The (pro)renin receptor (ATP6ap2) facilitates receptor-mediated endocytosis and lysosomal function in the renal proximal tubule.
The (pro)renin receptor (ATP6ap2) facilitates receptor-mediated endocytosis and lysosomal function in the renal proximal tubule.
复制标题
（原）肾素受体（ATP 6ap2）促进肾近端小管中受体介导的内吞作用和溶酶体功能。
DOI：
10.1007/s00424-021-02598-z
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Wagner CA
中科院分区：
文献类型：
--
作者：
Figueiredo M;Daryadel A;Sihn G;Müller DN;Popova E;Rouselle A;Nguyen G;Bader M;Wagner CA
ATP6ap2 (Pro)肾素受体蛋白与调节细胞器、细胞和全身酸碱稳态的 H+-ATP 酶相关。在肾脏中，ATP6ap2 与各种细胞类型（包括近端小管细胞）中的 H+-ATP 酶共定位。在那里，H+-ATP酶通过巨蛋白/cubilin受体参与受体介导的低分子量蛋白质的内吞作用。为了研究近曲小管中的 ATP6ap2 功能，我们使用了诱导型 shRNA Atp6ap2 敲除大鼠模型 (Kd) 和诱导型肾脏特异性 Atp6ap2 敲除小鼠模型。两种动物系均表现出较高的蛋白尿，尿液中白蛋白、维生素 D 结合蛋白和组织蛋白酶 B 升高。注射的液相标记物（FITC-葡聚糖，10 kDa）的内吞作用正常，而重组转铁蛋白（受体介导的内吞作用的标记物）到溶酶体的加工被延迟。虽然巨蛋白和cubilin表达没有变化，但参与受体介导的内吞作用的H+-ATP酶的几个亚基的丰度降低了。溶酶体完整性和 H+-ATP 酶功能与 mTOR 信号传导相关。在 ATP6ap2 中，KO 小鼠 mTOR 和磷酸化 mTOR 表现正常，但观察到自噬体 LC3-B 亚基丰度增加，表明在 ATP6ap2 缺失的情况下溶酶体功能存在更广泛的损害。因此，我们的数据表明 ATP6ap2 对小鼠和大鼠肾脏近端小管功能的作用，而受体介导的内吞作用存在缺陷。在线版本包含可在 10.1007/s00424-021-02598-z 获取的补充材料。
The ATP6ap2 (Pro)renin receptor protein associates with H+-ATPases which regulate organellar, cellular, and systemic acid–base homeostasis. In the kidney, ATP6ap2 colocalizes with H+-ATPases in various cell types including the cells of the proximal tubule. There, H+-ATPases are involved in receptor-mediated endocytosis of low molecular weight proteins via the megalin/cubilin receptors. To study ATP6ap2 function in the proximal tubule, we used an inducible shRNA Atp6ap2 knockdown rat model (Kd) and an inducible kidney-specific Atp6ap2 knockout mouse model. Both animal lines showed higher proteinuria with elevated albumin, vitamin D binding protein, and procathepsin B in urine. Endocytosis of an injected fluid-phase marker (FITC- dextran, 10 kDa) was normal whereas processing of recombinant transferrin, a marker for receptor-mediated endocytosis, to lysosomes was delayed. While megalin and cubilin expression was unchanged, abundance of several subunits of the H+-ATPase involved in receptor-mediated endocytosis was reduced. Lysosomal integrity and H+-ATPase function are associated with mTOR signaling. In ATP6ap2, KO mice mTOR and phospho-mTOR appeared normal but increased abundance of the LC3-B subunit of the autophagosome was observed suggesting a more generalized impairment of lysosomal function in the absence of ATP6ap2. Hence, our data suggests a role for ATP6ap2 for proximal tubule function in the kidney with a defect in receptor-mediated endocytosis in mice and rats. The online version contains supplementary material available at 10.1007/s00424-021-02598-z.
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影响因子：
3.7
作者：
Kotnik K;Popova E;Todiras M;Mori MA;Alenina N;Seibler J;Bader M
通讯作者：
Bader M
影响因子：
30.8
作者：
Frattini, A;Orchard, PJ;Villa, A
通讯作者：
Villa, A
影响因子：
4.5
作者：
Bacic, D;Capuano, P;Murer, H
通讯作者：
Murer, H
影响因子：
3.7
作者：
Daryadel A;Bourgeois S;Figueiredo MF;Gomes Moreira A;Kampik NB;Oberli L;Mohebbi N;Lu X;Meima ME;Danser AH;Wagner CA
通讯作者：
Wagner CA
影响因子：
14.8
作者：
Biber, Juerg;Stieger, Bruno;Murer, Heini
通讯作者：
Murer, Heini