Truncated Prorenin Comes Up … Short

Abstract

In the present issue of Hypertension , Xu et al1 report on a pivotal set of experiments that test the contribution of a key component to the action of the putative “intracellular renin-angiotensin system” (RAS; iRAS) in its normal physiological setting. In contrast to the classic circulating RAS, the iRAS has been proposed to be wholly contained within cells, where it produces angiotensin peptides that trigger noncanonical signaling (reviewed in Reference 2). The results reported by Xu et al1 suggest that an intracellular form of active prorenin cannot compensate for the loss of the classic secreted form of renin in some of the primordial roles of the RAS: directing kidney development, blood pressure regulation, and hematopiesis. The average mammalian cell makes many thousands of different proteins, each of which has to be delivered to the appropriate destination to exercise its function. The first major triage comes at the level of the secretory apparatus: all of the proteins that are destined to be released from the cell, expressed on the cell surface, or retained in one of the several vacuolar structures within the cell (secretory pathway, lysosomes, etc) first enter the membrane “bags” of the secretory pathway. This is accomplished by the recognition of a signal peptide on the newly made protein by a complex that docks the synthesis machinery on the membranes of the endoplasmic reticulum and ensures the extrusion of the protein into the lumen of the membrane sac. Proteins without a signal peptide are made within the cell cytoplasm, where they will either remain to exercise their function or where they are retargeted to other locations within the cell, such as the nucleus. Thus, whereas proteins …