This proposal is a competitive renewal application for HL-45136. Previous work showed that lung injury activates a local tissue angiotensin system in pulmonary alveolar epithelial cells (AECs) and demonstrated that de novo synthesis of angiotensin (ANG) II is required for AEC apoptosis and subsequent lung fibrosis in animal models. An important component of this system that has not been studied well is angiotensin converting enzyme-2 (ACE-2), a carboxypeptidase that degrades ANGII to form ANG1-7, a heptapeptide that blocks ANGII action. Exciting new Preliminary Data show that ACE-2 protein and mRNA are severely downregulated in both human Idiopathic Pulmonary Fibrosis and in animal models of this disease induced by bleomycin. In vivo and cell culture studies suggest that ACE-2 protects against lung fibrosis and AEC apoptosis by limiting the local accumulation of ANGII and by producing ANG1-7, which downregulates the ANGII receptor AT1. However, the roles and mechanisms of action of ACE-2 and its product ANG1-7 in AECs are unknown. This proposal is designed to begin elucidating the function(s) of ACE-2 and ANG1-7 in AEC survival in the context of lung fibrogenesis, and to begin defining the mechanisms by which ACE-2 is downregulated in experimental lung fibrosis.
Aim1 will determine if cell type-selective knockdown or overexpression of ACE-2 specifically in AECs is sufficient to enhance or inhibit, respectively, bleomycin-induced AEC apoptosis and lung fibrosis in mice.
Aim2 will define the molecular mechanisms responsible for downregulation of AEC-2 mRNA by profibrotic stimuli in cultured AECs and in a mouse model of lung fibrosis.
In Aim 3, the roles of ACE-2 and ANG1-7 in AEC survival will be elucidated in studies of cultured AECs.
Aim4 will begin defining the molecular mechanisms by which ANG1-7, acting through its receptor mas,inhibits the effects of ANGII on AECs. Together, these studies will increase our understanding of a critical component of the local angiotensin system in the lungs and may provide new information useful in the future design of novel therapeutics for Idiopathic Pulmonary Fibrosis.

Public Health Relevance

Previous work showed that lung injury activates a local tissue angiotensin system in pulmonary alveolar epithelial cells (AECs) and demonstrated that de novo synthesis of angiotensin (ANG) II is required for AEC apoptosis and subsequent lung fibrosis in animal models. An important component of this system that has not been studied well is angiotensin converting enzyme-2 (ACE-2), a carboxypeptidase that degrades ANGII to form ANG1-7, a heptapeptide that blocks ANGII action. This proposal is designed to begin elucidating the function(s) of ACE-2 and ANG1-7 in AEC survival in the context of lung fibrogenesis, and to begin defining the mechanisms by which ACE-2 is downregulated in experimental lung fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL045136-23
Application #
8318261
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
1990-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
23
Fiscal Year
2012
Total Cost
$295,066
Indirect Cost
$97,066
Name
Michigan State University
Department
Physiology
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Molina-Molina, M; Xaubet, A; Li, X et al. (2008) Angiotensinogen gene G-6A polymorphism influences idiopathic pulmonary fibrosis disease progression. Eur Respir J 32:1004-8