Diversity of pathways for intracellular angiotensin II synthesis

The renin-angiotensin system (RAS) has undergone continuous advancement since the initial identification of renin as a pressor agent. Traditionally considered a circulatory system, the RAS is now known to exist as a tissue system as well. Recently, the tissue RAS has been further categorized as intracellular and extracellular. Owing to the unique location, the intracellular RAS encompasses new components, such as cathepsin D and chymase, which participate in intracellular angiotensin (Ang) II synthesis. In this review, evidence of the intracellular RAS and the mechanism of Ang II synthesis in various cell types will be discussed.

A physiological role for intracellular Ang II in vascular and cardiac cells has recently been demonstrated. Evidence of intracellular Ang II generation has been shown in several cell types, particularly cardiac, renal, and vascular. Importantly, intracellular synthesis of Ang II is more prominent in hyperglycemic conditions and generally involves angiotensin-converting enzyme-dependent and angiotensin-converting enzyme-independent mechanisms.

There is significant diversity in the mechanism of intracellular synthesis of Ang II in various cell types and pathological conditions. These observations suggest that a therapeutic intervention to block the RAS should take into consideration the nature of the disorder and the cell type involved.