Loss of Collectrin, an ACE2 Homologue, Uncouples Endothelial Nitric Oxide Synthase and Causes Hypertension and Vascular Dysfunction
Background—Collectrin is an orphan member of the renin-angiotensin system and is a homologue of ACE2, sharing ~50% sequence identity. Unlike ACE2, collectrin lacks any catalytic domain. Collectrin has been shown to function as a chaperone of amino acid transporters. In rodents, the renal expression of collectrin is increased after sub-total nephrectomy and during high salt feeding, raising the question whether collectrin has any direct role in blood pressure regulation.
Methods and Results—Using a susceptible genetic background, we demonstrate that deletion of collectrin results in hypertension, exaggerated salt sensitivity and impaired pressure natriuresis. Collectrin knockout mice display impaired endothelial dependent vasorelaxation that is associated with vascular remodeling, eNOS uncoupling, decreased nitric oxide production and increased superoxide generation. Treatment with tempol, a superoxide scavenger, attenuates the augmented sodium sensitivity in collectrin knockout mice. We report for the first time that collectrin is expressed in endothelial cells. Furthermore, collectrin directly regulates L-arginine uptake and plasma membrane levels of CAT1 and y+LAT1 amino acid transporters in endothelial cells. Treatment with L-arginine modestly lowers blood pressure of collectrin KO mice.
Conclusions—Collectrin is a consequential link between the transport of L-arginine and eNOS uncoupling in hypertension.
- Received April 19, 2013.
- Revision received August 9, 2013.
- Accepted August 14, 2013.