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      Urinary CXCL1: A Novel Predictor of IgA Nephropathy Progression

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          Abstract

          Background

          IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. In recent years, consistent efforts have been made to develop new non-invasive biomarkers for IgAN progression. In our previous in vitro study we found mesangial derived CXCL1 as a contributor for kidney injury, and observed higher urinary CXCL1 levels in patients with IgAN. It implied that the urinary CXCL1 might be a potential biomarker.

          Methods

          In the present study, we enrolled 425 IgAN patients with follow-up data and detected their urinary CXCL1 levels at the time of renal biopsy, to explore the predictive value of urinary CXCL1 in IgAN progression. Urinary CXCL1 levels were measured using enzyme-linked immunosorbent assay.

          Results

          Urinary CXCL1 levels were associated with presently well established predictors of IgAN progression, including SBP (r = 0.138, p = 0.004), DBP (r = 0.114, p = 0.019), proteinuria (r = 0.155, p = 0.001), eGFR (r = -0.259, p<0.001) and tubular atrophy and interstitial fibrosis (r = 0.181, p<0.001). After adjusted for them, higher levels of urinary CXCL1 were independently associated with a greater risk of deterioration in renal function (HR, per s.d. increment of natural log–transformed CXCL1: 1.748; 95% CI: 1.222–2.499, P = 0.002). Furthermore, time-dependent receiver operating characteristic (ROC) curve showed that urinary CXCL1, when combined with proteinuria and eGFR, could enhance the prognostic value of these traditional predictors for IgAN progression.

          Conclusions

          The results in our present study suggested urinary CXCL1 as a new non-invasive predictor of IgAN progression.

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          Most cited references19

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          The commonest glomerulonephritis in the world: IgA nephropathy.

          G D'Amico (1987)
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            The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-induced angiogenic activity.

            We have previously shown that members of the ELR(+) CXC chemokine family, including IL-8; growth-related oncogenes alpha, beta, and gamma; granulocyte chemotactic protein 2; and epithelial neutrophil-activating protein-78, can mediate angiogenesis in the absence of preceding inflammation. To date, the receptor on endothelial cells responsible for chemotaxis and neovascularization mediated by these ELR(+) CXC chemokines has not been determined. Because all ELR(+) CXC chemokines bind to CXC chemokine receptor 2 (CXCR2), we hypothesized that CXCR2 is the putative receptor for ELR(+) CXC chemokine-mediated angiogenesis. To test this postulate, we first determined whether cultured human microvascular endothelial cells expressed CXCR2. CXCR2 was detected in human microvascular endothelial cells at the protein level by both Western blot analysis and immunohistochemistry using polyclonal Abs specific for human CXCR2. To determine whether CXCR2 played a functional role in angiogenesis, we determined whether this receptor was involved in endothelial cell chemotaxis. We found that microvascular endothelial cell chemotaxis in response to ELR(+) CXC chemokines was inhibited by anti-CXCR2 Abs. In addition, endothelial cell chemotaxis in response to ELR(+) CXC chemokines was sensitive to pertussis toxin, suggesting a role for G protein-linked receptor mechanisms in this biological response. The importance of CXCR2 in mediating ELR(+) CXC chemokine-induced angiogenesis in vivo was also demonstrated by the lack of angiogenic activity induced by ELR(+) CXC chemokines in the presence of neutralizing Abs to CXCR2 in the rat corneal micropocket assay, or in the corneas of CXCR2(-/-) mice. We thus conclude that CXCR2 is the receptor responsible for ELR(+) CXC chemokine-mediated angiogenesis.
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              The expression and role of CXC chemokines in colorectal cancer.

              Cancer is a life-threatening disease world-wide and colorectal cancer is the second common cause of cancer mortality. The interaction between tumor cells and stromal cells plays a crucial role in tumor initiation and progression and is partially mediated by chemokines. Chemokines predominantly participate in the chemoattraction of leukocytes to inflammatory sites. Nowadays, it is clear that CXC chemokines and their receptors (CXCR) may also modulate tumor behavior by several important mechanisms: regulation of angiogenesis, activation of a tumor-specific immune response by attracting leukocytes, stimulation of tumor cell proliferation and metastasis. Here, we review the expression and complex roles of CXC chemokines (CXCL1 to CXCL16) and their receptors (CXCR1 to CXCR6) in colorectal cancer. Overall, increased expression levels of CXC chemokines correlate with poor prognosis. Copyright © 2011 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                27 March 2015
                2015
                : 10
                : 3
                : e0119033
                Affiliations
                [1 ]Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
                [2 ]Peking University Institute of Nephrology, Beijing, China
                [3 ]Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
                [4 ]Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Peking University, Ministry of Education, Beijing, China
                [5 ]Renal Division, Department of Medicine, The First People’s Hospital of Aksu District, Xinjiang, China
                Radboud University Medical Center, NETHERLANDS
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: HZ LZ. Performed the experiments: YFZ QXZ TZ. Analyzed the data: YFZ. Contributed reagents/materials/analysis tools: SFS LJL JCL HZ. Wrote the paper: YFZ. Critical revision of the manuscript for important intellectual content: HZ LZ.

                Article
                PONE-D-14-28092
                10.1371/journal.pone.0119033
                4376727
                25816025
                fddf7fc3-2aee-47f7-aab4-4aa26f4edbb3
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 24 June 2014
                : 9 January 2015
                Page count
                Figures: 5, Tables: 6, Pages: 15
                Funding
                This work was supported by grants from the Major State Basic Research Development Program of China (973 program, No.2012CB517700) to HZ; Natural Science Foundation for Innovation Research Group of China (81321064) to HZ; National Science Foundation of China (Grant No. 81470945) to LZ; The Beijing Natural Science Foundation (Grant No. 7131016) to HZ and the Capital of Clinical Characteristics and the Applied Research Fund to LZ(Z141107002514037). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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