A hypertensive challenge has an early and sustained effect on RAGE up-regulation in brain vessels of the cortex and hippocampus in mice [2,39] and plasma sRAGE levels are decreased in patients with essential HT [2,40], which means that HMGB1 and RAGE contribute to the pathogenesis of HT, the key risk factor for stroke (Figure 1). The gene discussed is AGER; the disease is hematocrit.