SAT-057 Endoplasmic Reticulum Aminopeptidase-1 Is a Novel Regulator of the Renin-Angiotensin-Aldosterone System and Blood Pressure Homeostasis

Endoplasmic Reticulum Aminopeptidase-1 (ERAP1) has been proposed to metabolize angiotensin II (ANGII), an effector molecule of the renin-ANGII-aldosterone (ALDO) system (RAAS) and key regulator of volume and blood pressure (BP) homeostasis. ERAP1 plays an important role in immune function as it cleaves cytokine cell surface receptors and HLA binding precursors thereby modulating their inclusion into major histocompatibility complex-I (MHC). Indeed, absence of ERAP1 in vivo shows MHC-I peptide presentation defects and decreased T regulatory cells in mice. However, the interaction between ERAP1 and RAAS remains unclear. We hypothesized that ERAP1 mediates the interaction between BP homeostasis and cardiorenal disease. We studied ERAP1 deficient heterozygous (ERAP1+/-) mice; a mouse with a phenotype likely more equivalent to what would be seen in human subjects, i.e. reduced, not absent, ERAP1. We observed that ERAP1+/- mice had 45% lower ERAP1 levels by western blot analyses in heart and kidney as compared to wild-type (WT) littermate control mice maintained on regular rodent chow (n= 10 of each type, p=0.029). We measured ANGII tissue levels by LC/MS and show increased levels in heart, kidney and aortas from ERAP1+/- as compared to WT control mice (P<0.05). On regular rodent chow, urinary 24 hr ALDO levels were increased in ERAP1+/- compared to WT mice (7.11 ±0.82 [WT, n=10] vs 9.92 ±0.88 ng/dL [ERAP1+/-, n=8], p=0.03) while plasma renin activity (PRA) were not significantly different between the two mouse types (65.3±3.2 [WT, n=10] vs 66.16±2.3 ng/ml*h [ERAP1+/-, n=8]). We also evaluated BP by tail cuff on mice maintained on regular rodent chow and showed increased systolic BP in ERAP1+/- as compared to WT mice, (122.8±0.8 [ERAP1, n=9] vs. 110.2±1.6 mmHg [WT, n=12], p=0.003). We then studied the effects of salt intake on BP in these mice. ERAP1+/- mice had increased salt sensitivity of BP, defined as systolic BP on high, 1.6% Na+ diet minus systolic BP on low, 0.03% Na+ diet, when compared to WT mice (SSBP: 8.5±2.3 [ERAP1, n=15] vs -0.2 ±1.6 mmHg [WT, n=15], p=0.0043). Similar results were obtained using continuous intraarterial BP monitoring by telemetry in freely moving mice (SSBP by telemetry: 6.8±1.2 [ERAP1, n=3] vs 0.4±0.7 mmHg [WT, n=2], p<0.001). We then studied renal hemodynamics using 2D and Color-Doppler imaging and showed that ERAP1+/- mice have increased peak-systolic velocity (PSV) and end-diastolic velocity (EDV) compared to WT mice on regular mouse chow (PSV: 412.6±38.6 [WT, n=4] vs 570.2±27.7 mm/s [ERAP1+/-, n=3] p=0.027; EDV: 127.9±9.8 [WT, n=4] vs 191.0±16.3 mm/s [ERAP1+/-, n=6], p=0.02). In conclusion, ERAP1 deficiency is associated with SSBP, likely secondary both to increased ALDO and altered renovascular function.