Dataset Information

Ferroptosis related gene signature in T cell-mediated rejection after kidney transplantation.

ABSTRACT:

Background

T cell-mediated rejection is an important factor affecting early transplant kidney survival. Ferroptosis has been shown to play a pathogenic role in a variety of diseases, which was not reported in TCMR. Here we developed a model for assessing activation of ferroptosis-related genes in TCMR to find a better screening method and explore the contribution of ferroptosis in TCMR.

Methods

We performed unsupervised consensus clustering according to expression of ferroptosis-related genes based on RNA-seq data from kidney transplant biopsies, and developed an assessment model characterized by ferroptosis gene expression through PCA, which was evaluated in multiple external datasets as well as blood and urine samples. Pathway enrichment and immune cell infiltration analysis were used to explore the possible targets and pathways involved in ferroptosis and TCMR.

Results

A ferroptosis gene expression scoring model was established. The diagnostic specificity and sensitivity of TCMR in renal biopsy samples were both over 80%, AUC = 0.843, and AUC was around 0.8 in multi-dataset validation, and was also close to 0.7 in blood and urine samples, while in predicting of graft survival at 3 years, scoring model had a good prognostic effect as well. Pathway enrichment and PPI network speculated that TLR4, CD44, IFNG, etc. may be the key genes of ferroptosis in TCMR.

Conclusions

Ferroptosis scoring model could better diagnose TCMR and predict graft loss, and could be used as a potential screening method in blood and urine samples. We speculate that ferroptosis plays an important role in TCMR.

SUBMITTER: Zhang W

PROVIDER: S-EPMC9850582 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Ferroptosis related gene signature in T cell-mediated rejection after kidney transplantation.

Zhang Weixun W Gong Lian L Zhang Di D Hu Xiaopeng X

BMC medical genomics 20230119 1

<h4>Background</h4>T cell-mediated rejection is an important factor affecting early transplant kidney survival. Ferroptosis has been shown to play a pathogenic role in a variety of diseases, which was not reported in TCMR. Here we developed a model for assessing activation of ferroptosis-related genes in TCMR to find a better screening method and explore the contribution of ferroptosis in TCMR.<h4>Methods</h4>We performed unsupervised consensus clustering according to expression of ferroptosis-r ...[more]

PMID: 36658573

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Project description:Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss, but its pathogenesis is unclear. In order to uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of circulating peripheral blood mononuclear cells and, separately, of CD4+ T lymphocytes isolated from CAMR patients compared to kidney transplant recipients with normal graft function and histology. In total peripheral lympho-monocytes, forty-five genes resulted differentially expressed between the two groups, most of them were up-regulated in CAMR and were involved in type I interferon signaling. In addition, in the same set of patients, 16 microRNAs resulted down-regulated in CAMR subjects compared to controls: 4 were predicted modulators of 6 mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signaling. To further confirm this hypothesis, we investigated the transcriptomic profiles of CD4+ T lymphocytes in an independent group of patients and we observed that the activation of type I interferon signaling was a specific hallmark of CAMR. In addition, in CAMR patients we detected a reduction of circulating BDCA2+ dendritic cells, the natural type I interferon- producing cells and their recruitment into the graft along with an increased expression of MXA, a type I interferon-induced protein, at tubulointerstitial and vascular level. In conclusion, our data suggest that type I interferon signaling may represent the molecular signature of CAMR. For microarray analysis, we studied 5 patients included into the control-group and 4 included into the study group. The control group was represented by renal transplant recipients undergoing protocol graft biopsies, with normal renal function and histology, in the absence of circulating anti-HLA antibodies. Study group patients showed clinical and histological evidence of CAMR according to Banff 2011 criteria.

Project description:Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss, but its pathogenesis is unclear. In order to uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of circulating peripheral blood mononuclear cells and, separately, of CD4+ T lymphocytes isolated from CAMR patients compared to kidney transplant recipients with normal graft function and histology. In total peripheral lympho-monocytes, forty-five genes resulted differentially expressed between the two groups, most of them were up-regulated in CAMR and were involved in type I interferon signaling. In addition, in the same set of patients, 16 microRNAs resulted down-regulated in CAMR subjects compared to controls: 4 were predicted modulators of 6 mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signaling. To further confirm this hypothesis, we investigated the transcriptomic profiles of CD4+ T lymphocytes in an independent group of patients and we observed that the activation of type I interferon signaling was a specific hallmark of CAMR. In addition, in CAMR patients we detected a reduction of circulating BDCA2+ dendritic cells, the natural type I interferon- producing cells and their recruitment into the graft along with an increased expression of MXA, a type I interferon-induced protein, at tubulointerstitial and vascular level. In conclusion, our data suggest that type I interferon signaling may represent the molecular signature of CAMR. For microarray analysis, we studied 8 patients included into the control-group and 10 included into the study group. The control group was represented by renal transplant recipients undergoing protocol graft biopsies, with normal renal function and histology, in the absence of circulating anti-HLA antibodies. Study group patients showed clinical and histological evidence of CAMR according to Banff 2011 criteria.

Project description:Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss, but its pathogenesis is unclear. In order to uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of circulating peripheral blood mononuclear cells and, separately, of CD4+ T lymphocytes isolated from CAMR patients compared to kidney transplant recipients with normal graft function and histology. In total peripheral lympho-monocytes, forty-five genes resulted differentially expressed between the two groups, most of them were up-regulated in CAMR and were involved in type I interferon signaling. In addition, in the same set of patients, 16 microRNAs resulted down-regulated in CAMR subjects compared to controls: 4 were predicted modulators of 6 mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signaling. To further confirm this hypothesis, we investigated the transcriptomic profiles of CD4+ T lymphocytes in an independent group of patients and we observed that the activation of type I interferon signaling was a specific hallmark of CAMR. In addition, in CAMR patients we detected a reduction of circulating BDCA2+ dendritic cells, the natural type I interferon- producing cells and their recruitment into the graft along with an increased expression of MXA, a type I interferon-induced protein, at tubulointerstitial and vascular level. In conclusion, our data suggest that type I interferon signaling may represent the molecular signature of CAMR. We performed microarray experiments in CD4+ T cells isolated from a small independent group of 5 patients included into the control-group and 5 included into the study group. The control group was represented by renal transplant recipients undergoing protocol graft biopsies, with normal renal function and histology, in the absence of circulating anti-HLA antibodies. Study group patients showed clinical and histological evidence of CAMR according to Banff 2011 criteria.

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Dataset Information

Ferroptosis related gene signature in T cell-mediated rejection after kidney transplantation.

Background

Methods

Results

Conclusions

Publications

Ferroptosis related gene signature in T cell-mediated rejection after kidney transplantation.

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