Angiotensin and Aldosterone Biosynthesis

Abstract

Angiotensin II (Ang II) is, with extracellular potassium, the principal regulator of the biosynthesis of aldosterone, the main mineralocorticoid in man. Because various cardiovascular pathological states are often associated with inappropriate levels of circulating aldosterone, it is of importance to understand the intracellular molecular mechanisms leading to aldosterone output in the adrenal zona glomerulosa cell. The present chapter reviews the current knowledge on the events that are triggered by angiotensin II, from the interaction with membrane receptors to the final output of aldosterone. The initial signaling processes involve complex changes in intracellular phospholipid and calcium homeostasis resulting from effects of Ang II on various effector enzymes (phospholipases) and calcium channels, as well as on intracellular calcium stores. Concomitantly, a series of kinase pathways (protein kina se C, mitogenactivated protein kinase, tyrosine kinases, etc.) are activated. These intracellular signals then mediate a variety of localized responses along the entire cascade of events leading from uptake of cholesterol, the precursor of all steroids, to cholesterol supply to the mitochondrial enzymatic machinery that will process cholesterol to aldosterone. Indeed , Ang II increases HDL-cholesterol import at the cell surface, cholesterol ester hydrolysis in lipid droplets , scavenger receptor class B type I(HDL receptor), steroidogenic acute regulatory (StAR) protein or aldosterone synthase gene expression in the nucleus, or StAR-mediated cholesterol importation into mitochondria. In addition, recent work has shown that aldosterone can also be synthesized and act in nonclassic steroidogenic tissues such as brain, vessels and, most importantly, the heart, where it may have deleterious effects in some pathological situations such as heart failure or myocardial infarction