Despite overwhelming evidence for the role of the renin-angiotensin system (RAS) in blood pressure control, there is considerable disagreement over its involvement in hypertension. In part, this relates to the lack of a transgenic model which replicates endogenous renin gene expression and normal physiological regulation of the RAS. The general goal of the proposed studies is to investigate the mechanisms that direct appropriate cell-specific expression of the renin gene. In particular, the applicant wishes to determine the role of flanking and intervening sequences in the renin gene that contribute to appropriate cell- and tissue-specific expression of renin and prorenin. Because cell culture models of renal renin gene expression may not utilize physiologically relevant mechanisms to express the renin gene, the experiments proposed in this application make use of transgenic mice. Constructs will be generated to test the role of flanking and intervening sequences both in directing renin gene expression to appropriate physiological sites, and in preventing renin expression at inappropriate sites. The applicant will then use information generated in these studies to target a supervital marker, green fluorescent protein (GFP), to the renal juxtaglomerular (JG) cells. This will permit him to identify JG cells directly, in vivo, by fluorescence microscopy and to isolate these cells using flow cytometry sorting. It is hoped that these cells will prove useful as a model to study renin gene expression, prorenin processing and renin secretion in vitro. Understanding the mechanisms that regulate normal renin synthesis and secretion should help to identify pathophysiological changes in hypertensive patients that result in inappropriately high renin secretion, and thus provide new therapeutic targets for the treatment of hypertension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK045982-05
Application #
6045962
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Scherbenske, M James
Project Start
1996-02-01
Project End
2004-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
5
Fiscal Year
2000
Total Cost
$219,406
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065