Extracellular vesicles in renal inflammatory and infectious diseases

Karpman, Diana; Tontanahal, Ashmita

doi:10.1016/j.freeradbiomed.2021.04.032

Cited by 20 publications

(13 citation statements)

References 208 publications

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“…EVs can be involved in several aspects of this pathophysiological process, as demonstrated for other inflammatory renal diseases [ 42 ] as well as for lung during sepsis [ 43 ].…”

Section: Sepsis-associated Acute Kidney Injurymentioning

confidence: 99%

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Dual Role of Extracellular Vesicles in Sepsis-Associated Kidney and Lung Injury

et al. 2022

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Extracellular vesicles form a complex intercellular communication network, shuttling a variety of proteins, lipids, and nucleic acids, including regulatory RNAs, such as microRNAs. Transfer of these molecules to target cells allows for the modulation of sets of genes and mediates multiple paracrine and endocrine actions. EVs exert broad pro-inflammatory, pro-oxidant, and pro-apoptotic effects in sepsis, mediating microvascular dysfunction and multiple organ damage. This deleterious role is well documented in sepsis-associated acute kidney injury and acute respiratory distress syndrome. On the other hand, protective effects of stem cell-derived extracellular vesicles have been reported in experimental models of sepsis. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, regenerative, and immunomodulatory properties of parental cells and have shown therapeutic effects in experimental models of sepsis with kidney and lung involvement. Extracellular vesicles are also likely to play a role in deranged kidney-lung crosstalk, a hallmark of sepsis, and may be key to a better understanding of shared mechanisms underlying multiple organ dysfunction. In this review, we analyze the state-of-the-art knowledge on the dual role of EVs in sepsis-associated kidney/lung injury and repair. PubMed library was searched from inception to July 2022, using a combination of medical subject headings (MeSH) and keywords related to EVs, sepsis, acute kidney injury (AKI), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Key findings are summarized into two sections on detrimental and beneficial mechanisms of actions of EVs in kidney and lung injury, respectively. The role of EVs in kidney-lung crosstalk is then outlined. Efforts to expand knowledge on EVs may pave the way to employ them as prognostic biomarkers or therapeutic targets to prevent or reduce organ damage in sepsis.

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“…EVs can be involved in several aspects of this pathophysiological process, as demonstrated for other inflammatory renal diseases [ 42 ] as well as for lung during sepsis [ 43 ].…”

Section: Sepsis-associated Acute Kidney Injurymentioning

confidence: 99%

“…The first aspect appears to be relevant to kidney damage. Chemotactic and pro-inflammatory effects can be determined by molecules carried by circulating PMN-derived EVs (such as monocyte chemoattractant protein 1 and galectin-3), PLT-derived EVs (RANTES and P-selectin), and EC-derived EVs (IL-8) [ 42 , 64 ].…”

Section: Sepsis-associated Acute Kidney Injurymentioning

confidence: 99%

Dual Role of Extracellular Vesicles in Sepsis-Associated Kidney and Lung Injury

et al. 2022

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“…Urine extracellular vesicles (uEVs) are released from all segments of the nephron to the tubular fluid ( 18 – 20 ) and are attractive for studying tubular apical membranes. Complement attack has been studied in platelet and endothelial extracellular vesicles ( 21 ), and C3/iC3b and C9 have been detected in uEVs from patients with autosomal dominant polycystic kidney disease ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

Proteinuria is accompanied by intratubular complement activation and apical membrane deposition of C3dg and C5b-9 in kidney transplant recipients

Isaksson

Nielsen

Hinrichs

et al. 2022

American Journal of Physiology-Renal Physiology

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Proteinuria predicts accelerated decline in kidney function in kidney transplant recipients (KTRs). We hypothesized that aberrant filtration of complement factors causes intraluminal activation, apical membrane attack on tubular cells and progressive injury. Biobanked samples from two previous studies in albuminuric KTRs were used. Complement activation split products C3c, C3dg and sC5b-9 associated C9 neoantigen were analyzed by ELISA in urine and plasma using neoepitope-specific antibodies. Urinary extracellular vesicles (uEV) were enriched by lectin- and immunoaffinity-isolation and analyzed by immunoblotting. Urine complement excretion increased significantly in KTRs with albumin/creatinine ratio ≥ 300 mg/g compared to < 30 mg/g. Urine C3dg and C9 neoantigen excretion correlated significantly to changes in albumin excretion from 3 to 12 months after transplantation. The fractional excretion of C9 neoantigen was significantly higher than for albumin indicating post-filtration generation. C9 neoantigen was detected in uEVs in six of nine of albuminuric KTRs but was absent in non-albuminuric controls (n = 8). In C9 neoantigen positive KTRs, lectin-affinity enrichment of uEVs from the proximal tubules yielded signal for iC3b, C3dg, C9 neoantigen and SGLT2 but only weakly for AQP2. Co-isolation of podocyte markers and Tamm-Horsfall protein was minimal. Our findings show that albuminuria is associated with aberrant filtration and intratubular activation of complement with deposition of C3 activation split products and C5b-9 associated C9 neoantigen on uEVs from the proximal tubular apical membrane. Intratubular complement activation may contribute to progressive kidney injury in proteinuric kidney grafts.

