Abstract P148: Angiotensin II Type 1a Receptor Deletion In Renal Proximal Tubular Cells Does Not Attenuate Atherosclerosis In Hypercholesterolemic Mice

Abstract

Objective: AngII (Angiotensin II) acts through AT1aR (AngII type 1a receptor) to promote atherosclerosis. Despite the consistency that global inhibition of AT1aR markedly attenuates atherosclerosis, it remains undefined in which cell types that AT1aR contributes to atherosclerosis formation. Since renal AngII is associated with increased atherosclerosis in hypercholesterolemic mice, and AT1aR is abundant on PTCs (proximal tubular cells), the present study investigated the effects of AT1aR deletion in PTCs on atherosclerosis in hypercholesterolemic mice. Approach and Results: First, both male and female LDL receptor -/- mice were fed a Western diet and infused with either vehicle or losartan for 12 weeks. Losartan led to more profound increases of plasma renin concentrations and greater reduction of systolic blood pressure in female than in male mice, whereas atherosclerosis was attenuated by losartan equivalently in both sexes. Secondary, we determined whether the effects of losartan were attributed to inhibition of AT1aR on PTCs. To generate PTC-specific AT1aR -/- mice, AT1aR floxed mice were bred with mice expressing Cre under the control of the N-myc downstream regulated gene 1. These mice were injected with 150 mg/kg/day of tamoxifen for 5 days to activate Cre at the age of 4 - 6 weeks. RNAscope detected AT1aR mRNA in both PTCs and glomeruli; mRNA of AT1aR was absent in PTCs, but not glomeruli, of PTC-specific AT1aR -/- mice. Two weeks after completion of tamoxifen injection, these mice in LDL receptor -/- background were fed Western diet for 12 weeks. Deletion of AT1aR in PTCs did not affect plasma renin concentrations, blood pressure and atherosclerosis in either sex. Finally, to investigate the impacts of PCT-specific AT1aR deletion under the conditions with enhanced AngII stimulation, AngII was infused subcutaneously for 12 weeks. There were no differences in both blood pressure and atherosclerosis between genotypes. Conclusion: Although pharmacological inhibition of AT1aR reduced atherosclerosis profoundly in both sexes, PTC-specific AT1aR deletion did not affect atherosclerosis in hypercholesterolemic mice. Our future study will determine whether the presence of AT1aR in both PTCs and glomeruli are needed to promote atherosclerosis.