Our long range objective is to understand the role of renin- angiotensin system in hypertension. Angiotensin, the most active pressor substance known, is synthesized by the proteolytic cleavage of its precursor molecule, angiotensinogen. Understanding the regulation of angiotensinogen synthesis is of vital importance as the renin - angiotensin system is intimately involved in the pathogenesis of some forms of human hypertension. We have recently demonstrated that angiotensinogen is not only synthesized in the liver but also in the heart and the brain. The effects of brain and heart angiotensinogen on hypertension, the mechanism of its conversion into angiotensin and the regulation of its synthesis by different modulators, however, remains unknown. Similarly the structure of human angiotensinogen gene and the role of various nucleotide regions in the regulation of its synthesis remains unknown. The main objective of the present proposal is to understand the regulation of angiotensinogen synthesis. We will specifically identify cis-acting nucleotide sequences present in the promoter region of this gene and trans-acting protein factors that bind to the promoter region and regulate its gene expression. We will then compare the binding of trans-acting protein factors (isolated from the liver, brain and heart) with the angiotensinogen gene promoter so as to study its gene regulation in different tissues. Our next objective is to study the role of salt in angiotensinogen gene expression in different tissue of the rat. Salt depletion increases the angiotensinogen mRNA levels in the kidney but not in the liver. We will compare the angiotensinogen mRNA levels in the rat liver, brain, heart and kidney under sodium depletion and then study the mechanism involved in the modulation of its transcription by salt depletion. We will perform nuclear run-off assays to study the role of salt depletion on the rate of transcription and compare the binding of angiotensinogen promoter with nuclear proteins of salt depleted rat tissues using DNase footprinting and gel mobility shift assay. A successful completion of the present project, in the future, will help us understand the role of renin-angiotensin system in hypertension, and may help us devise potential therapies to control high blood pressure.
| Zhao, Y Y; Qasba, P; Siddiqui, M A et al. (1993) Multiple CCAAT binding proteins regulate the expression of the angiotensinogen gene. Cell Mol Biol Res 39:727-37 |
| Goswami, S K; Zhao, Y Y; Siddiqui, M A et al. (1993) MyoD transactivates angiotensinogen promoter in fibroblast C3H10T1/2 cells. Cell Mol Biol Res 39:125-30 |
