Hypertension and Angiotensin II Hypersensitivity in Aminopeptidase A—deficient Mice

Abstract

Local concentrations of the vasopressor peptide, angiotensin II (AngII), depend upon the balance between synthesis and degradation. Previous studies of blood pressure (BP) regulation have focused primarily on the generation of AngII and its receptors, and less attention has been devoted to angiotensin degradation. Aminopeptidase A (APA, EC 3.4.11.7) is responsible for the N-terminal cleavage of AngII, a hydrolytic event that serves as a rate-limiting step in angiotensin degradation. To evaluate the physiological role of APA, we examined BP homeostasis in APA-deficient mice. We measured basal BP and BP with continuous infusion of AngII in APA mutant mice by tail-cuff method. We also evaluated the development and histology of AngII-targeted organs as well as urine excretion in these mice. Homozygous APA mutant mice were found to have elevated basal systolic BP when compared with heterozygous mutant and wild-type littermate mice. Infusion of AngII led to an enhanced systolic BP response in the APA-deficient mice. Despite the sustained elevation of BP in APA knockout mice, neither their renal and cardiac sizes nor their histological appearances were not different from control mice. Moreover, the volume, osmolality, and electrolyte content of the urine were normal in APA-deficient mice. APA deficiency increased baseline BP and enhanced the hypertensive response to increased levels of AngII. These findings indicate a physiological role for APA in lowering BP and offer novel insight into the mechanisms for developing hypertension.

Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: A potential treatment of salt-dependent hypertension

“…injection of EC33. In this context, the recent report of Mitsui et al (42) showing a slight elevation of systolic BP in APA genetically deficient mice cannot be easily explained. However, on one hand, the mechanism by which APA deficiency results in hypertension was not addressed in that paper, and on the other, one must consider that the chronic inactivation of APA achieved in APA-deficient mice cannot be easily compared to an acute blockade of this enzyme as in the present study.…”

Functional genetic variation in aminopeptidase A (ENPEP): Lack of clear association with focal and segmental glomerulosclerosis (FSGS)

“…Along these same lines, homozygous mice that have targeted deletion of ENPEP (Lin, et al, 1998) have elevated baseline blood pressure, which can be increased by continual infusion of angiotensinogen II to a greater extent compared to wild type mice (Mitsui, et al, 2003). In addition, high blood pressure caused by hyperactive brain RAAS in the DOCA-salt sensitive rat can be reduced for up to 24 hours by a selective inhibitor of APA that is able to transgress the blood-brain barrier (Fournie-Zaluski, et al, 2004).…”

Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver

“…These include mannose-binding lectin 2 (MBL2) 49,50) and glutamyl aminopeptidase ENPEP 51,52) . MBL is an important protein of the humoral innate immune system, and it has been reported that the serum MBL concentrations are decreased in obese subjects, accompanied by an increase in inflammatory markers 49) .…”

“…ENPEP is an enzyme that facilitates the conversion of angiotensin , the main effector protein of the renin-angiotensin-aldosterone system, to angiotensin 51) . In addition, Enpep KO mice develop hypertension, and recombinant ENPEP treatment significantly decreases systolic blood pressure 52) , suggesting that ENPEP is an essential enzyme for controlling blood pressure. Interestingly, these two genes were dose-dependently upregulated in the primary human hepatocytes, but oppositely downregulated in the mouse liver by K-877.…”