Dataset Information

C-X-C Chemokine Receptor Type 4 Plays a Crucial Role in Mediating Oxidative Stress-Induced Podocyte Injury.

ABSTRACT:

Aims

Oxidative stress plays a role in mediating podocyte injury and proteinuria. However, the underlying mechanism remains poorly understood. In this study, we investigated the potential role of C-X-C chemokine receptor type 4 (CXCR4), the receptor for stromal cell-derived factor 1? (SDF-1?), in mediating oxidative stress-induced podocyte injury.

Results

In mouse model of adriamycin nephropathy (ADR), CXCR4 expression was significantly induced in podocytes as early as 3 days. This was accompanied by an increased upregulation of oxidative stress in podocyte, as demonstrated by malondialdehyde assay, nitrotyrosine staining and secretion of 8-hydroxy-2'-deoxyguanosine in urine, and induction of NOX2 and NOX4, major subunits of NADPH oxidase. CXCR4 was also induced in human kidney biopsies with proteinuric kidney diseases and colocalized with advanced oxidation protein products (AOPPs), an established oxidative stress trigger. Using cultured podocytes and mouse model, we found that AOPPs induced significant loss of podocyte marker Wilms tumor 1 (WT1), nephrin, and podocalyxin, accompanied by upregulation of desmin both in vitro and in vivo. Furthermore, AOPPs worsened proteinuria and aggravated glomerulosclerosis in ADR. These effects were associated with marked activation of SDF-1?/CXCR4 axis in podocytes. Administration of AMD3100, a specific inhibitor of CXCR4, reduced proteinuria and ameliorated podocyte dysfunction and renal fibrosis triggered by AOPPs in mice. In glomerular miniorgan culture, AOPPs also induced CXCR4 expression and downregulated nephrin and WT1. Innovation and Conclusion: These results suggest that chemokine receptor CXCR4 plays a crucial role in mediating oxidative stress-induced podocyte injury, proteinuria, and renal fibrosis. CXCR4 could be a new target for mitigating podocyte injury, proteinuria, and glomerular sclerosis in proteinuric chronic kidney disease. Antioxid. Redox Signal. 27, 345-362.

SUBMITTER: Mo H

PROVIDER: S-EPMC6435352 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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C-X-C Chemokine Receptor Type 4 Plays a Crucial Role in Mediating Oxidative Stress-Induced Podocyte Injury.

Mo Hongyan H Wu Qinyu Q Miao Jinhua J Luo Congwei C Hong Xue X Wang Yongping Y Tang Lan L Hou Fan Fan FF Liu Youhua Y Zhou Lili L

Antioxidants & redox signaling 20170328 6

<h4>Aims</h4>Oxidative stress plays a role in mediating podocyte injury and proteinuria. However, the underlying mechanism remains poorly understood. In this study, we investigated the potential role of C-X-C chemokine receptor type 4 (CXCR4), the receptor for stromal cell-derived factor 1α (SDF-1α), in mediating oxidative stress-induced podocyte injury.<h4>Results</h4>In mouse model of adriamycin nephropathy (ADR), CXCR4 expression was significantly induced in podocytes as early as 3 days. This ...[more]

PMID: 27960539

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Project description:BACKGROUND:We have shown that phospholipase C? (PLC?), an effector of Ras and Rap1 small GTPases, plays pivotal roles in inflammation and inflammation-associated carcinogenesis by augmenting proinflammatory cytokine production from epithelial cells of various organs. The purpose of this study is to analyze its role in neutrophilic alveolar inflammation accompanying acute lung injury (ALI), focusing on that in alveolar epithelial cells (AECs), which are known to make a major contribution to the pathogenesis of ALI. METHODS:We examine the effect of the PLC? genotypes on the development of ALI induced by intratracheal administration of lipopolysaccharide (LPS) to PLC? wild-type (PLC?+/+) and knockout (PLC??X/?X) mice. Pathogenesis of ALI is analyzed by histological examination of lung inflammation and measurements of the levels of various cytokines, in particular neutrophil-attracting chemokines such as Cxcl5, by quantitative reverse transcription-polymerase chain reaction and immunostaining. Primary cultures of AECs, established from PLC?+/+ and PLC??X/?X mice, are used to analyze the roles of PLC?, protein kinase D (PKD) and nuclear factor-?B (NF-?B) in augmentation of LPS-induced Cxcl5 expression. RESULTS:Compared to PLC?+/+ mice, PLC??X/?X mice exhibit marked alleviation of lung inflammation as shown by great reduction in lung wet/dry weight ratios, accumulation of inflammatory cells in the alveolar space and thickening of alveolar walls as well as the number of neutrophils and the protein concentration in bronchoalveolar lavage fluid. Also, LPS-induced expression of the CXC family of chemokines, in particular Cxcl5, is substantially diminished in the total lung and AECs of PLC??X/?X mice. Moreover, LPS-induced Cxcl5 expression in primary cultured AECs is markedly suppressed on the PLC??X/?X background (p?<?0.05 versus PLC?+/+ AECs), which is accompanied by the reduction in phosphorylation of inhibitor ?B (I?B), PKD and nuclear translocation of NF-?B p65. Also, it is suppressed by the treatment with inhibitors of PKD and I?B kinase, suggesting the involvement of the PLC?-PKD-I?B-NF-?B pathway. CONCLUSIONS:PLC?-mediated augmentation of the production of the CXC family of chemokines, in particular Cxcl5, in AECs plays a crucial role in neutrophilic alveolar inflammation accompanying ALI, suggesting that PLC? may be a potential molecular target for the treatment of acute respiratory distress syndrome.

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Dataset Information

C-X-C Chemokine Receptor Type 4 Plays a Crucial Role in Mediating Oxidative Stress-Induced Podocyte Injury.

Aims

Results

Publications

C-X-C Chemokine Receptor Type 4 Plays a Crucial Role in Mediating Oxidative Stress-Induced Podocyte Injury.

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