Human Urinary Exosomes as Innate Immune Effectors

Hiemstra, Thomas F.; Charles, P. David; Gracia, Tannia; Hester, Svenja; Gatto, Laurent; Al‐Lamki, Rafia S.; Floto, R. Andres; Ya, SU; Skepper, Jeremy N.; Lilley, Kathryn S.; Karet, Fiona E.

doi:10.1681/asn.2013101066

Cited by 141 publications

(127 citation statements)

References 50 publications

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“…25,53 More recently, CD14 was shown to be abundant in normal human urinary exosomes with antimicrobial properties. 54 Finally, CD14 and the TRIF pathway are implicated in upstream signaling leading to HO1 expression. 34 Collectively, these data impart CD14 with unique properties, and it is tempting to speculate about its possible role as an essential intermediary in the macrophage-tubule crosstalk.…”

Section: Discussionmentioning

confidence: 99%

The Macrophage Mediates the Renoprotective Effects of Endotoxin Preconditioning

Hato¹,

Winfree²,

Kalakeche³

et al. 2015

Journal of the American Society of Nephrology

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Preconditioning is a preventative approach, whereby minimized insults generate protection against subsequent larger exposures to the same or even different insults. In immune cells, endotoxin preconditioning downregulates the inflammatory response and yet, preserves the ability to contain infections. However, the protective mechanisms of preconditioning at the tissue level in organs such as the kidney remain poorly understood. Here, we show that endotoxin preconditioning confers renal epithelial protection in various models of sepsis in vivo. We also tested the hypothesis that this protection results from direct interactions between the preconditioning dose of endotoxin and the renal tubules. This hypothesis is on the basis of our previous findings that endotoxin toxicity to nonpreconditioned renal tubules was direct and independent of immune cells. Notably, we found that tubular protection after preconditioning has an absolute requirement for CD14-expressing myeloid cells and particularly, macrophages. Additionally, an intact macrophage CD14-TRIF signaling pathway was essential for tubular protection. The preconditioned state was characterized by increased macrophage number and trafficking within the kidney as well as clustering of macrophages around S1 proximal tubules. These macrophages exhibited increased M2 polarization and upregulation of redox and ironhandling molecules. In renal tubules, preconditioning prevented peroxisomal damage and abolished oxidative stress and injury to S2 and S3 tubules. In summary, these data suggest that macrophages are essential mediators of endotoxin preconditioning and required for renal tissue protection. Preconditioning is, therefore, an attractive model to investigate novel protective pathways for the prevention and treatment of sepsis. 26: 134726: -136226: , 201526: . doi: 10.1681 Gram-negative sepsis is a formidable and challenging clinical condition that carries very high morbidity and mortality. Indeed, it is estimated that mortality from sepsis can exceed 70%, especially when complicated by organ failure. 1 AKI is frequently seen in patients with sepsis and dramatically increases morbidity and mortality. To date, treatment of sepsis and sepsis-induced AKI remains supportive and relies primarily on antibiotic therapy, fluid and electrolyte management, and hemodynamic support. 2 One hallmark of sepsis is widespread tissue oxidative stress. Uncontrolled reactive oxygen species rapidly react with all biologic macromolecules and result in deleterious tissue damage, including organ failure. We and others have shown that the endotoxin (LPS) receptor Tolllike receptor 4 (TLR4) and coreceptor CD14 are expressed in renal tubules and upregulated in sepsis and ischemia. [3][4][5][6][7][8] We also showed that systemic endotoxin is freely filtered and interacts with S1 J Am Soc Nephrol

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Section: Discussionmentioning

confidence: 99%

The Macrophage Mediates the Renoprotective Effects of Endotoxin Preconditioning

Hato¹,

Winfree²,

Kalakeche³

et al. 2015

Journal of the American Society of Nephrology

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“…Compared with other biomarkers, circulating EVs and uEVs are one of a kind, because they not only have a diagnostic or prognostic role but also, are believed to have a functional and therapeutic role. 8 For example, they have been found to be antibacterial in urinary tract infections 14 or renal protective in models of kidney injury. 15 Because of the heterogeneity of these vesicles, their low refractive index, and the inability of most techniques to detect the whole size range, the accurate assessment of these vesicles has remained elusive.…”

mentioning

confidence: 99%

Extracellular Vesicles in Renal Diseases

Erdbrügger

2016

Journal of the American Society of Nephrology

168

175

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Extracellular vesicles from the urine and circulation have gained significant interest as potential diagnostic biomarkers in renal diseases. Urinary extracellular vesicles contain proteins from all sections of the nephron, whereas most studied circulating extracellular vesicles are derived from platelets, immune cells, and the endothelium. In addition to their diagnostic role as markers of kidney and vascular damage, extracellular vesicles may have functional significance in renal health and disease by facilitating communication between cells and protecting against kidney injury and bacterial infection in the urinary tract. However, the current understanding of extracellular vesicles has derived mostly from studies with very small numbers of patients or in vitro data. Moreover, accurate assessment of these vesicles remains a challenge, in part because of a lack of consensus in the methodologies to measure extracellular vesicles and the inability of most techniques to capture the entire size range of these vesicles. However, newer techniques and standardized protocols to improve the detection of extracellular vesicles are in development. A clearer understanding of the composition and biology of extracellular vesicles will provide insights into their pathophysiologic, diagnostic, and therapeutic roles.

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“…1 This program was based on a study of rehospitalization rates by Jencks et al, 2 which highlighted inadequate care coordination by hospitals in Medicare patient hospital discharges, resulting in an approximately 20% readmission rate within 30 days of discharge. The Readmission Reduction Program established a Medicare diagnosis-related group (DRG) payment reduction for hospitals that exceeded the adjusted national average readmission rate for three diagnoses: acute myocardial infarction, congestive heart failure, and pneumonia.…”

Section: Disclosuresmentioning

confidence: 99%

“…3 This 70% higher rate of hospital readmission brought readmissions of the dialysis population into consideration for a quality metric of the Quality Improvement Program, which can affect up to 2% of the Prospective Payment System for dialysis. 1 The study by Erickson et al 4 in this issue of JASN highlights the potential relationship between the rate of readmission of dialysis patients and the frequency of face-to-face health care provider (physician and/or advanced practitioner) visits at the dialysis facility in the month after hospital discharge. The mean number of provider-patient interactions among patients who were rehospitalized or died within 30 days of a hospital discharge was 2.161.6 episodes, significantly below the frequency of 3.361.2 episodes among patients who were not rehospitalized and did not die within 30 days of discharge.…”

Section: Disclosuresmentioning

confidence: 99%