# Atherosclerosis Mechanisms: Angiotensin II production and action

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2021 · $486,886

## Abstract

Abstract
 The renin angiotensin system (RAS) plays a critical role in the development of
atherosclerosis. Mechanisms by which the RAS contributes to atherosclerosis have been
focusing on effects of angiotensin II (AngII) production and its action through AT1a receptors
within atherosclerotic lesions. On the basis of our preliminary data, we challenge this concept
and propose a new hypothesis: Renal AngII production through a megalin-mediated
pathway in proximal convoluted tubules (PCTs) promotes atherosclerosis via its local
stimulation of AT1a receptors. Angiotensinogen (AGT), the substrate of the RAS, derived
from hepatocytes is filtered through glomeruli and retained by megalin, a member of LDL
receptor superfamily, in PCTs. Our protein sequence and structure analyses identified two
conserved sequences that may associate with its binding to megalin. Aim 1 will define how
hepatocyte-derived AGT regulates renal AngII production and contributes to atherosclerosis.
We will use site-mutagenesis, surface plasmon resonance, and cell culture system to determine
how AGT and megalin interact in vitro. Subsequently, we will use an adeno-associated viral
(AAV) system to manipulate conserved sequences of AGT in hepatocyte-specific AGT deficient
mice to determine whether conserved sequences of AGT influence renal AngII production and
atherosclerosis. Effects of megalin on renal AngII production and atherosclerosis will be
determined using PCT-specific megalin deficient mice. Since AGT is cleaved by two critical
enzymes, renin and angiotensin-converting enzyme (ACE), to produce AngII, Aim 2 will first
determine whether renin or ACE derived from PCTs contributes to renal AngII production and
atherosclerosis using PCT-specific renin and ACE deficient mice, respectively. Studies
proposed in Aim 1 for AGT and megalin interaction and Aim 2 for the two enzymes (renin and
ACE) do not provide direct evidence whether AngII produced in PCTs contributes to
atherosclerosis. To answer this question, we will use a transgenic mouse model that has
restricted production of AngII in PCTs. AngII promotes atherosclerosis through AT1a receptor-
mediated mechanism. Therefore, subsequent experiments will determine whether PCTs are the
location for AT1a receptors to promote atherosclerosis. Completion of proposed studies will
provide evidence whether renal PCTs are the major source for each classic RAS component to
promote atherosclerosis. Demonstration of this new concept may change our understanding of
the AngII/AT1a receptor-mediated mechanisms of atherosclerosis, which may also provide
insights into developing new therapeutic strategies.

## Key facts

- **NIH application ID:** 10132375
- **Project number:** 5R01HL139748-04
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Alan Daugherty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $486,886
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132375

## Citation

> US National Institutes of Health, RePORTER application 10132375, Atherosclerosis Mechanisms: Angiotensin II production and action (5R01HL139748-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10132375. Licensed CC0.

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