Emerging Frontiers in acute kidney injury: The role of extracellular vesicles

Abstract

Acute kidney injury (AKI) remains a prevalent and critical clinical condition. Although considerable advancements have been achieved in clinical and fundamental research in recent decades, the enhancements in AKI diagnosis and therapeutic approaches, such as the development of emerging biomarkers including neutrophil gelatinase-associated lipocalin (NGAL) and liver fatty acid-binding protein (FABP1) for early detection of AKI and the exploration of "goal-directed" hemodynamic treatment methods and renal replacement therapies, have yet to fulfill the demands of modern medicine. Extracellular vesicles (EVs) serve as pivotal messengers in cell-to-cell communication, exerting a vital impact on both physiological and pathological processes. They exhibit immense potential as disease regulators, innovative biomarkers, therapeutic agents, and drug delivery vehicles. In recent times, the diagnostic and therapeutic potential of EVs in AKI has garnered widespread recognition and exploration, making them a focal point in clinical research. Consequently, a comprehensive overview of EVs' role in AKI is of great importance. This review delves into the multifaceted roles of EVs from diverse cellular sources, including tubular epithelial cells (TECs), mesenchymal stem cells (MSCs), progenitor cells, platelets and macrophages, within the context of AKI. It scrutinizes their contributions to disease progression and mitigation, their diagnostic marker potential, and encompasses a variety of conventional and novel EVs extraction techniques suitable for AKI clinical applications. Moreover, it underscores four innovative strategies for engineering EVs to boost production efficiency, targeting precision, circulatory stability and therapeutic potency. These advancements pave the way for novel approaches in the diagnosis and treatment of AKI. We are optimistic that as research into EVs progresses, the future will bring about earlier detection, more tailored treatments, and a more holistic management of AKI.

Keywords: Acute kidney injury; Biomarkers of AKI diagnosis; Engineered or modified EVs; Extracellular vesicles.

Graphical abstract

Fig. 1

EVs can be primarily categorized into three types based on their origin: exosomes, ectosomes, and apoptosis bodies.

Fig. 2

The dual role of TECs-derived EVs in the progression and alleviation of AKI. Upon the onset of AKI, compromised TECs emit a substantial quantity of EVs that modulate the progression of AKI through intercellular signaling. These EVs can interact with KIM-1 on the TECs surface via PS, gaining entry into the cells. They contribute to the exacerbation of AKI by fueling inflammation, oxidative stress, cell death, and fibrosis. Moreover, EVs have the capacity to infiltrate fibroblasts, reducing the expression of SOCS1, which amplifies kidney fibrosis, or they can enter and activate macrophages, intensifying inflammatory responses. However, on the other hand, EVs that enter TECs contain ATF-3 mRNA and CD26, which can dampen inflammatory reactions, while miR-122 can inhibit pyroptosis, thereby mitigating TECs damage. Additionally, EVs that infiltrate vascular endothelial cells carry VEGF-A, promoting angiogenesis and reducing tissue damage.

Fig. 3

The potential roles of MSCs and progenitor cell-derived EVs in the treatment of AKI. In the realm of regenerative medicine, the significance of diverse MSCs and progenitor cells is escalating, especially regarding their secreted EVs which demonstrate substantial potential in AKI therapy. We detail the contributions of EVs from six extensively studied cell subtypes-BMSCs, hucMSCs, AMSCs, hPMSCs, hUSCs and EPC/ECFCs-in mitigating AKI. Evidence suggests that these EVs ameliorate AKI and hinder its transition to CKD by fostering cell proliferation and angiogenesis, curbing diverse cell death mechanisms including apoptosis, ferroptosis, pyroptosis, necrosis, and autophagy, and by dampening inflammation, oxidative stress, and fibrosis.

Fig. 4

Four engineering strategies to augment the efficacy of EVs in AKI therapy. a. Enhance the production efficiency of EVs by using PRP, which increases the stemness and proliferation of MSCs, thereby promoting EVs secretion; 3D culture systems and calcium ion currents can significantly boost EVs yields from MSCs. b. Extend the in vivo half-life of EVs by complexing them with KMP2, RGD hydrogels, or collagen matrices, which protect EVs from degradation and facilitate a sustained release at the site of injury. c. Improve tissue specificity of EVs by incorporating attachment peptides, which target injured kidneys expressing KIM-1, P-selectin and other molecules can be utilized for enhanced targeting. NEX, a complex of EVs and neutrophil membranes, leverages neutrophil membrane proteins for targeted delivery to injured renal tissues. d. Enhancing therapeutic potency can be achieved through two strategies: Genetic modification, which involves overexpressing Oct-4, Ace2, GDNF, and IDO in MSCs to boost the therapeutic impact of EVs via multiple mechanisms; and Pre-treatment, which improves EVs secretion by hypoxia or pan PPAR agonists, thereby reducing apoptosis, inflammation, oxidative stress, and modulating immune responses. Additionally, administering pFUS to MSCs before EVs treatment optimizes outcomes by activating the MAPK/ERK, PI3K/Akt, and eNOS/SIRT3 pathways, inhibiting inflammasome activation.