2006 Donald Seldin Lecture—Molecular Genetics of Cardiovascular Risks: The Kidney as the Cause of Hypertension
Hypertension affects 1 billion people worldwide and is a major contributor to death from myocardial infarction, stroke, congestive heart failure, and kidney failure. Its pathogenesis has been unknown because of the complexity of blood pressure regulation, and only a minority of patients is adequately treated. To identify key pathways involved in long-term determination of blood pressure, we have investigated rare families from around the world in which hypertension or hypotension show evidence of transmission via the effects of a single gene. Using molecular genetic analysis, we have identified the specific genes and mutations that cause these disorders and have determined their biochemical mechanisms of action. These include mutations in 9 genes that cause hypertension and 8 that cause hypotension. These genes converge on a final common pathway that regulates renal salt homeostasis; mutations that cause increased renal salt reabsorption raise blood pressure, whereas those that reduce salt reabsorption lower blood pressure. Mutated genes include those encoding ion channels and transporters that mediate or regulate salt reabsorption, enzymes and receptors that regulate production of aldosterone and transduction of its signal, and a novel family of serine-threonine kinases that regulate diverse flux pathways to coordinate the balance between renal salt reabsorption and K+ secretion. These studies demonstrate the key role of renal salt handling in determination of blood pressure and identify promising new targets for therapeutic intervention. Moreover, they underscore the importance of reduction of salt balance in the treatment of hypertension in the general population while revealing limitations of single-agent diuretic therapies.