This is a revised proposal to study angiotensinogen and how mutations of either its gene or protein might predispose to hypertension. The investigators have tested the involvement of genes of the renin-angiotensin system in human hypertension by linkage analysis in pairs of affected siblings. In two large (379 pairs) series of patients form Utah and France, they have obtained evidence of genetic linkage between the angiotensinogen gene (AGT) and hypertension, demonstrated association of a common molecular variant of the gene (T235) with the disease, and found significant differences in plasma concentrations of angiotensinogen among hypertensive subjects as a function of AGT genotype at residue 235. Subsequently, they have reported a similar association with preeclampsia (or 'toxemia'), a common hypertensive disorder of pregnancy. These and other data support the hypothesis that molecular variants of AGT constitute inherited predispositions to essential hypertension. This hypothesis is the focus of the renewal application with the long- term objective of obtaining some clues about pathophysiological mechanisms. Initially, they define four specific aims: (1) to test the functional significance of naturally-occurring missense variants of human angiotensinogen through in vitro mutagenesis and expression followed by physical, biochemical, and metabolic analyses of recombinant products; (2) to produce and purify human angiotensinogen on a scale amenable to physical studies; (3) to investigate systematically determinants of the substrate which affect the reaction rate of mouse renin with mouse angiotensinogen, using synthetic peptides and in vitro recombinant products as substrates and recombinant mouse renin as enzyme; (4) to exploit homologous recombination in mice in order to generate transgenic animals with increased or decreased reactivity or expression of angiotensinogen for future physiological and biochemical studies on the role of angiotensinogen in the regulation of blood pressure and the pathogenesis of hypertension. Since their initial submission, they have found that another molecular variant occurring at the -6 position of the transcription start site was present in most genes coding for T235. This region is known to harbor elements that critically affects the basal transcription rate and initiating using segments of the angiotensinogen promoter with each of the two alleles observed at residue -6.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL045325-07
Application #
2415572
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1990-09-15
Project End
2000-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
7
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Utah
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Lalouel, Jean-Marc; Rohrwasser, Andreas (2007) Genetic susceptibility to essential hypertension: insight from angiotensinogen. Hypertension 49:597-603
Morgan, Terry K; Rohrwasser, Andreas; Zhao, Ling et al. (2006) Hypervolemia of pregnancy is not maintained in mice chronically overexpressing angiotensinogen. Am J Obstet Gynecol 195:1700-6
Lantelme, Pierre; Rohrwasser, Andreas; Vincent, Madeleine et al. (2005) Significance of urinary angiotensinogen in essential hypertension as a function of plasma renin and aldosterone status. J Hypertens 23:785-92
Gociman, Barbu; Rohrwasser, Andreas; Lantelme, Pierre et al. (2004) Expression of angiotensinogen in proximal tubule as a function of glomerular filtration rate. Kidney Int 65:2153-60
Rohrwasser, Andreas; Ishigami, Tomoaki; Gociman, Barbu et al. (2003) Renin and kallikrein in connecting tubule of mouse. Kidney Int 64:2155-62
Rohrwasser, Andreas; Zhang, Shuhua; Dillon, Harrison F et al. (2002) Contribution of Sp1 to initiation of transcription of angiotensinogen. J Hum Genet 47:249-56
Lantelme, Pierre; Rohrwasser, Andreas; Gociman, Barbu et al. (2002) Effects of dietary sodium and genetic background on angiotensinogen and Renin in mouse. Hypertension 39:1007-14
Nakajima, Toshiaki; Inoue, Ituro; Cheng, Tong et al. (2002) Molecular cloning and functional analysis of a factor that binds to the proximal promoter of human angiotensinogen. J Hum Genet 47:7-13
Lalouel, J M (2001) From genetics to mechanism of disease liability. Adv Genet 42:517-33
Lalouel, J M; Rohrwasser, A (2001) Development of genetic hypotheses in essential hypertension. J Hum Genet 46:299-306

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