Department of Endocrinology, Metabolism, and Nephrology, Keio University School of Medicine, Tokyo, Japan.
Circ Res. 2010 Jul 9;107(1):30-4. doi: 10.1161/CIRCRESAHA.110.224667. Epub 2010 Jun 22.
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.
We investigated the role of (P)RR/ATP6AP2 in murine cardiomyocytes.
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.
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.
（前）肾素受体[（P）RR]，在 ATP6AP2 中编码，在局部肾素-血管紧张素系统（RAS）的激活中发挥关键作用。（P）RR 的一种截断形式，称为 M8.9，也与液泡 H（+）-ATP 酶（V-ATPase）相关，暗示 ATP6AP2 具有非 RAS 相关的功能。
我们研究了（P）RR/ATP6AP2 在鼠心肌细胞中的作用。
心肌细胞特异性敲除 Atp6ap2 导致致命性心力衰竭；心肌细胞含有 RAB7 和溶酶体相关膜蛋白 2（LAMP2）阳性的多泡体，特别是在核周区域。肌原纤维和线粒体仍然位于细胞外周。心肌细胞死亡伴随着大量自噬空泡，其中包含未消化的细胞成分，这是由于自噬降解受损所致。值得注意的是，Atp6ap2 的缺失选择性地抑制了 V-ATPase 的 V（O）亚基的表达，导致细胞内囊泡的酸化。此外，用巴弗洛霉素 A1 或氯喹处理抑制细胞内酸化可再现观察到的（P）RR/ATP6AP2 缺陷型心肌细胞的表型。
Atp6ap2 的基因缺失创建了 V-ATPase 的功能丧失模型。ATP6AP2 的产物被认为有 2 种作用方式：（1）作为（P）RR，发挥 RAS 相关的功能；（2）作为 V-ATPase 相关蛋白，发挥非 RAS 相关的功能，这对细胞存活至关重要。
