Abstract 229: Effects Of Human Angiotensinogen And Human Renin In Proximal Tubule Cells On Development Of Atherosclerosis In Hypercholesterolemic Mice

Abstract

Objective: This study determined whether angiotensinogen (AGT) interacted with renin in renal proximal tubule cells (PTCs) to promote atherosclerosis. Approach and Results: Since hepatocyte-produced AGT can be filtered by glomeruli and retained in renal PTCs, we first determined whether hepatocyte-derived AGT interacts with renin in PTCs to promote atherosclerosis. Transgenic mice expressing human renin in PTCs driven by a kidney androgen-related protein promoter (KAP-hREN) in an LDLR -/- background were used. To induce synthesis of human AGT in hepatocytes, an adeno-associated viral vector (AAV) containing human AGT with a liver-specific promoter was injected intraperitoneally. Three groups of male littermates were administered testosterone to activate human renin expression in PTCs: (1) wild type mice administered null AAV, (2) KAP-hREN transgenic mice administered null AAV, and (3) KAP-hREN transgenic mice administered AAV containing human AGT. Two weeks after administration of testosterone and AAVs, mice were fed a Western diet for 6 weeks. Induction of human AGT in liver and human renin in PTCs did not increase atherosclerosis, comparing to the other two groups. Next, to evaluate the direct interaction of AGT and renin in PTCs for promoting atherosclerosis, KAP-human AGT (KAP-hAGT) and KAP-hREN double transgenic mice were fed a Western diet for 12 weeks. Although immunostaining confirmed the presence of human AGT and human renin in PTCs, double transgenic mice did not have increased percent atherosclerotic lesion area, comparing to either wild type or single transgenic littermate groups. Surprisingly, retired male double transgenic breeders (46-67 weeks old) showed severe atherosclerosis spontaneously without Western diet feeding, while their single transgenic littermates had minimal to modest atherosclerotic lesions. The sample size was small so statistical analysis was not performed. Conclusions: The presence of human AGT in liver or PTCs with combination of human renin in PTCs did not augment Western diet-induced atherosclerosis in mice. Further studies with increased numbers are needed to determine whether retired male breeders containing human AGT and human renin in PTCs develop severe atherosclerosis.