Abstract P159: Induction Of Human Angiotensinogen In Hepatocytes And Human Renin In Renal Proximal Tubule Cells Does Not Accelerate Atherosclerosis In Mice

Abstract

Objective: Hepatocyte-produced angiotensinogen (AGT) can be filtered by glomeruli and retained in renal proximal tubules. Renin protein has also been detected in proximal tubules (PTC) of kidney. However, it is unknown whether AGT and renin in proximal tubules contribute to atherosclerosis. This study aimed to determine whether hepatocyte-derived AGT interacts with renin in proximal tubules to promote atherosclerosis. Approach and Results: Transgenic mice expressing human renin driven by a kidney androgen-related protein promoter (KAP-hREN) in an LDLR -/- background were administered subcutaneously with testosterone (15 mg/mouse, constant release for 60 days) to activate the human renin transgene in PTCs. To induce synthesis of human AGT in hepatocytes, adeno-associated viral (AAV; 3 x 10 10 genomic copies/mouse) vector containing human AGT with a liver-specific promoter was injected intraperitoneally. Three groups of male littermates were administered testosterone: (1) wild type mice administered null AAV (n=11), (2) KAP-hREN transgenic mice administered null AAV (n=7), and (3) KAP-hREN transgenic mice (n=8) administered AAV containing human AGT. Two weeks after administration of testosterone and AAVs (either null or human AGT), all mice were fed a Western diet for 6 weeks. Induction of human renin was confirmed by mRNA abundance of human renin in kidney of KAP-hREN transgenic mice. In mice administered human AGT AAV, presence of human AGT was detected in plasma with a human AGT ELISA kit. Induction of both human AGT in liver and human renin in proximal tubules did not affect plasma cholesterol concentrations or systolic blood pressure. Atherosclerotic lesion sizes, as quantified by percent lesion area using an en face method, were not different among the 3 groups (Group 1 vs 2 vs 3: 3.7 ± 0.4% vs 3.3 ± 0.9% vs 2.3 ± 0.3%; P = 0.19). Conclusions: Induction of human AGT in hepatocytes and human renin in proximal tubules does not augment atherosclerosis in hypercholesterolemic mice.