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• W3148674927 abstract "Dear EditorWe read with great interest the article by Uijl et al. [1] who reported that liver-directed small interfering RNA (siRNA) targeted to angiotensinogen (AGT) does not reverse the hypertension induced in male Sprague–Dawley rats by the implant of a deoxycorticosterone acetate (DOCA) pellet and 9.0% saline in lieu of tapwater. In the elegantly conducted experiments, a 97% suppression of circulating AGT in siRNA-treated rats doubled brainstem AGT mRNA while having no effect on corresponding brain tissue AGT concentrations. While we consider the presented results important, we do highlight concerns limiting the correct interpretation of the published data. First, Uijl et al. [1] detailed analysis of the changes in circulating and tissue angiotensins over interprets the data reported for brainstem Ang II concentrations between DOCA+salt vehicle and siRNA DOCA+salt treated rats. The data illustrated in their Figure 4 (Panel B) show that brainstem Ang II concentrations were below the level of assay detectability in five of seven rats given the DOCA+salt vehicle treatment compared with all seven rats receiving the siRNA treatment. This implies that statistical differences were heavily biased based on the two values recorded in seven rats in which brainstem Ang II was above the lower limit of quantification detection (>6 fmol/g of tissue measured by liquid chromatography with tandem mass spectrometry [LC-MS/MS]; Supplementary Table S1) [1]. Moreover, the appropriate comparison (non-DOCA+salt vehicle vs non-DOCA+salt siRNA) is absent due to the lack of a control group with a non-siRNA intervention. Hence, the conclusion that increased brainstem AGT expression following hepatic AGT silencing is accompanied by suppressed brainstem tissue Ang II concentration is unwarranted based on the limitations imposed by the low sensitivity of the Ang II assay and the employed statistical assumptions. Likewise, the fact that the combination of silencing hepatic AGT and DOCA+salt hypertension resulted in increased brainstem AGT mRNA and no changes in AGT protein does not agree with the authors’ conclusion that Ang II in the brain is not generated from locally synthesized AGT [1]. No explanation is given to the paradoxical up-regulation of brainstem AGT mRNA expression after siRNA treatment. Multiple studies provide strong evidence for the existence of a brainstem blood pressure control mechanism in which locally synthetized Ang II functions as a neurotransmitter [2–6]. More sensitive procedures such as RIA, quantitative fluorescence immunohistochemistry or electron microscopy, and a larger sample size will be required to validate the authors’ conclusion. To further endorse their results, the authors might consider the use of sniffer cells [7], a technique that provides high temporal and spatial resolution of neuropeptides targeted specifically to brain tissue. Second, it is unclear whether oligonucleotides that function via the RNA interference (RNAi), as employed in this and their previous study in spontaneously hypertensive rats (SHRs) [8], were equally able (at the given doses) to cross the blood–brain barrier (BBB) or reach the brainstem nuclei through the gaps in the BBB such as the area postrema or other circumventricular organs [9,10]. Authors need to consider the possibility that siRNA penetration through the fenestrated endothelia in circumventricular organs may have suppressed AGT expression and Ang II generation without changing total AGT expression in brainstem.Ren et al. [11] reported that siRNAs do not readily cross the cell membrane, nor do siRNAs cross an intact BBB without modifications [12]. The limitations of current RNAi approaches to silence brain genes are documented [13]. Indeed, direct administration of AGT antisense oligonucleotides (ASOs) into the brain of hypertensive rodent models has been shown to reduce blood pressure and alter brain but not plasma Ang II levels [14]. Multiple studies provide evidence for an intrinsic brain RAS in which Ang II acts as a neurotransmitter [2–4,15]. While the successful application of trivalent N-acetylgalactosamine (GalNAc)–siRNA conjugates for targeted delivery of siRNA to the liver takes advantage of the rich presence on hepatocytes of the endocytosis promoting asialoglycoprotein receptor [16], effective and safe systemic delivery of siRNA into the brain remains challenging and may require nanotechnology [17]. The advocated tissue specificity of the (GalNAc)–siRNA by the authors remains questionable as AGT protein levels were markedly decreased in kidney and adipose tissue (Figure 3C in Uijl et al. [1]).The enthusiasm for employing these novel tools to prevent AGT expression either via ASO [18] or siRNA assumes that AGT’s sole function is to be the only known substrate for the generation of angiotensins. As illustrated in Figure 1, the human AGT protein is composed of 452 amino acids of which the N-terminus signal peptide is contained in the first 33 amino acids [19]. The amino acid sequence containing the peptides Ang-(1-25) [20], Ang-(1-12) [21], Ang I, Ang-(1-9), Ang-(1-8), Ang-(1-7), Ang-(2-8), and other fragments is initiated by Aspartic acid in position 34 from the N-terminus Methionine1. Potential biological functions of the non-angiotensin coding region of the AGT molecule, named des-(Ang I)-AGT, remains unappreciated [14,22,23]. This is surprising as Corvol et al. first called attention to the antiangiogenic actions of des-(Ang I)-AGT [24,25] while more recently, overexpression of human AGT was reported to protect mice from sinusoid’s remodeling and arterialization in cancerous tissue [26]. Other studies demonstrate that AGT acts as a VGEF inhibitor of endothelial cell migration [27], a modulator of BBB permeability, diet-induced obesity, and hepatic steatosis [28,29]. Alnylam Pharmaceuticals (Cambridge, MA, U.S.A) reported, at the recent 2020 American Heart Association (AHA) Scientific Sessions, positive interim data from their ongoing Phase 1 study of liver-expressed AGT siRNA [ALN-AGT RNAi] [30]. Briefly, patients receiving the investigational ALN-AGT gene silencing drug experienced dose-dependent reductions in blood pressure which, as underscored by Dzau and Balatbat, [31] points toward the therapeutic potential for RNAi-mediated AGT in the treatment of hypertension. As AGT lies upstream from other RAS targets, the potential arises for off-target-mediated, yet non-RAS or non-blood pressure mediated effects of des-(Ang I)-AGT.We close by complimenting the authors on their comprehensive study and look forward to their future advances in this field of RNA-based therapeutics to reduce cardiovascular disease risk. Novel therapeutic targets modulating AGT or, preferably one of its fragments [e.g. Ang-(1-12)] may represent novel and more efficient approaches to the treatment of primary hypertension and target organ damage. However, further advances should be made to better understand how RNA-based precision medicine for the modulation of gene/protein expression of angiotensins influence individual tissue RAS generation (e.g., brain and its various compartments) and non-RAS, off-target effects.The authors declare that there are competing interests associated with the manuscript.This work was supported by the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health [grant number HL-051952 (to C.M.F.)]." @default.
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• W3148674927 title "Letter to the Editor: Brain renin–angiotensin system and liver-directed siRNA targeted to angiotensinogen" @default.
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