Blood Pressure Lowering and Safety Improvements With Liver Angiotensinogen Inhibition in Models of Hypertension and Kidney Injury

Hypertension. 2017 Sep;70(3):566-576. doi: 10.1161/HYPERTENSIONAHA.117.09755. Epub 2017 Jul 17.


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.

Keywords: acute kidney injury; angiotensin II; angiotensinogen; blood pressure; hypertension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury* / etiology
  • Acute Kidney Injury* / metabolism
  • Acute Kidney Injury* / physiopathology
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Angiotensinogen / metabolism*
  • Animals
  • Antihypertensive Agents / pharmacology
  • Blood Pressure / drug effects
  • Blood Pressure / physiology
  • Disease Models, Animal
  • Drug Resistance / physiology
  • Hypertension* / drug therapy
  • Hypertension* / metabolism
  • Hypertension* / physiopathology
  • Kidney / metabolism
  • Kidney / physiopathology
  • Oligonucleotides, Antisense* / metabolism
  • Oligonucleotides, Antisense* / pharmacology
  • Rats
  • Rats, Inbred SHR
  • Renin-Angiotensin System* / drug effects
  • Renin-Angiotensin System* / physiology
  • Treatment Outcome


  • Angiotensin-Converting Enzyme Inhibitors
  • Antihypertensive Agents
  • Oligonucleotides, Antisense
  • Angiotensinogen