title: Suppressing angiotensinogen synthesis attenuates kidney cyst formation in a Pkd1 mouse model.
abstract: Activation of the intrarenal renin angiotensin system (RAS) is believed to play an important role in the development of hypertension and cystogenesis in autosomal dominant polycystic kidney disease (ADPKD). Results of clinical studies testing RAS inhibitors in slowing the progression of cystic disease in ADPKD are inconclusive, and we hypothesized that current RAS inhibitors do not adequately suppress intrarenal RAS. For this study, we compared a novel Gen 2 antisense oligonucleotide (ASO) that inhibits angiotensinogen (Agt) synthesis to lisinopril in adult conditional Pkd1 systemic-knockout mice, a model of ADPKD. Six weeks after Pkd1 global gene knockout, the mice were treated with Agt-ASO (66 mg/kg/wk), lisinopril (100 mg/kg/d), PBS (control), or scrambled ASO (66 mg/kg/wk) for 10 wk, followed by tissue collection. Agt ASO resulted in significant reduction in plasma, liver, and kidney Agt, and increased kidney renin compared with control treatments. Kidneys from Agt-ASO-treated mice were not as enlarged and showed reduced cystic volume compared with lisinopril or control treatments. Blood pressure was better controlled with lisinopril than with Agt-ASO. Agt-ASO suppressed cell proliferation in both cystic and noncystic cells compared with lisinopril and control treatments. However, Agt-ASO did not reduce cell proliferation in liver, which indicates that Agt-ASO targets cell signaling pathways that specifically suppresses cystogenesis in the kidney. These data suggest that Agt-ASO effectively attenuates intrarenal RAS and therefore can be a novel and effective agent for treating ADPKD.
authors.affiliation: *Division of Nephrology and Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina, USA; Ralph Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA; and Isis Pharmaceuticals, Carlsbad, California, USA saigusa@musc.edu bellpd@musc.edu.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Saigusa
authors.affiliation: *Division of Nephrology and Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina, USA; Ralph Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA; and Isis Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Dang
authors.affiliation: *Division of Nephrology and Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina, USA; Ralph Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA; and Isis Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Adam E
authors.initials: AE
authors.lastname: Mullick
authors.affiliation: *Division of Nephrology and Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina, USA; Ralph Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA; and Isis Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Steve T
authors.initials: ST
authors.lastname: Yeh
authors.affiliation: *Division of Nephrology and Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina, USA; Ralph Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA; and Isis Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.affiliation: *Division of Nephrology and Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina, USA; Ralph Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA; and Isis Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Catalin F
authors.initials: CF
authors.lastname: Baicu
authors.affiliation: *Division of Nephrology and Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina, USA; Ralph Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA; and Isis Pharmaceuticals, Carlsbad, California, USA saigusa@musc.edu bellpd@musc.edu.
authors.forename: P Darwin
authors.initials: PD
authors.lastname: Bell
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D017706:Lisinopril / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism*; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000808:Angiotensinogen; D017706:Lisinopril; D050396:TRPP Cation Channels
keywords: antisense oligonucleotide; hypertension; polycystic kidney disease; renin angiotensin system