期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 185, 期 5, 页码 1264-1274出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2015.01.015
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资金
- Medical Research Council [G0802260/2]
- Kidney Research UK
- MRC [G0802260] Funding Source: UKRI
- Academy of Medical Sciences (AMS) [AMS-SGCL12-Pepper] Funding Source: researchfish
- Kidney Research UK [RP46/2013] Funding Source: researchfish
- Medical Research Council [G0802260] Funding Source: researchfish
Glomerulonephritis is a common cause of end-stage renal disease. Infiltrating leukocytes interacting with renal cells play a critical role during the initiation and progression of glomerulonephritis, but the exact mechanisms are not clearly defined. By using the murine model of nephrotoxic nephritis, we investigated the role of S100A8/A9 [myeloid-related protein (MRP) 8/14, calprotectin] in promoting glomerulonephritis. In nephrotoxic nephritis, wild-type (WT) mice with glomerutonephritis have elevated serum levels of S100A8/A9, whereas mice deficient in MRP14 (5100a9(-/-)), and hence S100A8/A9, are significantly protected from disease. By using bone marrow transplants, we showed that MRP14 deficiency is required in both the hemopoietic and intrinsic cells for the protective effect. In vitro, both the WT bone marrow - derived macrophages and renal mesangial cells stimulated with S100A8/A9 secrete IL-6, CXCL1, and tumor necrosis factor alpha; however, Mrp14(-/-) cells exhibit significantly blunted proinflammatory responses. The interaction of WT bone marrow derived macrophages with renal microvascular endothelial cells results in increased levels of monocyte chemotactic protein 1, IL-8, and IL-6 cytokines, which is attenuated in Mrp14(-/-) bone marrow derived macrophages. Data shows that S100A8/A9 plays a critical rote during glomerulonephritis, exerting and amplifying autocrine and paracrine proinflammatory effects on bone marrow derived macrophages, renal endothelial cells, and mesangial cells. Therefore, complete S100A8/A9 blockade may be a new therapeutic target in glomerulonephritis.
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