Atherosclerosis Mechanisms: Angiotensin II Production and Action

The renin angiotensin system (RAS) plays a critical role in atherosclerosis. Mechanisms how the RAS contributing to atherosclerosis have been focusing on direct effects of the RAS components in the atherosclerosis-prone vasculature. On the basis of our preliminary data, we challenge this concept and propose to test a novel hypothesis that kidney orchestrates AGT derived from hepatocytes with renal renin and angiotensin-converting enzyme (ACE) to regulate renal AngII production and activate renal AT1a receptor, thereby contributing to atherosclerosis. We will test this hypothesis by addressing 2 aims. Aim 1 defines how AGT, the substrate of the RAS, derived from hepatocytes regulates renal AngII production and contributes to atherosclerosis. AGT from hepatocytes is filtered through glomeruli and retained by megalin, a member of LDL receptor superfamily, in renal proximal convoluted tubules (PCT). Our protein sequence and structure analyses from fish to mammals identified 2 conserved sequences that are potentially associated with its binding to megalin. We will determine whether conserved sequences of AGT, through its interaction with megalin, influence renal AngII production and atherosclerosis using hepatocyte-specific AGT or PCT-specific megalin deficient mice, and adeno-associated viral system. Aim 2 determines whether renal AngII and its interaction with renal AT1aR contribute to atherosclerosis. We will use kidney-specific renin or ACE deficient mice and mice with restricted AngII production in PCTs to determine whether renal AngII production contributes to atherosclerosis, while effects of renal AT1aR will be determined using renal AT1aR deficient mice. Proposed studies will provide evidence whether kidney is the major source for each classic RAS component to promote atherosclerosis. This is a conceptually new viewpoint that liver and kidney synchronize the RAS components to promote atherosclerosis in the aorta. Demonstration of this new concept will change our paradigm for understanding mechanisms of atherosclerosis and developing new relative therapeutic strategies.