Angiotensinogen Suppression: A New Tool to Treat Cardiovascular and Renal Disease

Abstract

Multiple types of renin-angiotensin system (RAS) blockers exist, allowing interference with the system at the level of renin, angiotensin-converting enzyme, or the angiotensin II receptor. Yet, in particular, for the treatment of hypertension, the number of patients with uncontrolled hypertension continues to rise, either due to patient noncompliance or because of the significant renin rises that may, at least partially, overcome the effect of RAS blockade (RAS escape). New approaches to target the RAS are either direct antisense oligonucleotides that inhibit angiotensinogen RNA translation, or small interfering RNA (siRNA) that function via the RNA interference pathway. Since all angiotensins stem from angiotensinogen, lowering angiotensinogen has the potential to circumvent the RAS escape phenomenon. Moreover, antisense oligonucleotides and small interfering RNA require injections only every few weeks to months, which might reduce noncompliance. Of course, angiotensinogen suppression also poses a threat in situations where the RAS is acutely needed, for instance in women becoming pregnant during treatment, or in cases of emergency, when severe hypotension occurs. This review discusses all preclinical data on angiotensinogen suppression, as well as the limited clinical data that are currently available. It concludes that it is an exciting new tool to target the RAS with high specificity and a low side effect profile. Its long-term action might revolutionize pharmacotherapy, as it could overcome compliance problems. Preclinical and clinical programs are now carefully investigating its efficacy and safety profile, allowing an optimal introduction as a novel drug to treat cardiovascular and renal diseases in due time.

Keywords: angiotensin; angiotensinogen; hypotension; oligonucleotides, antisense; renin.

Figure 1.

The renin angiotensin system and its therapeutic targets. ACE indicates angiotensin-converting enzyme; ACEi, ACE inhibitor; ARBs, angiotensin II type 1 receptor blockers; ARNI, angiotensin receptor neprilysin inhibitor; ASO, antisense oligonucleotides; AT₁R, angiotensin II type 1 receptor; DRI=direct renin inhibitor and siRNA, small interfering RNA.

Figure 2.

Schematic of the RNA-based approaches used to target liver-derived AGT (angiotensinogen). Antisense oligonucleotides (ASOs) bind to their targeted RNA and use endogenous RNase H1, an enzyme that leads to RNA cleavage. The RNA interference (RNAi) utilizes the RNAi-induced silencing complex (RISC) containing a small interfering RNA (siRNA) to specifically degrade the targeted RNA.

Figure 3.

Overview of the effects of AGT (angiotensinogen) small interfering RNA (siRNA), Ang (angiotensin) II type 1 receptor blockade, or their combination on blood pressure, circulating Ang II, and renal Ang II in various hypertensive rat models. In the spontaneously hypertensive rats and the deoxycorticosterone acetate (DOCA) salt rats, valsartan was used, while in the 5/6th nephrectomy rats losartan was used. Ang indicates angiotensin; ARB, Ang II type 1 receptor blockers; DOCA, deoxycorticosterone acetate; and MAP, mean arterial blood pressure. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. Data have been modified from Uijl et al. and Bovée et al.^–

Figure 4.

Angiotensinogen (AGT) gene expression and protein abundance in tissues of rats. Top, tissue AGT gene expression (represented as mean fold induction relative to Agt expression in the livers of non–deoxycorticosterone acetate [DOCA] controls) in rats not given DOCA-salt (non-DOCA) or given DOCA-salt for 7 wk and treated with vehicle or AGT small interfering RNA (siRNA) during the final 3 wk (n=7 per group). Middle, AGT protein abundance of AGT in tissues of non-DOCA and DOCA-salt–treated rats given vehicle or siRNA, represented as mean fold induction relative to AGT abundance in the non-DOCA controls of each tissue. AGT mRNA (normalized vs β₂-microglobulin) and protein (fold induction vs GAPDH) levels in kidneys of Sprague-Dawley rats subjected to 5/6th nephrectomy, and treated with either vehicle, AGT siRNA, AGT siRNA+losartan, losartan, or losartan+captopril for 28 days (n=7–12). Treatment was started after 5 wk of recovery. Data are mean±SEM. AT indicates adipose tissue. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. Data have been modified from Uijl et al¹⁸ and Bovée et al.¹⁶