The (pro)renin receptor/ATP6AP2 is essential for vacuolar H+-ATPase assembly in murine cardiomyocytes.
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.
Kinouchi
Kenichiro
K
Department of Endocrinology, Metabolism, and Nephrology, Keio University School of Medicine, Tokyo, Japan.
Ichihara
Atsuhiro
A
Sano
Motoaki
M
Sun-Wada
Ge-Hong
GH
Wada
Yoh
Y
Kurauchi-Mito
Asako
A
Bokuda
Kanako
K
Narita
Tatsuya
T
Oshima
Yoichi
Y
Sakoda
Mariyo
M
Tamai
Yoshitaka
Y
Sato
Hiromu
H
Fukuda
Keiichi
K
Itoh
Hiroshi
H
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
C458319:ATP6AP2 protein, human; D011498:Protein Precursors; D011956:Receptors, Cell Surface; D012083:Renin; D025262:Vacuolar Proton-Translocating ATPases; D000093342:Prorenin Receptor