Molecular variation in the angiotensinogen gene and implications for essential hypertension

Advances in the field of human genetics in the last four decades have enabled researchers to move from characterizing extremely rare diseases caused by gross chromosomal abnormalities to common diseases influenced by single base substitutions. The task now at hand is to investigate how subtle variation in the human genome can cause alterations in gene function that predispose to disease. Essential hypertension is a common disease that affects 10-25% of industrialized populations. To date one gene has been shown to influence susceptibility to essential hypertension in multiply reproduced studies by independent groups of investigators: angiotensinogen. Evidence for a disease-associated molecular mechanism involving increased transcriptional activity of this gene has created the need for a detailed understanding of the general mechanisms that activate angiotensinogen. An introduction chapter describes the basic mechanisms of short-term and long-term regulation of blood pressure, the search for genes predisposing to essential hypertension, and the details of findings implicating alleles of angiotensinogen as predisposing factors to essential hypertension. Chapter 2 describes the characterization of four transcription factor binding sites within the human angiotensinogen proximal promoter. Upstream Stimulatory Factor, Estrogen Receptor, Sp1, and TATA Binding Protein are investigated individually within the context of genetic variation and response to extracellular stimuli as well as within the context of a transcriptionally active whole. Chapter 3 describes a comparison between the proximal promoters of human and mouse angiotensinogen and characterizes functional differences as well as functional similarities between the two promoters. Chapter 4 describes an intrarenal Renin-Angiotensin System which operates in conjunction with as well as independently of the systemic Renin-Angiotensin System. This tubular system in the kidney exhibits differential expression of angiotensinogen in the proximal tubule and renin in the distal tubule as a function of dietary sodium. Chapter 5 discusses challenges inherent to studying the genetics of common diseases. This chapter also discusses possible reasons for the lack of insight into the genetics of essential hypertension which engineered strains of laboratory animals with high blood pressure have provided, and concludes with a comment on potential pitfalls that may occur with the introduction of genetic information into mainstream society.