Background: The intrarenal renin angiotensin system (RAS) is activated in polycystic kidney disease. We have recently shown in the Pkd1 mouse that Gen 2 antisense oligonucleotide (ASO), which suppresses angiotensinogen (Agt) synthesis, is efficacious in slowing kidney cyst formation compared to lisinopril. The aim of this current study was to determine 1) if unilateral nephrectomy accelerates cystogenesis in Pkd1 mice (as previously shown in cilia knockout mice), and 2) whether Agt ASO can slow the progression in this accelerated cystic mouse model. Methods: Adult Pkd1conditional floxed allele mice expressing cre were administered tamoxifen resulting in global knockout of Pkd1. Three weeks after tamoxifen injection, mice underwent left unilateral nephrectomy. Mice were then treated with Agt ASO (75 mg/kg/wk) or aliskiren (20 mg/kg/d) +Agt ASO or control for total of 8 weeks. Results: Unilateral nephrectomy accelerated kidney cyst formation compared to non-nephrectomized mice. Both Agt ASO and Aliskiren+Agt ASO treatment significantly reduced plasma and urinary Agt levels. Blood pressure was lowest in Aliskiren+Agt ASO among all treatment groups and control group had the highest BP. All mice developed significant kidney cysts at 8 wks after nephrectomy but Agt ASO and Aliskiren+Agt ASO group had fewer kidney cysts compared to control. Renal pAKT, pS6 levels and apoptosis were significantly suppressed in those receiving Agt ASO compared control. Conclusions: These results indicate that suppressing Agt using an ASO slowed the progression of accelerated cystic kidney disease induced by unilateral nephrectomy in Pkd1 mice by suppressing intrarenal RAS, mTOR pathway and cell proliferation.