The bradykinin type 2 receptor (B2) mediates virtually all of the known effects of the kallikrein-kinin system on vascular, renal, and cardiovascular homeostasis. Bradykinin, through a B2 receptor dependent-mechanism, is an integral contributor to the efficacy of angiotensin converting enzyme inhibitors. Animal studies suggest that genetic variation altering the regulation or function of the B2 receptor has direct vascular consequences. In the human B2 receptor, common sites of genetic variation have been defined in the 5' and 3' regulatory regions. Differences in the frequency of genetic variation in the B2 receptor may increase cardiovascular risk and contribute to the discrepant burden of hypertension and associated target organ damage among ethnic groups. In African Americans, an association has been reported between the -58C allele of a C-to-T transition polymorphism at position -58 in the core promoter and hypertension. Similar results have been reported in Japanese and Chinese populations. As of yet, functional effects have not been ascribed to the known B2 receptor polymorphisms, and few studies are currently available regarding the molecular regulation of the human B2 receptor. Data from our laboratory suggest a 4-fold difference among haplotypes of 5' promoter/exon 1 polymorphisms in basal transcriptional activity. Among the alleles in a 3'-UTR polymorphism, data indicate a 5-fold variation of reporter gene activity. Based on these data, we hypothesize that the B2 receptor contains functional polymorphic variants in 5' and 3' regulatory areas that affect gene expression. B2 receptor polymorphisms may contribute to ethnic differences in vascular reactivity. Data from our laboratory suggest decreased vascular sensitivity to bradykinin in normotensive African Americans compared to Caucasians. The ethnic differences in response to vasoconstrictors are largely untested. We hypothesize that B2 receptor polymorphisms contribute to bradykinin-dependent alterations and ethnic differences in vascular sensitivity. Basic and clinical studies in humans are pcoposed to determine functionality of genetic variation in the B2 receptor and its role as a susceptibility factor to alterations in vascular reactivity.
The SPECIFIC AIMS of this proposal are: 1: To characterize variation in gene expression associated with B2 receptor polymorphisms. 2: To determine how receptor expression is altered by B2 receptor polymorphisms.3: To test the significance of B2 receptor polymorphisms on vascular sensitivity. This combination of studies will generate relevant, new information regarding the genetic and physiologic regulation of the B2 receptor, which will help to delineate further the role of the kallikrein kinin system in vascular, renal and cardiovascular pathology and the utility of the B2 receptor as a therapeutic target.
| Pretorius, M M; Gainer, J V; Van Guilder, G P et al. (2008) The bradykinin type 2 receptor BE1 polymorphism and ethnicity influence systolic blood pressure and vascular resistance. Clin Pharmacol Ther 83:122-9 |
| Zamorano, Rocio; Suchindran, Sunil; Gainer, James V (2006) 3'-Untranslated region of the type 2 bradykinin receptor is a potent regulator of gene expression. Am J Physiol Renal Physiol 290:F456-64 |
