Subcellular characteristics of functional intracellular renin-angiotensin systems

Abstract

The renin-angiotensin system (RAS) is now regarded as an integral component in not only the development of hypertension, but also in physiologic and pathophysiologic mechanisms in multiple tissues and chronic disease states. While many of the endocrine (circulating), paracrine (cell-to-different cell) and autacrine (cell-to-same cell) effects of the RAS are believed to be mediated through the canonical extracellular RAS, a complete, independent and differentially regulated intracellular RAS (iRAS) has also been proposed. Angiotensinogen, the enzymes renin and angiotensin-converting enzyme (ACE) and the angiotensin peptides can all be synthesized and retained intracellularly. Angiotensin receptors (types I and 2) are also abundant intracellularly mainly at the nuclear and mitochondrial levels. The aim of this review is to focus on the most recent information concerning the subcellular localization, distribution and functions of the iRAS and to discuss the potential consequences of activation of the subcellular RAS on different organ systems.

Fig. 1

Diagrammatic representation of the renin-angiotensin system depicting the peptide cascade and interactions of enzymes, proteins and receptors.

Fig. 2

Scheme foriRAS. In endoplasmic reticulum(ER), renin cleaves angiotensinogen to ANG I, which is subsequently processed to ANG II by angiotensin-converting enzyme (ACE). The different components including the processing enzymes, ang peptides and receptors can be transported intracellularly via secretory vesicles to the cell surface. These different components can be transported directly either to the mitochondria or the nucleus. In the mitochondria, Ang II binds to mtAT₂ Rsand stimulates NO formation through mtNOS, suppressing mitochondrial oxygen consumption. Nuclear Ang II can stimulate NO formation (via AT₂Rs) or Ca²⁺ and phosphoinositol 3 kinase (PI3K) (via AT₁Rs).

Fig. 3

Cellular distribution of different iRAS components.

Fig. 4

A hypothetical model for changes in mitochondrial angiotensin receptors with aging. Note that with aging the balance is tipped toward more expression of mtAT₁Rs and less mtAT₂Rs. The imbalance between mtAT₁Rs and mtAT₂Rs with aging may accelerate the development of age related oxidative stress, mtDNA mutations, apoptosis and senescence. ACEi, ACE inhibitor; ARBs, Ang II receptor blockers.