Liver-targeted N-acetylgalactosamine-conjugated AGT ASO produced robust blood pressure reductions in hypertensive rats without causing the acute kidney injury seen with standard RAAS blockade.
Does liver-targeted AGT inhibition reduce blood pressure and improve safety compared to traditional RAAS blockade in rat models of hypertension and kidney injury?
Liver-selective AGT inhibition provides robust blood pressure lowering while preserving renal function during severe RAAS challenge in rat models, suggesting a potential safety and efficacy advantage over traditional RAAS blockade.
Uncontrolled hypertension is an important contributor to cardiovascular disease. Despite the armamentarium of antihypertensive treatments, there remains a need for novel agents effective in individuals who cannot reach acceptable blood pressure levels. Inhibitors targeting the renin-angiotensin-aldosterone system (RAAS) are widely used but may not optimally inhibit RAAS and demonstrate an acceptable safety profile. Experiments were conducted to characterize a series of AGT (angiotensinogen) antisense oligonucleotides (ASOs) and compare their efficacy and tolerability to traditional RAAS blockade. AGT ASOs which target multiple systemic sites of AGT versus an N-acetylgalactosamine-conjugated AGT ASO that targets the liver were compared with captopril and losartan. Spontaneously hypertensive rats fed an 8% NaCl diet, a model of malignant hypertension resistant to standard RAAS inhibitors, demonstrated robust and durable blood pressure reductions with AGT ASO treatments, which was not observed with standard RAAS blockade. Studies in rat models of acute kidney injury produced by salt deprivation revealed kidney injury with ASO treatment that reduced kidney-expressed AGT, but not in animals treated with the N-acetylgalactosamine AGT ASO despite comparable plasma AGT reductions. Administration of either captopril or losartan also produced acute kidney injury during salt deprivation. Thus, intrarenal RAAS derived from kidney AGT, and inhibited by the standard of care, contributes to the maintenance of renal function during severe RAAS challenge. Such improvements in efficacy and tolerability by a liver-selective AGT inhibitor could be desirable in individuals not at their blood pressure goal with existing RAAS blockade.
Mullick et al. (Tue,) conducted a other in Hypertension and Kidney Injury. AGT antisense oligonucleotides (ASOs) including N-acetylgalactosamine-conjugated AGT ASO vs. Captopril and losartan was evaluated on Blood pressure reductions and kidney injury. Liver-targeted N-acetylgalactosamine-conjugated AGT ASO produced robust blood pressure reductions in hypertensive rats without causing the acute kidney injury seen with standard RAAS blockade.