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

Author:

Kinouchi Kenichiro1,Ichihara Atsuhiro1,Sano Motoaki1,Sun-Wada Ge-Hong1,Wada Yoh1,Kurauchi-Mito Asako1,Bokuda Kanako1,Narita Tatsuya1,Oshima Yoichi1,Sakoda Mariyo1,Tamai Yoshitaka1,Sato Hiromu1,Fukuda Keiichi1,Itoh Hiroshi1

Affiliation:

1. From the Department of Endocrinology, Metabolism, and Nephrology (K.K., A.I., A.K.-M., K.B., T.N., M.S., H.I.), the Department of Endocrinology and Anti-Aging Medicine and Internal Medicine (A.I., Y.O.), and the Department of Cardiology (M.S., K.F.), Keio University School of Medicine, Tokyo, Japan; Precursory Research for Embryonic Science and Technology (PRESTO) (M.S.), Japan Science and Technology Agency, Saitama, Japan; the Department of Biochemistry (G.-H.S.-W.), Faculty of Pharmaceutical...

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 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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