Extracellular vesicles (EVs) are endogenously produced, membrane-bound vesicles that are released from cells into the extracellular space (1). Exosomes and microvesicles (MVs) are major subtypes of EVs. They are known to serve important roles in homeostasis, immune modulation, and tissue regeneration under physiologic conditions (2, 3). EVs can also mediate inflammation, thrombosis, fibrosis, and tumorigenesis in pathologic conditions (4, 5). EVs contain various biologic materials including mRNA, microRNA (miRNA), proteins, and lipids. Their contents are determined by the type of host cells and microenvironments of host cells (6). The biologic function of EVs depends on their compositions and downstream responses of recipient cells.
EVs serve several pivotal roles in renal physiology including immune modulation, tissue proliferation/regeneration, antimicrobial effect, and electrolyte/water balance, which contributes to maintenance of renal homeostasis (3). In pathologic conditions, however, EVs can contribute to propagation of disease courses by enhancing inflammation, fibrosis, coagulation, and tumorigenesis in various renal disease conditions (3). The role of EVs as a novel biomarker gained a lot of attention and comprised a major proportion of EV studies in kidneys. This topic is well summarized in the review article by Karpman
Based on the recent advancement of stem cell research and biomedical engineering technique on EV loading and modification (7), EVs have received a lot of medical attention for treatment of various kidney diseases including AKI, CKD, and transplant graft rejection even though further verification through human studies is limited. EVs serve a crucial role in intercel-lular communication by delivering biological cargo to recipient cells. The potential use of EVs as biocarriers has been exploited for the delivery of endogenous or exogenous therapeutic materials (3). Diverse cargos including miRNAs, proteins, and drugs, can be delivered to target cells by modulating EV production and cargo sorting. In this review, we will focus on the potential of EVs as intrinsic therapeutics, therapeutic targets, and drug carriers for various renal diseases.
More recently, both
AKI is a clinical syndrome originating from acute loss of renal excretory function and typically results in accumulation of renal toxins or reduction in urine output. AKI can originate from various etiologies including dehydration, toxins, hemodynamic instability, or obstruction. AKI is associated with increased mortality and healthcare-related costs. Therefore, many studies have focused on finding novel therapeutics using EVs to prevent or improve AKI outcome which will be addressed more in detail below.
MSC-derived EVs have shown a profound protective effect on AKI through their anti-apoptotic, antioxidant, anti-inflammatory, and angiogenic activities. In a study by Chen
As identification and characterization of noncoding RNAs become more widely available, several studies have shown therapeutic potentials of exosomal miRNAs in ischemic AKI by post-transcriptional regulation. Li
Several studies have shown therapeutic effects of EVs derived from various sources other than MSCs (13, 14). Pan
Renal fibrosis is a major contributor to CKD pathophysiology and can cause irreversible deterioration of renal function. The severity of renal fibrosis is significantly correlated with progression of CKD. Pathways, diagnostic potential, and therapeutic potential of EV-regulated renal fibrosis in CKD are well described in a review article by Brigstock (17). Here, we will review some representative
The most common etiology of CKD is diabetic nephropathy, a microvascular complication from hyperglycemia-induced oxidative injury and inflammation that can ultimately lead to renal fibrosis. MSC-derived exosomes have shown renal-protective effects on diabetic nephropathy (18, 19), although the exact mechanism has not been completely understood. Using a rat model of streptozotocin-induced diabetes mellitus model, Ebrahim
Hypertension is the second leading etiology of CKD, causing damage to blood vessels and filtering function of the kidney. In a deoxycorticosterone acetate-salt hypertensive model, EVs from adipose-derived MSCs could ameliorate pro-inflammatory response and recruitment of immune cells into the kidney (20). Moreover, administration of these EVs could prevent cardiac tissue fibrosis and induce better blood pressure control. Further miRNA microarray profile suggested that EV administration could affect signaling pathway of epithelial-mesenchymal transition and prevent inflammation as well as fibrosis in the kidney. In an angio-tensin II-induced hypertensive model, exosomes from cardios-phere-derived cells improved renal function and cardiac hy-pertrophy while diminishing inflammation and fibrosis in both kidney and heart in association with altered levels of IL-10 expression (21).
