Increased urinary exosomal SYT17 levels in chronic active antibody-mediated rejection after kidney transplantation via the IL-6 amplifier

Abstract

Chronic active antibody-mediated rejection (CAAMR) is a particular problem in kidney transplantation (KTx), and ~25% of grafts are lost by CAAMR. Further, the pathogenesis remains unclear, and there is no effective cure or marker. We previously found that a hyper NFκB-activating mechanism in non-immune cells, called the IL-6 amplifier, is induced by the co-activation of NFκB and STAT3, and that this activation can develop various chronic inflammatory diseases. Here, we show that synaptotagmin-17 (SYT17) is increased in an exosomal fraction of the urine from CAAMR patients, and that this increase is associated with activation of the IL-6 amplifier. Immunohistochemistry showed that SYT17 protein expression was increased in renal tubule cells of the CAAMR group. While SYT17 protein was not detectable in whole-urine samples by western blotting, urinary exosomal SYT17 levels were significantly elevated in the CAAMR group compared to three other histology groups (normal, interstitial fibrosis and tubular atrophy, and calcineurin inhibitors toxicity) after KTx. On the other hand, current clinical laboratory data could not differentiate the CAAMR group from these groups. These data suggest that urinary exosomal SYT17 is a potential diagnostic marker for CAAMR.

Genome-wide association studies for production, respiratory disease, and immune-related traits in Landrace pigs

“…For immune-related traits, the significant QTL for CAPA_105 was detected on SSC3 and the Synaptotagmin-17 ( SYT17 ) gene was the candidate gene in the QTL region. SYT17 is increased in the exosomal fraction of urine, and this increase is associated with activation of the IL-6 amplifier in humans 41 . Complement component 3 (C3), which plays a vital role in CAPA, is an acute-phase protein whose expression is regulated by cytokines such as IL-6 42 .…”

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

“…Synaptotagmin-17 (SYT17) is also specifically and highly expressed in the kidney. After kidney transplantation, the expression level of SYT17 in urinary exosomes was specifically elevated during CAMR compared to that in normal conditions, renal tubulointerstitial lesions, or CsA nephrotoxicity [ 29 ] ( Table 1 ). The general tetraspanin marker CD9 was used to set up a normalization of urine dilution and showed that SYT17/CD9 could diagnose CAMR with a high AUC value of 0.82.…”

Prevention of Chronic Rejection of Marginal Kidney Graft by Using a Hydrogen Gas-Containing Preservation Solution and Adequate Immunosuppression in a Miniature Pig Model

“…This indicates that CD4+ T cell-derived cytokines such as IL-17A may lead to sustained activation of IL-6 due to T-cell activation and local accumulation that are not related to antigen specificity ( 51 ). To support this, it is shown that synaptotagmin-17, a type of urinary exosome, is increased in association with IL-6 amplifiers in patients with chronic active antibody-mediated rejection in kidney transplantation ( 52 ). These were considered that may be relating the suppression of cytokines by hydrogen and may affect the results of mild fibrosis and tubular atrophy in the H-DCD20 ( 29 , 34 ).…”