Redox‐sensitive Sp‐3 Transcription Factor via Renal AT1 Receptor Contributes to Age‐related Hypertension

Abstract

Renal angiotensin II type 1 receptor (AT1R) plays pivotal role in blood pressure control. We recently reported an exaggerated AT1 receptor function and hypertension in aged (21 month) Fisher 344 X Brown Norway (FBN) rats. Antioxidant tempol treatment reduced AT1R function and blood pressure in these rats suggesting a role of oxidative stress in this phenomenon. However, oxidative stress mechanism for higher AT1R function is not known. Therefore, we became interested in delineating the mechanism of oxidative stress induced up‐regulation of AT1R in aging kidney. mRNA levels of renal AT1R were measured by qRT‐PCR while nuclear Sp‐3 and AT1R protein levels were measured by western blot. To further examine whether oxidative stress increases nuclear translocation of Sp‐3 and up‐regulation of renal AT1R expression, we treated human kidney 2 (HK2) cells with pro‐oxidants diethyldithiocarbamate (DDC) and hydrogen peroxide (H2O2). Acute treatment of DDC (30min) and H2O2 (20min)increased nuclear levels of Sp‐3 which was attenuated with tempol treatment. DDC chronic treatment (2.5 hour) increased the expression of AT1R while tempol treatment attenuated this effect. Moreover, Sp‐3 plasmid increased and Sp‐3 siRNA decreased the levels of AT1R protein in HK2 cells. Our results suggest that redox‐sensitive Sp‐3 transcription factor up‐regulates renal AT1 receptor and may contribute to age‐related hypertension.Source of research support: NIH/NIA AG039856