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Bozic, M. Extracellular Vesicles and Renal Fibrosis. Encyclopedia. Available online: https://encyclopedia.pub/entry/8762 (accessed on 13 December 2025).
Bozic M. Extracellular Vesicles and Renal Fibrosis. Encyclopedia. Available at: https://encyclopedia.pub/entry/8762. Accessed December 13, 2025.
Bozic, Milica. "Extracellular Vesicles and Renal Fibrosis" Encyclopedia, https://encyclopedia.pub/entry/8762 (accessed December 13, 2025).
Bozic, M. (2021, April 18). Extracellular Vesicles and Renal Fibrosis. In Encyclopedia. https://encyclopedia.pub/entry/8762
Bozic, Milica. "Extracellular Vesicles and Renal Fibrosis." Encyclopedia. Web. 18 April, 2021.
Extracellular Vesicles and Renal Fibrosis
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This entry is adapted from the peer-reviewed paper 10.3390/ijms22083887

Renal fibrosis is a complex disorder characterized by the destruction of kidney parenchyma. There is currently no cure for this devastating condition. It has been demonstrated that extracellular vesicle (EV)-mediated crosstalk between various kidney cells has an essential role in the development of renal fibrosis. Importantly, EVs released from various mesenchymal stem cells (MSCs) and other cell sources have emerged as a powerful cell-free therapy in different models of renal fibrosis due to their antifibrotic characteristics and tissue regeneration capacity. 

extracellular vesicles exosomes cellular communication renal fibrosis CKD

1. Introduction

Renal fibrosis is the final manifestation of chronic kidney disease (CKD), characterized by progressive destruction of kidney parenchyma and the subsequent loss of renal function. Due to the complexity of this condition and the inability to establish a proper hierarchy of involved mechanisms during the development of renal fibrosis, there is currently no effective antifibrotic therapy in clinical use [1]. Over the past decade, extensive research has focused on the prevention and reversal of kidney fibrosis, with specific emphasis on the regeneration of the injured parenchyma using, among others, different cell-based approaches with multipotent progenitor cells for the reparation of an injured organ [1]. Nevertheless, among diverse approaches proposed as potential therapies for renal fibrosis, the use of extracellular vesicles (EVs) as a cell-free therapeutic approach has now started to be extensively investigated.

In recent years, numerous studies have pointed to EVs as important players in various physiological and pathophysiological processes, including kidney diseases. Apart from being active players in various biological processes [2][3], EVs have been identified as important means of communication alongside the nephron [4]. Furthermore, owing to their versatile characteristics, EVs represent a potential basis for the development of novel therapies [5][6]. Thus, EVs derived from mesenchymal stem cells (MSCs) have emerged as a powerful cell-free therapy for a variety of disease states, renal fibrosis being one of them [7].

2. Extracellular Vesicles: Classification, Biogenesis, and Function

EVs are membrane-limited vesicles that cells release in order to transfer biomolecules to other cells and thus communicate with them [2]. In the last decade, knowledge about EVs vastly expanded, revealing EVs as a novel paradigm in intercellular communication. Numerous studies have demonstrated the involvement of EVs in various physiological and pathophysiological processes, hence highlighting their importance for both functioning of the organism and the design of novel diagnostic tools and therapies [2][3].

EVs encompass diverse populations of membrane-limited vesicles released by virtually all cells in the organism. The diversity of EVs refers to their biogenesis, composition, size, and role [8].

2.1. Classification and Biogenesis of Extracellular Vesicles

EVs are currently classified into two main types based on their biogenesis: exosomes and microvesicles (MVs) (Figure 1). In a wider sense, apoptotic bodies may also be classified as EVs, although their involvement in intercellular communication is far less studied and will not be considered here [2][8]. The process of biogenesis encompasses the selection of cargo molecules, inducing curvature of the membrane and detachment of the vesicle. Although details of these processes are still elusive, significant advances in understanding their basics have recently been made. Hence, the formation of an exosome starts in a multivesicular body (MVB). Two main mechanisms govern this process: endosomal sorting complex required for transport (ESCRT)-dependent mechanism or ESCRT-independent mechanism [8][9]. In the former, ubiquitinated proteins are selected by the members of the ESCRT complex [9][10][11], while in the latter, sphingosine-1-phosphate, Hsc70, and tetraspanins participate in protein selection [9][12]. In addition, the sorting of some proteins may depend on their interaction with lipid raft components [13]. The sorting of miRNAs is based on their interaction with RNA-binding proteins that are targeted to EVs, their abundance in cells, and their sequence [8][14]. Invagination of the MVB limiting membrane is accomplished by the action of phosphatidic acid and sphingolipids [15][16]. This process results in the formation of vesicles in the lumen of MVB—intraluminal vesicles (ILVs) (Figure 1). In order for cells to release ILVs as exosomes, MVB must be targeted to and fused with the plasma membrane. The process of guidance of MVBs to the plasma membrane is governed by RAB proteins [8][17][18], while the fusion of MVB with the plasma membrane is mediated by RAB and SNARE proteins (N-ethylmaleimide-sensitive fusion attachment protein (SNAP) receptors) [19].

Ijms 22 03887 g001 550

Figure 1. Extracellular vesicles (EVs) release and transfer. EVs comprise exosomes (Exs), microvesicles (MVs), and apoptotic bodies (not shown). Exs are released from a donor cell upon fusion of a multivesicular body (MVB) with the plasma membrane. Microvesicles (MVs) are formed by budding of the originating cell’s plasma membrane. EVs reach target cells of the same tissue or they are transferred by body fluids to distant cells (i.e., EVs enter blood vessels (Bv) and are transferred by blood to distant organs/tissues/cells). EVs may deliver information to the target cell by (a) fusion (Fu) with its plasma membrane; (b) endocytosis (Ec) of EVs by target cells; or (c) interaction of surface molecules on EVs and the cell (not shown).

