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Expression of S100A12, a small calcium-binding protein, by neutrophils and monocytes/macrophages induces proinflammatory responses via ligation with the receptor for advanced glycation end-products (RAGE) and subsequent activation of intracellular signal transduction pathways such as the nuclear factor (NF)-κB pathway. Although S100A12 has been demonstrated to be a useful biomarker during inflammatory conditions, its precise role in the pathogenesis of renal and cardiovascular diseases has not been fully understood. Recently, several studies have employed S100A12 transgenic mice to investigate its pathological effects. Further studies using these models are required before we can translate these findings to human diseases such as renal and cardiovascular diseases.