This is the first report demonstrating equal ligand activities of both, renin and prorenin, on the (pro)renin receptor - promyelocytic zinc finger protein-phosphatidylinositol-3 kinase-p85alpha pathway. The failure of aliskiren to inhibit the noncatalytic effects of renin and prorenin may be of clinical relevance considering the increase in plasma concentrations of (pro)renin under aliskiren treatment.

Abstract-The losartan metabolite EXP3174 exhibits angiotensin II receptor 1 (AT1R)-blocking properties, whereas the metabolite EXP3179 potently induces the activity of the insulin-sensitizing peroxisome proliferator-activated receptor ␥ (PPAR␥) as a partial agonist in vitro. We investigated whether chronic treatment with losartan leads to sufficient serum levels of EXP3179 to activate PPAR␥ in monocytes derived from losartan-treated patients. Hypertensive patients (nϭ15) treated with losartan (100 mg/daily for at least the past 2 months) and untreated control patients (nϭ7) were included. Monocytes were extracted by negative isolation using a Dynal Monocyte Kit, followed by analysis of PPAR␥ target gene expression (CD36, ABC transporter G1 [ABCG1]) by quantitative real-time RT-PCR. Serum was prepared before, 2, 4, and 6 hours after losartan (100 mg) ingestion for HPLC-based determination of losartan, EXP3174, and EXP3179. Chronic treatment with losartan resulted in basal levels of losartan, EXP3174, and EXP3179 of 348.3Ϯ101.8 ng/mL, 115.3Ϯ56.1 ng/mL, and 176.2Ϯ143.4 ng/mL, respectively. Levels of both EXP3174 and EXP3179 were time-dependently increased in serum with a maximum 2 hours after drug intake (1706.0Ϯ760.1 ng/mL, 808.9Ϯ618.2 ng/mL, respectively). In consonance with detectable PPAR␥-activating EXP3179 serum levels, monocytic PPAR␥ target gene expression was significantly upregulated in patients treated with losartan by 3.75Ϯ0. Key Words: peroxisome proliferator-activated receptor gamma Ⅲ angiotensin receptor blocker Ⅲ losartan Ⅲ CD36 Ⅲ ABCG1 Ⅲ monocytes Ⅲ hypertension