Orosomucoid 1 is involved in the development of chronic allograft rejection after kidney transplantation

Abstract

Chronic allograft rejection is the most common cause of long-term allograft failure. One reason is that current diagnostics and therapeutics for chronic allograft rejection are very limited. We here show that enhanced NFκB signaling in kidney grafts contributes to chronic active antibody-mediated rejection (CAAMR), which is a major pathology of chronic kidney allograft rejections. Moreover, we found that urinary orosomucoid 1 (ORM1) is a candidate marker molecule and therapeutic target for CAAMR. Indeed, urinary ORM1 concentration was significantly higher in kidney transplant recipients pathologically diagnosed with CAAMR than in kidney transplant recipients with normal histology, calcineurin inhibitor toxicity, or interstitial fibrosis and tubular atrophy. Additionally, we found that kidney biopsy samples with CAAMR expressed more ORM1 and had higher NFκB and STAT3 activation in tubular cells than samples from non-CAAMR samples. Consistently, ORM1 production was induced after cytokine-mediated NFκB and STAT3 activation in primary kidney tubular cells. The loss- and gain-of-function of ORM1 suppressed and promoted NFκB activation, respectively. Finally, ORM1-enhanced NFκB-mediated inflammation development in vivo. These results suggest that an enhanced NFκB-dependent pathway following NFκB and STAT3 activation in the grafts is involved in the development of chronic allograft rejection after kidney transplantation and that ORM1 is a non-invasive candidate biomarker and possible therapeutic target for chronic kidney allograft rejection.

Orosomucoid 1 Attenuates Doxorubicin-Induced Oxidative Stress and Apoptosis in Cardiomyocytes via Nrf2 Signaling

“…ORM1 performs various activities, acting as an acute-phase reactant and disease marker, regulating immunity, maintaining the capillary barrier function, regulating sphingomyelin metabolism, and scavenging reactive oxygen species (ROS) [ 12 – 14 ]. However, the current understanding of ORM1 is limited [ 15 , 16 ], and its role in cardiovascular disease is not clear.…”

PSMP Is Discriminative for Chronic Active Antibody-Mediated Rejection and Associate With Intimal Arteritis in Kidney Transplantation

“…In this study, we explored potential diagnostic and therapeutic biomarkers for chronic renal transplant rejection, include CAAMR and CAMR. Long-term graft failure caused by CAAMR has been a key challenge in renal transplantation ( 18 ). Chronic rejection needs pass through an early and active chronicity rejection phase ( 7 ) before the eventual develop to chronic graft injury.…”

Identification of Potential Biomarkers in PBMC of Systemic Lupus Erythematosus: Results from Bioinformatic Analysis

“…Given the roles of ve novel genes in SLE as shown in Table 4, several novel genes, including ORM1, SLPI, OLFM4, TCN1 and CRISP3 may also have diagnostic value in the condition. ORM1 (orosomucoid 1) is an acute phase plasma protein known to activate NFκB, p38 and JNK pathways in macrophages, and it has been reported in rheumatoid arthritis (RA) [57], sarcoidosis and other immune diseases [58]. In experimental autoimmune encephalomyelitis, SLPI (secretory leukocyte peptidase inhibitor) exerted potent pro-in ammatory actions by regulating T cell activity, a process that might bene t the patient [59].…”