Renin^|^ndash;Angiotensin System, Hypertension, and Chronic Kidney Disease: Pharmacogenetic Implications

Abstract

Abstract. About 80% of CKD (chronic kidney disease) patients are hypertensive, and kidney function and blood pressure are clearly related to both physiologic and pathologic conditions in a "vicious cycle". In this pathologic scenario, there is a renin-angiotensin system (RAS) hyperactivity associated to progression of renal damage. Current guidelines indicate as the first choice of antihypertensive intervention, the pharmacologic blockade of the RAS. Nonetheless, both response to treatment and renal protection have considerable inter-individual variability. The main aims of this review are to describe the genetic characteristics of RAS components and to identify the possible pharmacogenetic implications for RAS-blocker drugs in the hypertension-CKD scenario. To date, RAS polymorphisms have not been consistently associated to antihypertensive response and studies focusing on CKD are scarce. Nonetheless, pharmacogenetic studies for the RAS-blocker drugs could still be further explored, especially with new generation tools and focusing not only on the antihypertensive response, but also on renal protection as well.

Proprotein convertase furin/PCSK3 and atherosclerosis: New insights and potential therapeutic targets

“…Lots of evidence showed that the renin-angiotensin system contributes to the initiation and aggregation of hypertension [50]. The (P)RR is a 35-kDa transmembrane protein involved in the generation of angiotensin in tissue and activation of nonproteolytic prorenin.…”

Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System

“…32 Interestingly, consistent with earlier observation, 16 expression of sKlotho in vivo was able to induce membranous Klotho expression ( Figure 4, B and C), presumably as a result of blocking the TGF-b1emediated repression of endogenous Klotho expression. Because RAS plays a pivotal role in the pathogenesis of CKD, 7,33 we then determined the effect of exogenous Klotho on RAS expression in remnant kidneys. Interestingly, exogenous Klotho was able to markedly inhibit the expression of all RAS components ( Figure 4A).…”

“…Notably, a recent study has implicated Klotho deficiency in causing salt-sensitive hypertension in mice, 20 supporting the role of Klotho in regulating blood pressure. In view of the fact that RAS activation, not only plays a role in the evolution and progression of CKD, but also is a causative factor for developing hypertension and cardiovascular diseases, 7,45 our studies on the intimate connection between loss of Klotho and RAS activation would have wide implications beyond CKD.…”

Sonic hedgehog signaling in kidney fibrosis: a master communicator

“…As a general rule, tissue fibrosis develops in virtually every form of CKD, as both a consequence and a characteristic feature of disease progression. From a cell biological standpoint, the intricate process of renal fibrosis has been linked, more or less, to an inappropriate activation of some key signaling pathways, such as transforming growth factor-β (TGF-β), renin-angiotensin system (RAS), Wnt/β-catenin, and sonic hedgehog (Shh) (He and Dai, 2015; Meng et al, 2015; Santos et al, 2012; Sweetwyne et al, 2014; Tan et al, 2014). Most of the time, these diverse signals reciprocally crosstalk through cell-to-cell communication that involves all resident cells in the kidney, as well as the infiltrating cells (Duffield, 2014; Liu, 2011; Zeisberg and Neilson, 2010).…”