Expression and Function of Mas-Related G Protein-Coupled Receptor D and Its Ligand Alamandine in Retina

A local renin-angiotensin system (RAS) exists in the retina and plays a critical role in retinal neurovascular function. The protective axis of RAS comprising of angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) [Ang-(1-7)]/Mas receptor attenuate the deleterious actions of increased levels of angiotensin II (Ang II), the main effector peptide of RAS. A new peptide, alamandine, and its receptor Mas-related G protein-coupled receptor D (MrgD) have been recently identified that share structural and functional similarity to Ang-(1-7) and its receptor, Mas, establishing another new protective axis of RAS. Here, we examined the expression and cellular localization of MrgD in the retina, the effect of MrgD deficiency on mouse retinal structure and function, as well as the biological function of alamandine in cultured retinal cells. We showed that MrgD is expressed in the retinal neurons, retinal vasculature, Muller glial and RPE cells, similar to Mas receptor expression. MrgD-deficient mice did not exhibit gross change in retinal morphology and thickness; however, these mice did show a progressive decrease in both scotopic and photopic a-wave and b-wave amplitudes, and increase in retinal capillary loss with age compared to age-matched wild-type mice. In vitro studies in human retinal cells showed that alamandine attenuated the Ang II and LPS-induced increases in inflammatory cytokine gene expression, NF-kappa B activation, Ang II and hydrogen peroxide-induced production of reactive oxygen species, comparable to that mediated by Ang-(1-7). These results support the notion that alamandine/MrgD may represent another new protective axis of RAS in the retina exerting anti-oxidative and anti-inflammatory effects.