The (Pro)renin receptor/ATP6AP2 is essential for vacuolar H +-ATPase assembly in murine cardiomyocytes

Kenichiro Kinouchi, Atsuhiro Ichihara, Motoaki Sano, Ge Hong Sun-Wada, Yoh Wada, Asako Kurauchi-Mito, Kanako Bokuda, Tatsuya Narita, Yoichi Oshima, Mariyo Sakoda, Yoshitaka Tamai, Hiromu Sato, Keiichi Fukuda, Hiroshi Itoh

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204 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)30-34
Number of pages5
JournalCirculation research
Volume107
Issue number1
DOIs
Publication statusPublished - 2010 Jul 9

Keywords

  • Autophagy
  • Bafilomycin
  • Heart failure
  • Renin-angiotensin system
  • V-ATPase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Kinouchi, K., Ichihara, A., Sano, M., Sun-Wada, G. H., Wada, Y., Kurauchi-Mito, A., Bokuda, K., Narita, T., Oshima, Y., Sakoda, M., Tamai, Y., Sato, H., Fukuda, K., & Itoh, H. (2010). The (Pro)renin receptor/ATP6AP2 is essential for vacuolar H +-ATPase assembly in murine cardiomyocytes. Circulation research, 107(1), 30-34. https://doi.org/10.1161/CIRCRESAHA.110.224667