Abstract-The renin-angiotensin-aldosterone system plays an important role in blood pressure regulation by influencing salt-water homeostasis and vascular tone. The purpose of the present study was to search for associations of single nucleotide polymorphisms on 3 major candidate genes of this system with the plasma concentrations of the corresponding renin-angiotensin-aldosterone system components considered as quantitative phenotypes. Genotyping was performed in 114 normotensive subjects for different variants of the angiotensinogen (AGT) gene (C-532T, G-6A, M235T), the angiotensin I-converting enzyme (ACE) gene [4656(CT) 2/3 ], the aldosterone synthase (CYP11B2), and the type 1 angiotensin II receptor (AT1R) gene (A1166C) by hybridization with allele-specific oligonucleotides (ASO) or enzymatic digestion of polymerase chain reaction products. Plasma levels of AGT, ACE, angiotensin II (Ang II), aldosterone, and immunoreactive active renin were measured according to standard techniques. Platelet binding sites for Ang II were analyzed by the binding of radioiodinated Ang II to purified platelets. B max and K D values of the Ang II binding sites on platelets of each individual were calculated to examine a possible relationship between these parameters and the AT1R genotype. A highly significant association of the ACE 4656(CT) 2/3 variant with plasma ACE levels was observed (PϽ0.0001). ANOVA showed a significant effect of the AGT C-532T polymorphism on AGT plasma levels (Pϭ0.017), but no significant effect was detectable with the other AGT polymorphisms tested, such as the G-6A or the M235T. A significant effect association was also found between the C-344T polymorphism of the CYP11B2 gene and plasma aldosterone levels, with the T allele associated with higher levels (Pϭ0.02 Key Words: angiotensinogen Ⅲ angiotensin-converting enzyme Ⅲ angiotensin II Ⅲ aldosterone Ⅲ polymorphism Ⅲ blood pressure S ingle nucleotide biallelic polymorphisms are powerful tools when used to search for a linkage disequilibrium between a marker genotype and a disease, mainly of multifactorial origin. With these markers, candidate genes of the renin-angiotensin-aldosterone system (RAAS), including those of angiotensinogen (AGT), the angiotensin I-converting enzyme (ACE), and type I angiotensin (Ang) II receptor (AT1R), have been investigated in association studies with cardiovascular diseases, such as hypertension or myocardial infarction. As examples of these associations, the ACE insertion/deletion (I/D) polymorphism was found associated with myocardial infarction, cardiac hypertrophy after physical exercise, and Alzheimer disease, 1,2 and the AGT or AT1R genes were found to be associated with hypertension. 3,4 Therefore, it is of interest to establish relationships between these marker genotypes and intermediate phenotypes related to the disease and to the gene tested to understand the physiopathology of these associations, thus helping to clarify inconsistent results issued from some association studies. Among these observations, the st...

No abstract

Hypertension is frequently associated with the development of renal vascular and glomerular fibrosis. The purpose of the present study was to investigate whether epidermal growth factor receptor (EGFR) activation participates in the development of renal fibrosis and to test if blockade of EGFR activation would have therapeutic effects. Experiments were performed during nitric oxide (NO) deficiency-induced hypertension in rats (L-NAME model). After 4 weeks of L-NAME treatment, animals developed hypertension associated to deterioration of renal structure and function. Over the same period, EGFR was activated twofold within glomeruli. This activation was accompanied by increased activity of the mitogen-activated protein kinase (MAPK) p42/p44 pathway and exaggerated collagen I expression. Gefitinib, an EGFR-tyrosine kinase inhibitor, given concomitantly with L-NAME, normalized MAPK activation and collagen I expression and prevented the decline of renal function and the development of fibrosis. Since endothelin mediates the L-NAME-induced fibrogenesis, the endothelin-EGFR interaction was tested in transgenic mice expressing luciferase under the control of collagen I-alpha2 promoter: In renal cortex of these animals, the endothelin-induced collagen I gene activity was inhibited by an EGFR-phosphorylation inhibitor. These results provide the first evidence that EGFR activation plays an important role in the progression of renal vascular and glomerular fibrosis.