In contrast to exosomes, microvesicles are formed by direct outward budding of the plasma membrane. Reshaping of the membrane is accomplished by changing its lipid composition at the budding site and disassembly of the cytoskeleton by Ca++ ions-dependent enzymes, although it has been shown that specific members of the ESCRT complex are also involved in this process [8][20][21].

Even though modes of biogenesis define two main types of EVs, their other properties are not so distinctive. As for composition, EVs can carry all types of biomolecules (proteins, RNA, lipids, metabolites) involved in a number of processes such as adhesion, metabolism, signal transduction, membrane fusion, organization and trafficking, etc., in addition to molecules involved in EVs biogenesis [2][8]. The composition of a particular EV population also depends on the type and physiological condition of its cell of origin [22]. Different molecules specific for cell type or physiological states, such as specific surface receptors, enzymes, or cell markers, may be packed into EVs making them useful as liquid biopsies [23].

All these biogenesis and sorting mechanisms give rise to subpopulations of EVs with partially overlapping cargo [24]. Due to this overlapping and despite the presence of some biogenesis machinery components, no true marker of EV types exists. Although tetraspanins (CD63, CD9, and CD81) are being used as exosome markers, they are present on both exosomes and microvesicles and thus are unable to distinguish these two types of EVs [25].

EVs also differ in size and shape. Although it is often stated that exosomes are generally smaller than microvesicles (30–150 nm vs. 100–1000 nm), their sizes in fact overlap and thus cannot be used as a distinctive criterion for the determination of the EV type [26]. As for morphology, most of the EVs of both types have a round shape under an electron microscope, but other forms (elongated and multilayered vesicles) are also observed, adding to EVs heterogeneity. It should be noted that most of the available data have been derived from heterogeneous populations of EVs, comprising both exosomes and microvesicles and their subpopulations since there is no method available for their complete and precise separation [23][27][28]. Additionally, the terms “exosomes” and “microvesicles” have been used in the literature in an inconsistent manner. Nevertheless, in this review, we will use original terms for EVs described by authors in their publications.

2.2. Main Proposed Functions of Extracellular Vesicles

EVs have numerous roles in the body. They are important players in virtually all physiological processes such as placentation, embryonic development, immunity, coagulation, liver homeostasis, nervous system function, tissue repair, and kidney function [2][29]. EVs also participate as key communicators in pathophysiological processes such as cancer, diabetes, atherosclerosis, and endothelial dysfunction, cardiovascular and immune diseases, inflammation, obesity, fibrosis, etc. [3][30][31]. To exert their roles, EVs may use biofluids to reach the target cell and are able to cross the blood–tissue barrier. EVs deliver bio-information to target cells either by the interaction of surface molecules on EVs and the cell or through uptake/fusion of EVs by a target cell [2][32][33], where proteins and RNA can both be effector molecules.

Aside from their fundamental roles in the organism, EVs can have valuable functions as either diagnostic or therapeutic agents, or the combination of both, known as theranostics tools. EVs reflect the physiological state of the cell they originate from, and they are readily available in biofluids, and as such, they can be used in novel diagnostic platforms [5][34]. This is especially important for the diagnosis of diseases in organs in which tissue biopsy should be avoided whenever possible, such as brain or kidneys. Of note, EVs in urine (uEVs) can originate from different parts of the urinary tract, including the kidney. Carrying diverse molecular cargo from parental cells, uEVs represent an excellent readout of the physiological and pathophysiological state of different parts of the nephron. Thus, uEVs have drawn significant attention as potential biomarkers for diagnostic and prognostic purposes in various renal diseases [35]. For instance, miR-146a from urinary exosomes (uEx) was proposed as a potential biomarker of albuminuria in essential hypertension [36], while miR-29c was suggested as a novel, noninvasive marker for renal fibrosis [37]. miR-145 from uEx was demonstrated to be a promising candidate biomarker for type 1 diabetic nephropathy (DN) [38], while miR-192 was shown to be useful as a predictor of early stage DN [39]. Moreover, CD2AP mRNA in urinary exosomes has been suggested as a noninvasive tool for the detection of changes in kidney function and tubulointerstitial fibrosis, while CCL2 mRNA has been shown as a good predictor of renal function deterioration in IgAN [40]. In addition to miRNAs and mRNAs, various proteins in uEVs were shown to be biomarkers for different renal diseases, among them fetuin-A, ATF3, WT-1, aquaporin-1, etc. [30][41][42][43]. Since the use of EVs as potential diagnostic and prognostic tools for renal diseases has been covered elsewhere [30][41][42][43][44], in this review, we will focus our attention on the potential therapeutic utility of EVs in renal diseases.

Specific properties of EVs such as biocompatibility, biological barrier crossing, selective targeting, and the possibility to be modified make these vesicles a very promising basis for the development of novel therapies [5][6]. Importantly, EVs convey effects of cell therapy without presenting the same hazard as live cells, such as the case for EVs from mesenchymal stem cells (MSC-EVs) [45]. EVs have already been shown to be a beneficial therapy as antitumor vaccines [46], as immune-suppressive agents in graft-vs-host disease [47], and as drug-delivery agents [48][49]. As fundamental tools in cellular communication, EVs hold great promise for both understanding processes that take place in the organism and the design of novel diagnostic and therapeutic tools.

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