. [83] Further ROC analysis revealed that miR-4534 had a relatively high area under the curve (AUC) of 0.786 (95% confidence interval [CI]: 0.607–0.965), which indicated that the quantification of miRNAs in urinary EVs can be utilized as a primary or at least an auxiliary diagnostic criterion of DKD. Zang et al. [84] further identified differential expression of EV-derived miR-21-5p and miR-30b-5p in patients with DKD and renal dysfunction. The AUC reached as high as 0.830 (CI: 0.673–0.986; p = 0.004) when taking the miR-21-5p into consideration and was slightly decreased when using miR-30b-5p (AUC: 0.813; 95% CI: 0.652–0.974; p = 0.006), which represent potential biomarkers related to the pathogenesis of DKD [84]. Our previous study has found that miRNA-615-3p in the urinary exosomes is significantly upregulated in DKD patients and positively correlated with the expression of inflammation and fibrosis molecules associated with DKD, making it a novel biomarker for evaluating the progression of DKD [85]. Besides diagnostic value, EV-derived miR-155, miR-424, miRNA-451-5p, and miR-99a-5p have been also proved to hold prognostic value as an early and sensitive noninvasive indicator of renal disease [86‒88]. Taken together, these studies suggested that EV-derived ncRNAs in biofluids have exhibited tremendous potential in the development of noninvasive biomarkers, and their clinical applications deserve further research. In addition to serving as diagnostic and prognostic biomarkers, EVs also have therapeutic potential. Some preclinical studies have shown that EVs from stem cells can protect DKD by transferring renal protective ncRNAs to damaged MCs (miR-125a and miR-222) [56, 89], podocytes (miR-26a-5p and miR-215-5p) [53, 90], and renal TECs (miR-125b and miR-let7c) [91, 92]. Considering the crucial biological functions of EV-derived ncRNAs in DKD, the strategies on specifically targeting EVs or their cargoes, such as the ncRNAs, can be prospective therapeutic choices for DKD. Additionally, the research of Luo et al. [93] revealed the transcriptome characteristics and heterogeneity of EVs at the single EV level through high-throughput methods for the first time, providing an important basis for the functional research and modification application of EVs.

This review summarized the mechanisms of EV-derived ncRNAs in DKD occurrence and progression and their potential as diagnostic biomarkers and therapeutic targets. To date, studies have indicated that EV-derived ncRNAs play a versatile role in DKD by modulating inflammation and OS, EMT, cell death, ECM deposition, and the signal transduction pathway. However, only a small fraction of EV-derived ncRNAs have been identified, and systematic recognition of the role of EV-derived ncRNAs in DKD initiation and progression should be performed. Recently, Luo et al. [93] reported the single EV profiling method via single-cell RNA sequencing, which may help to better understand the specific mechanisms of EV-ncRNA-related DKD phenotype regulation, thereby providing novel insights that link EV biology and DKD diagnosis, prognosis, and treatment. Currently, tremendous advances have emerged in identifying possible candidate biomarkers in DKD early diagnosis, whereas more large-scale, multicenter clinical trials should be well designed to verify their utility. Furthermore, there are still some considerable obstacles, such as therapeutic-scale EV production and high-efficacy recipient cell recognition, hindering the clinical application of EV-derived ncRNAs in DKD. Therefore, certain efforts should be made to fulfill the basic mechanism of understanding and possible clinical translation.

The authors report no declarations of interest.

This work was supported by the National Natural Science Foundation of China (81600565 and 81700129), the Natural Science Foundation of Jiangsu Province for Distinguished Young Scholars (BK20190052) and Science and Technology Plan of Suzhou City (SKY2022042).

Miao Hu and Ling Zhou conceived the review. Xiahong Shen and Ling Zhou designed the review and provided supervision. Miao Hu drafted the manuscript and prepared the figures. Xiahong Shen and Ling Zhou helped to modify the figures and revise the manuscript. All authors read and approved the final manuscript.

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