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  • That increased longevity was not the


    That increased longevity was not the exclusive result of blood pressure reduction. This was demonstrated by analysis of life-long, whole body deletion of AT1A receptors in normotensive mice. These animals exhibited a very significant increase in lifespan when compared to wild- type mice [159], [160]. The hypothesis was advanced that protective mechanisms beyond blood pressure decrease include in addition to reduction of inflammation and oxidative injury and protection of mitochondrial injury, overexpression of genes such as sirtuin 3, of demonstrated pro-survival effects and a factor that also enhances mitochondrial metabolism and integrity and maintains genomic stability [161] .
    Conclusions Many in vitro, in vivo and clinical studies conclusively demonstrate the surprisingly strong neuroprotective effects achieved by ARB administration. Blocking AT1 receptors not only ameliorates several JDTic 2HCl disorders but it also appears to increase lifespan. The brain disorders described above are at present, for the most part, without effective treatment (Fig. 6). For this reason, the search for a novel therapeutic approach is a medical necessity. Current proposals from the Alzheimer’s Drug Discovery Foundation emphasize the need to propose novel treatments, while discouraging the continuing search for medicines attempting to reduce pathological events at late stages of the disease such as those addressing Amyloid-β production, as well the search for additional drugs involved in mechanisms of currently FDA-approved medications such as cholinesterase inhibitors and partial glutamate NMDA receptor blockers (Fig. 6).
    Conflict of interest
    Introduction Non-communicable diseases (NCDs), including hypertension, diabetes, atherosclerosis and chronic kidney disease (CKD), are major health burdens and cause significant mortality and morbidity worldwide. Recent studies have shown that chronic low-grade inflammation via dysregulation of the immune system may play a role in the pathogenesis of NCDs [[1], [2], [3], [4], [5]]. In addition, excessive activation of the renin-angiotensin system (RAS) in local tissue may mediate the development and progression of NCDs, at least in part, by provoking dysregulation of the immune system [[6], [7], [8]]. The existence of functional RAS with its components expression has been proposed in leukocytes and the immune system [9, 10]. In animal studies, angiotensin II type 1 receptor (AT1R) signaling in mouse bone marrow-derived cells and leukocytes affected the inflammatory status and differentiation of immune cells and was implicated in the pathogenesis of angiotensin II-induced hypertension [11,12], subsequent renal injuries [12,13] and unilateral ureteral obstruction (UUO)-induced renal fibrosis [14, 15]. Other previous studies have shown that the activation of angiotensin-converting enzyme (ACE) and renin in bone marrow-derived cells was associated with the development of atherosclerosis [16,17]. Furthermore, exaggerated activation of human leukocyte RAS components, including ACE and (pro) renin receptor ([P]RR), has also been implicated in the pathophysiology of NCDs, as has the RAS in other local tissues and organs [18,19]. We previously identified AT1R-associated protein (ATRAP) as a specific binding protein to AT1R and as a promoting molecule of AT1R internalization [[20], [21], [22], [23], [24], [25], [26]]. In several animal models of NCDs, we showed that the enhancement of local ATRAP expression, such as in the heart, vasculature and kidney, ameliorated tissue injury, probably through the inhibition of hyperactivation of the local tissue AT1R signaling [[22], [23], [24]]. Furthermore, the results of our studies showed that ATRAP deficiency lead to blood pressure elevation in a remnant kidney model and insulin resistance induced by a high-fat diet, concomitant with enhancement of inflammation markers [25, 26]. However, the expression and significance of ATRAP in leukocytes in the physiology and pathophysiology of NCDs have not been evaluated.