Sex-specific differences in endoplasmic reticulum aminopeptidase 1 modulation influence blood pressure and renin-angiotensin system responses
| Autor: | Jose R. Romero, Isis Akemi Katayama, Sanjay Ranjit, Gail K. Adler, Stephen A. Maris, Jian Yao Wong, Chee Sin Tay, Gordon H. Williams, Luminita H. Pojoga, Alicia Rivera, Jia Wei Tan, Kelly Yin Han Wong, Jonathan S. Williams, Jessica Lee, Amanda E Garza, Danielle L Brooks |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adult Male medicine.medical_specialty Diastole Blood Pressure Aminopeptidases Minor Histocompatibility Antigens Renin-Angiotensin System 03 medical and health sciences chemistry.chemical_compound ENDOPLASMIC RETICULUM AMINOPEPTIDASE 1 Mice 0302 clinical medicine Sex Factors Internal medicine Renin–angiotensin system medicine Animals Humans Sodium Chloride Dietary Aldosterone business.industry Angiotensin II General Medicine Middle Aged In vitro 030104 developmental biology Blood pressure Endocrinology chemistry 030220 oncology & carcinogenesis Renal blood flow Female business |
| Zdroj: | JCI insight. 4(21) |
| ISSN: | 2379-3708 |
| Popis: | Salt sensitivity of blood pressure (SSBP) and hypertension are common, but the underlying mechanisms remain unclear. Endoplasmic reticulum aminopeptidase 1 (ERAP1) degrades angiotensin II (ANGII). We hypothesized that decreasing ERAP1 increases BP via ANGII-mediated effects on aldosterone (ALDO) production and/or renovascular function. Compared with WT littermate mice, ERAP1-deficient (ERAP1+/-) mice had increased tissue ANGII, systolic and diastolic BP, and SSBP, indicating that ERAP1 deficiency leads to volume expansion. However, the mechanisms underlying the volume expansion differed according to sex. Male ERAP1+/- mice had increased ALDO levels and normal renovascular responses to volume expansion (decreased resistive and pulsatility indices and increased glomerular volume). In contrast, female ERAP1+/- mice had normal ALDO levels but lacked normal renovascular responses. In humans, ERAP1 rs30187, a loss-of-function gene variant that reduces ANGII degradation in vitro, is associated with hypertension. In our cohort from the Hypertensive Pathotype (HyperPATH) Consortium, there was a significant dose-response association between rs30187 risk alleles and systolic and diastolic BP as well as renal plasma flow in men, but not in women. Thus, lowering ERAP1 led to volume expansion and increased BP. In males, the volume expansion was due to elevated ALDO with normal renovascular function, whereas in females the volume expansion was due to impaired renovascular function with normal ALDO levels. |
| Databáze: | OpenAIRE |
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