A study by Cantaluppi
Renal transplant has become the treatment of choice for most of the advanced kidney disease by placing a healthy kidney from a donor into a recipient’s body. Transplant procedure itself induces some degree of ischemic-reperfusion damage as well as tissue damage which has significant impact on early graft function (25). Long-term immunosuppressive treatment is also crucial to prevent graft rejection and to prolong the graft survival as well as its function maintenance. EVs are known to serve a various role in transplanted kidney through their modulatory functions in innate immunity, complement system, and coagulation system, either by activating or inhibiting them depending on the microenvironment and EV content (25). EVs are also involved in allorecognition, IRI, and the autoimmune component of antibody-mediated rejections, affecting on the graft function and survival (25). Kidney endothelial- and tubular-derived EVs can trigger graft rejection by inducing alloimmune and autoimmune responses, while MSC-derived EVs have been investigated for their therapeutic potential in experimental transplant models (26-28). The role of EVs in the crosstalk between the renal graft and immune systems as well as the diagnostic and therapeutic role of EVs in renal transplantation are well summarized in the review article by Quaglia
In a rat model of kidney transplantation, exosomes derived from regulatory T cells could delay allograft rejection, prolong the survival time of transplanted kidney, and inhibit T cell proliferation (26). This protective effect was more prominent by using the exosomes collected from donors compared to those from recipients. Pang
EVs exhibit potent effects in processes of thrombosis, inflammation, and apoptosis and are involved in propagation of various renal diseases. Therefore, blocking the release and uptake of exosomes can potentially carry beneficial effects during the disease course, even if the blocking is temporary. Various pharmacological agents can block release and uptake of EVs, including antiplatelet agents, statins, calcium channel blockers, and abciximab (29-31). However, whether modifying the release and uptake of exosomes can affect outcomes of renal diseases has not been fully investigated yet. Mossberg
Better understanding of biological mechanisms of EVs and simultaneous advancement of bio-engineering technology to modulate EV production and cargo sorting have made EV one of the most preferred drug delivery systems. There are multiple biological benefits of EVs as vectors over other methods, including their stability, reduced toxicity, biostability, and low immunogenicity (34). Specific cell surface molecules on EVs enable targeted delivery of therapeutics into subcellular structures including mitochondria and nucleus, while minimizing off-target effects (35). Exosomal delivery of biologic materials can modulate disease processes by altering genetic profiles and biological responses of recipient cells (36).
Several studies have investigated the therapeutic potential of EVs as a vector for drug delivery in various kidney diseases. Tang
More recently, Yim
As noncoding RNAs have gained more recognition for their important roles in various biological processes, delivery of noncoding RNAs as novel therapeutics for regulating renal disease progression using exosomes is in the limelight. Wang
EVs carry high potentials as a novel therapeutic tool for modulation of disease courses and for drug delivery. However, application of EVs to renal diseases is still in its infancy stage despite the explosive advancement in EV research during the past decade. Clinical application of exosomes as a therapeutic tool has been mainly focused on cancer therapy and related studies in the nephrology field are relatively scarce. There are also several technical challenges to be surmounted including retaining high yields of pure exosomes, enhancing the capability of loading various cargoes, and improving targeting specificity (35). Therefore, further advancements of therapeutic application of EVs in various renal diseases need a multidisciplinary approach harnessed with better understanding of renal pathophysiology, multi-omics studies to find a novel therapeutic target, and supplementation of bioengineering technique to enhance the quality of exosomes as biocarriers. Further optimi-zation of EV isolation techniques and scrupulous manipulation of genetic or protein compositions of EVs are mandatory to expand the therapeutic applicability of EVs. Rigorous
The authors thank Medical Illustration & Design, part of the Medical Research Support Services of Yonsei University College of Medicine, for all artistic support related to this work.
Tae Hyun Yoo is a Scientific Advisory Board member at ILIAS Biologics Inc. The authors have no additional financial interests.
Therapeutic application of extracellular vesicles from various origins in different kidney diseases
|Disease Model||Origin||EV type||Mechanism||Ref.|
|Human urine||Not specified||
|Human renal tubular cells||Exosomes||
|Graft dysfunction after renal trans-plantation||Tregs||Exosomes||
EV: extracellular vesicles, AKI: acute kidney injury, hWJMSCs: human Wharton’s Jelly mesenchymal stromal cells, MVs: microvesicles, miR: microRNA, HUVEC: human umbilical vein endothelial cells, IRI: ischemia-reperfusion injury, HGF: hepatocyte growth factor, hUC-MSCs: human umbilical cord mesenchymal stem cells, HK-2: human tubule epithelial cells, hUSCs: human urine-derived stem cells, H/R: hypoxia/reoxygenation, hBM: human bone marrow, MSCs: mesenchymal stem cells, AKT: protein kinase B, ERK: extracellular signal-regulated kinase, mTECs: mouse tubular epithelial cells, mTOR: mammalian target of rapamycin, HLSCs: human liver stem-like cells, CKD: chronic kidney disease, DOCA: deoxycorticosterone acetate, TGF-β1: transforming growth factor beta-1, hCB-MSCs: human cord blood mesenchymal stem cells, UUO: unilateral ureteral obstruction, GDNF: Glial cell line-derived neutrophic factor, SIRT1: Sirtuin 1, eNOS: endothelial nitric oxide synthase, hEPC: human endothelial progenitor cells, Tregs: regulatory T cells, DCs: dendritic cells.