Podocyte-Released Migrasomes in Urine Serve as an Indicator for Early Podocyte Injury

Abstract

<b><i>Background:</i></b> Levels of urinary microvesicles, which are increased during various kidney injuries, have diagnostic potential for renal diseases. However, the significance of urinary microvesicles as a renal disease indicator is dampened by the difficulty to ascertain their cell source. <b><i>Objectives:</i></b> The aim of this study was to demonstrate that podocytes can release migrasomes, a unique class of microvesicle with size ranging between 400 and 2,000 nm, and the urine level of migrasomes may serve as novel non-invasive biomarker for early podocyte injury. <b><i>Method:</i></b> In this study, immunofluorescence labeling, electronic microscopy, nanosite, and sequential centrifugation were used to purify and analyze migrasomes. <b><i>Results:</i></b> Migrasomes released by podocytes differ from exosomes as they have different content and mechanism of release. Compared to podocytes, renal tubular cells secrete markedly less migrasomes. Moreover, secretion of migrasomes by human or murine podocytes was strongly augmented during podocyte injuries induced by LPS, puromycin amino nucleoside (PAN), or a high concentration of glucose (HG). LPS, PAN, or HG-induced podocyte migrasome release, however, was blocked by Rac-1 inhibitor. Strikingly, a higher level of podocyte migrasomes in urine was detected in mice with PAN-nephropathy than in control mice. In fact, increased urinary migrasome number was detected earlier than elevated proteinuria during PAN-nephropathy, suggesting that urinary migrasomes are a more sensitive podocyte injury indicator than proteinuria. Increased urinary migrasome number was also detected in diabetic nephropathy patients with proteinuria level <5.5 g/day. <b><i>Conclusions:</i></b> Our findings reveal that podocytes release the “injury-related” migrasomes during migration and provide urinary podocyte migrasome as a potential diagnostic marker for early podocyte injury.

Urinary Extracellular Vesicles Are a Novel Tool to Monitor Allograft Function in Kidney Transplantation: A Systematic Review

“…In 2018, another miRNome study of uEV from donors reported that the profile of miRNA did not discriminate between living donors and deceased donors before transplantation [ 62 ]. The role of miRNA in uEV after kidney transplantation is not yet fully explored as currently most diagnostic findings of miRNA are based on human kidney disease before transplantation [ 59 ], cultured kidney cell [ 30 , 63 ], animal model [ 63 , 64 ], or urine sample only with no uEV isolation or detection [ 57 , 65 , 66 , 67 , 68 ], rather than on uEV from KTR after transplantation.…”

“…In addition, some important findings or clues that are not included in Table 1 are introduced in this review to help highlight the directions for future studies. Kidney-specific markers are of great value in studying kidney allograft function and could reflect minimal changes, such as age-associated changes of the kidney in living donors [30][31][32]. Donor-specific markers could be identified by human leukocyte antigen (HLA) or specific gene sequences in nucleic acid cargos, according to differences in the genetic make-up between donor and recipient.…”

CUBN Gene Mutations May Cause Focal Segmental Glomerulosclerosis (FSGS) in Children

“…Gianesello et.al [18] proved that cubilin mediates albumin endocytosis in human podocytes, CUBN gene mutation may lead to the dysfunction of cubilin, thus affect albumin endocytosis. The development of proteinuria is usually related to podocyte damage, such as podocyte foot process effacement and cell loss [19]. Compared to megalin, cubilin is thought to have higher binding a nity for albumin [20].…”

Migrasome biogenesis and functions

“…This article is protected by copyright. All rights reserved More recently, Liu et al (2020) found that injured kidney podocytes generate more migrasomes than healthy podocytes. They proposed that urinary podocyte migrasomes could potentially be used as diagnostic markers for detecting early podocyte injury [13].…”

“…All rights reserved More recently, Liu et al (2020) found that injured kidney podocytes generate more migrasomes than healthy podocytes. They proposed that urinary podocyte migrasomes could potentially be used as diagnostic markers for detecting early podocyte injury [13]. Additionally, given the known physiological functions of migrasomes in cell-cell communication and in maintaining cellular homeostasis, we expect that in the future migrasomes will be implicated in diseases involving migrating cells such as tumour metastasis, immune disorders, developmental disorders and many others.…”