title: The (pro)renin receptor/ATP6AP2 is essential for vacuolar H+-ATPase assembly in murine cardiomyocytes.
abstract: BACKGROUND
  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.
  
  
  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 V(O) 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.
authors.affiliation: Department of Endocrinology, Metabolism, and Nephrology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kinouchi
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Ichihara
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
authors.forename: Ge-Hong
authors.initials: GH
authors.lastname: Sun-Wada
authors.forename: Yoh
authors.initials: Y
authors.lastname: Wada
authors.forename: Asako
authors.initials: A
authors.lastname: Kurauchi-Mito
authors.forename: Kanako
authors.initials: K
authors.lastname: Bokuda
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Narita
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Oshima
authors.forename: Mariyo
authors.initials: M
authors.lastname: Sakoda
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Tamai
authors.forename: Hiromu
authors.initials: H
authors.lastname: Sato
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000235:genetics; D006333:Heart Failure / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D011498:Protein Precursors / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012083:Renin / Q000235:genetics / Q000502:physiology*; D025262:Vacuolar Proton-Translocating ATPases / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D000093342:Prorenin Receptor
chemical_list: C458319:ATP6AP2 protein, human; D011498:Protein Precursors; D011956:Receptors, Cell Surface; D012083:Renin; D025262:Vacuolar Proton-Translocating ATPases; D000093342:Prorenin Receptor