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“…19 Despite the impressive progress, most of the studies only employ a single biomarker and ignore the heterogeneity of uEV surface proteins. 6,19,20 In addition, these diagnosis strategies are still limited by the sensitivity and accuracy of current detection technology, especially with the consideration that the concentration of uEV biomarkers is ultralow at the early stage of tumors. 21 It is noteworthy that human uEVs have a more complex and heterogeneous composition than the cell line derived EVs, and it is a key problem to decipher the huge amount of garbled information within EVs.…”

mentioning

confidence: 99%

“…Lee et al presented integrated kidney exosome analysis for the detection of kidney transplant rejection . Despite the impressive progress, most of the studies only employ a single biomarker and ignore the heterogeneity of uEV surface proteins. ,, In addition, these diagnosis strategies are still limited by the sensitivity and accuracy of current detection technology, especially with the consideration that the concentration of uEV biomarkers is ultralow at the early stage of tumors . It is noteworthy that human uEVs have a more complex and heterogeneous composition than the cell line derived EVs, and it is a key problem to decipher the huge amount of garbled information within EVs. − Machine learning (ML) algorithms are capable of modeling complicated networks and leveraging valuable information within observed data for the accurate estimation and prediction of practical samples. − They have shown superior performance to analyze spectroscopic signals in complex samples, , thus becoming trustworthy solutions to this issue.…”

mentioning

confidence: 99%

Ratiometric 3D DNA Machine Combined with Machine Learning Algorithm for Ultrasensitive and High-Precision Screening of Early Urinary Diseases

Zhang

Xia

et al. 2021

ACS Nano

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Urinary extracellular vesicles (uEVs) have received considerable attention as a potential biomarker source for the diagnosis of urinary diseases. Present studies mainly focus on the discovery of biomarkers based on high-throughput proteomics, while limited efforts have been paid to applying the uEVs’ biomarkers for the diagnosis of early urinary disease. Herein, we demonstrate a diagnosis protocol to realize ultrasensitive detection of uEVs and accurate classification of early urinary diseases, by combing a ratiometric three-dimensional (3D) DNA machine with machine learning (ML). The ratiometric 3D DNA machine platform is constructed by conjugating a padlock probe (PLP) containing cytosine-rich (C-rich) sequences, anchor strands, and nucleic-acid-stabilized silver nanoclusters (DNAAgNCs) onto the magnetic nanoparticles (MNPs). The competitive binding of uEVs with the aptamer releases the walker strand, thus the ratiometric 3D DNA machine was activated to undergo an accurate amplification reaction and produce a ratiometric fluorescence signal. The present biosensor offers a detection limit of 9.9 × 103 particles mL–1 with a linear range of 104–108 particles mL–1 for uEVs. Two ML algorithms, K-nearest neighbor (KNN) and support vector machine (SVM), were subsequently applied for analyzing the correlation between the sensing signals of uEV multibiomarkers and the clinical state. The disease diagnostic accuracy of optimal biomarker combination reaches 95% and 100% by analyzing with KNN and SVM, and the disease type classification exhibits an accuracy of 94.7% and 89.5%, respectively. Moreover, the protocol results in 100% accurate visual identification of clinical uEV samples from individuals with disease or as healthy control by a t-distributed stochastic neighbor embedding (tSNE) algorithm.

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Extracellular vesicles in renal inflammatory and infectious diseases

Cited by 20 publications

References 208 publications

Dual Role of Extracellular Vesicles in Sepsis-Associated Kidney and Lung Injury

Dual Role of Extracellular Vesicles in Sepsis-Associated Kidney and Lung Injury

Proteinuria is accompanied by intratubular complement activation and apical membrane deposition of C3dg and C5b-9 in kidney transplant recipients

Ratiometric 3D DNA Machine Combined with Machine Learning Algorithm for Ultrasensitive and High-Precision Screening of Early Urinary Diseases

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