The (Pro)renin Receptor/ATP6AP2 is Essential for Vacuolar H+-ATPase Assembly in Murine Cardiomyocytes

RATIONALE:The (pro)renin receptor [(P)RR], encoded in ATP6AP2, plays a key role in the activation of local renin-angiotensin system (RAS). A truncated form of (P)RR, termed M8.9, was also found to be associated with the vacuolar H-ATPase (V-ATPase), implicating a non–RAS-related function of ATP6AP2....

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Bibliographic Details
Published in:Circulation research 2010-07, Vol.107 (1), p.30-34
Main Authors: Kinouchi, Kenichiro, Ichihara, Atsuhiro, Sano, Motoaki, Sun-Wada, Ge-Hong, Wada, Yoh, Kurauchi-Mito, Asako, Bokuda, Kanako, Narita, Tatsuya, Oshima, Yoichi, Sakoda, Mariyo, Tamai, Yoshitaka, Sato, Hiromu, Fukuda, Keiichi, Itoh, Hiroshi
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cardiology. Vascular system
Cell Survival - genetics
Fundamental and applied biological sciences. Psychology
Heart
Heart Failure - enzymology
Heart Failure - mortality
Heart Failure - pathology
Heart failure, cardiogenic pulmonary edema, cardiac enlargement
Medical sciences
Mice
Mice, Knockout
Myocytes, Cardiac - enzymology
Myocytes, Cardiac - pathology
Protein Precursors - genetics
Protein Precursors - physiology
Receptors, Cell Surface - deficiency
Receptors, Cell Surface - genetics
Receptors, Cell Surface - physiology
Renin - genetics
Renin - physiology
Vacuolar Proton-Translocating ATPases - deficiency
Vacuolar Proton-Translocating ATPases - metabolism
Vacuolar Proton-Translocating ATPases - physiology
Vertebrates: cardiovascular system
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Summary:RATIONALE:The (pro)renin receptor [(P)RR], encoded in ATP6AP2, plays a key role in the activation of local renin-angiotensin system (RAS). A truncated form of (P)RR, termed M8.9, was also found to be associated with the vacuolar H-ATPase (V-ATPase), implicating a non–RAS-related function of ATP6AP2. OBJECTIVE:We investigated the role of (P)RR/ATP6AP2 in murine cardiomyocytes. METHODS AND RESULTS:Cardiomyocyte-specific ablation of Atp6ap2 resulted in lethal heart failure; the cardiomyocytes contained RAB7- and lysosomal-associated membrane protein 2 (LAMP2)-positive multivesicular vacuoles, especially in the perinuclear regions. The myofibrils and mitochondria remained at the cell periphery. Cardiomyocyte death was accompanied by numerous autophagic vacuoles that contained undigested cellular constituents, as a result of impaired autophagic degradation. Notably, ablation of Atp6ap2 selectively suppressed expression of the VO subunits of V-ATPase, resulting in deacidification of the intracellular vesicles. Furthermore, the inhibition of intracellular acidification by treatment with bafilomycin A1 or chloroquine reproduced the phenotype observed for the (P)RR/ATP6AP2-deficient cardiomyocytes. CONCLUSIONS:Genetic ablation of Atp6ap2 created a loss-of-function model for V-ATPase. The gene product of ATP6AP2 is considered to act as in 2 ways(1) as (P)RR, exerting a RAS-related function; and (2) as the V-ATPase-associated protein, exerting a non–RAS-related function that is essential for cell survival.
ISSN:0009-7330
1524-4571
DOI:10.1161/CIRCRESAHA.110.224667