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Aging and the renin-angiotensin system.

Angiotensin II (Ang II), the dominant effector molecule of the renin-angiotensin system (RAS), exerts its effects on binding of 2 pharmacologically distinct rhodopsin-like G protein–associated receptors, the type 1 and the type 2 (AT1 and AT2) receptors.1 Human cells express a single AT1 receptor, whereas 2 isoforms, AT1A and AT1B with 95% of amino acid sequence identity and similar affinities for Ang II, are present in rodents. The AT1A receptor, the closest murine homologue to the human AT1 receptor, predominates in most tissues, including heart, kidney, and brain. Expression of the AT2 receptor is ubiquitous in fetal tissues of rodents and humans and it decreases after birth, remaining at a low level in adulthood in adrenal medulla, uterus, ovary, vascular endothelium, and distinct brain areas.2

Arterial blood pressure is regulated by diverse pathways that include vasomotion, regulation of sodium and water excretion by the kidney, and activity of the central and sympathetic nervous systems. Circulating Ang II through activation of the AT1 receptor contributes to an increase in blood pressure and promotes renal tubular sodium and water retention.3,4

The discovery of tissue-specific RAS components in the heart, kidney, brain, and immune system led to the definition of local RAS that exerts organ-specific functions and can operate independently or in close interaction with circulating RAS components. A role of intrarenal RAS in hypertension has been suggested by cross-transplantation experiments showing that the development of hypertension is predominantly dependent on the presence of the AT1A receptor in the kidney.5 Based on the evidence that activation of the brain RAS regulates fluid balance and energy metabolism, the involvement of altered brain RAS signaling in high- and low-renin forms of hypertension has been proposed.6 Intriguing actions of …