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Exogenous Lipocalin 2 Ameliorates Acute Rejection in a Mouse Model of Renal Transplantation.

ABSTRACT: Lipocalin 2 (Lcn2) is rapidly produced by damaged nephron epithelia and is one of the most promising new markers of renal injury, delayed graft function and acute allograft rejection (AR); however, the functional importance of Lcn2 in renal transplantation is largely unknown. To understand the role of Lcn2 in renal AR, kidneys from Balb/c mice were transplanted into C57Bl/6 mice and vice versa and analyzed for morphological and physiological outcomes of AR at posttransplantation days 3, 5, and 7. The allografts showed a steady increase in intensity of interstitial infiltration, tubulitis and periarterial aggregation of lymphocytes associated with a substantial elevation in serum levels of creatinine, urea and Lcn2. Perioperative administration of recombinant Lcn2:siderophore:Fe complex (rLcn2) to recipients resulted in functional and morphological amelioration of the allograft at day 7 almost as efficiently as daily immunosuppression with cyclosporine A (CsA). No significant differences were observed in various donor-recipient combinations (C57Bl/6 wild-type and Lcn2(-/-) , Balb/c donors and recipients). Histochemical analyses of the allografts showed reduced cell death in recipients treated with rLcn2 or CsA. These results demonstrate that Lcn2 plays an important role in reducing the extent of kidney AR and indicate the therapeutic potential of Lcn2 in transplantation.

SUBMITTER: Ashraf MI

PROVIDER: S-EPMC4996417 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Exogenous Lipocalin 2 Ameliorates Acute Rejection in a Mouse Model of Renal Transplantation.

Ashraf M I MI Schwelberger H G HG Brendel K A KA Feurle J J Andrassy J J Kotsch K K Regele H H Pratschke J J Maier H T HT Aigner F F

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20151123 3

Lipocalin 2 (Lcn2) is rapidly produced by damaged nephron epithelia and is one of the most promising new markers of renal injury, delayed graft function and acute allograft rejection (AR); however, the functional importance of Lcn2 in renal transplantation is largely unknown. To understand the role of Lcn2 in renal AR, kidneys from Balb/c mice were transplanted into C57Bl/6 mice and vice versa and analyzed for morphological and physiological outcomes of AR at posttransplantation days 3, 5, and 7 ...[more]

PMID: 26595644

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Project description:BackgroundSubclinical acute rejection (subAR) can only be diagnosed by protocol biopsy and is correlated with worse graft outcomes. However, noninvasive biomarkers of subAR are lacked for kidney transplantation recipients in clinic. This study aims to utilize to construct a peripheral blood-based gene signature for subAR diagnosis after kidney transplantation.MethodsAfter systematically screening databases, two cohorts of high quality with 3-month blood profiles and biopsy-proven graft status from the Gene Expression Omnibus databases were employed as training and validation cohorts. Then, the support vector machine recursive feature elimination (SVM-RFE) and the least absolute shrinkage and selection operator (LASSO) logistic regression were used to identify key biomarkers for subAR. Subsequently, the stepwise logistic regression method was applied to construct a gene signature for subAR in the training cohort. Patients were divided into high-risk and low-risk groups based on the cutoff point identified by the receiver operating characteristic (ROC) curve. Then, the signature was validated in a validation cohort with fixed formula. The single-sample gene set enrichment analysis was used to estimate immune cells in the blood.ResultsFifty key biomarkers were filtered out with the machine learning algorithms. Then, a novel six-gene signature was constructed using the LASSO and stepwise logistic regression method. The signature had high accuracy in both training [area under the curve (AUC) =0.923] and validation cohort (AUC =0.855). Additionally, these six genes were found to have significant and consistent relationships with blood immune cells in both cohorts, especially for T cells subtypes.ConclusionsWe developed and validated a novel noninvasive six-gene signature based on peripheral blood to diagnose subAR, which offered a potential tool for clinical practice. The six-gene signature offered a potential method to monitor patients following transplantation and make a timely intervention.

Dataset Information

Exogenous Lipocalin 2 Ameliorates Acute Rejection in a Mouse Model of Renal Transplantation.

Publications

Exogenous Lipocalin 2 Ameliorates Acute Rejection in a Mouse Model of Renal Transplantation.

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