An intracellular renin-angiotensin system in neurons: fact, hypothesis, or fantasy

Abstract

The renin-angiotensin system in the brain acts to regulate a number of physiological processes. Evidence suggests that angiotensin peptides may act as neurotransmitters, although their biosynthetic pathways are poorly understood. We review evidence for neuronal production of angiotensin peptides and hypothesize that angiotensin may be synthesized intracellularly in neurons.

Figure 1. The Renin-Angiotensin System

Recent advances in understanding the complex biochemistry of the RAS have prompted new interest in the significance of alternative peptide products. Alternate processing pathways result in the stimulation of distinct receptor populations on target cells, and thus the presence or absence of individual enzymes in the local environment, and receptor subtypes expressed in target cells, can grossly alter the effects of angiotensin signaling on target cells. Although typically assumed to function entirely in the interstitium, emerging evidence suggests possible mechanisms of intracellular formation of the various peptides. For a more detailed review of the known enzymatic pathways involved, see (47; 48).

Figure 2. Synthesis of Intracellular Renin

The hypothesized biosynthetic pathway for intracellular renin is shown. Classically, preprorenin is the primary translation product of the renin-A mRNA transcribed from the classical renin promoter and including exon-1a. Preprorenin is processed (red arrows) first by removal of the signal peptide and then by removal of the prosegment. Active renin is subsequently released into the systemic circulation. In the brain, a different renin mRNA termed renin-b is transcribed from an unknown promoter within intron-1 (in mice) or 6.2 kb upstream of the classical renin promoter (in humans) to result in a novel transcript lacking exon-1a, and including exon-1b. There are no ATG sequences in exon-1b in rat, mouse, or human, and thus translation begins at the highly conserved ATG present in exon-2. This product encodes the entire active renin protein and ⅔ of the prosegment. It is unclear, if the prosegment is removed. As the protein lacks a signal peptide, it is unlikely to be secreted. Additional studies are needed to determine if this protein is stable, remains intracellularly, and within which intracellular structures it resides.

Figure 3. Neuronal RAS- A Provocative Hypothesis

The findings reviewed herein suggest the intriguing possibility for the intracellular generation of angiotensin peptides (ANG) derived from the intracellular conversion of angiotensinogen (AGT) by renin-b or intracellular renin (icREN). The fate of intracellular angiotensin peptides synthesized in this way remains undefined. We hypothesize that some mechanism may exist for these peptides to be packaged into neurosecretory bodies and perhaps transported through axons to the synapse. Similarly, we hypothesize that the presence of the prorenin receptor [(P)RR] on the neuronal surface may provide a mechanism for prorenin or renin in the extracellular space to be concentrated in the proximity of angiotensinogen released from either glial cells or neurons. This, in the presence of other angiotensin converting enzymes may lead to the synthesis of angiotensin peptides in the proximity of neuronal angiotensin receptors (ATR).