<br>（原）肾素受体（Atp6ap2）在分子和系统水平上的功能：在高血压、肾脏和大脑发育、炎症和纤维化中的病理意义,Pharmacological Research

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（原）肾素受体（Atp6ap2）在分子和系统水平上的功能：在高血压、肾脏和大脑发育、炎症和纤维化中的病理意义
Pharmacological Research ( IF 9.1 ) Pub Date : 2021-10-02 , DOI: 10.1016/j.phrs.2021.105922
Nadin Hoffmann ₁ , Jörg Peters ₁

Affiliation

（原）肾素受体 [（P）RR， Atp6ap2] 最初被发现是肾素原和肾素的膜结合伴侣。A 可溶性（P）RR 具有额外的旁分泌作用，并参与代谢综合征和肾脏损伤同时，很明显，（P）RR 的大部分作用与肾素无关。在肾脏中，（P）RR 通过激活促炎和促纤维化分子在肾功能障碍中发挥重要作用。在大脑中，（P）RR 在心血管调节核中表达，并与高血压有关。（P）已知 RR 是 v-ATP 酶的重要组成部分，是一种关键辅助蛋白，通过调节细胞外空间和细胞内区室的 pH 值，在肾脏、大脑和心脏中发挥重要作用。V-ATP 酶和（P）RR 共同作用于 WNT 和 mTOR 信号通路，这些通路负责细胞稳态和自噬。（P）RR 通过其在 v-ATP 酶组装和功能中的作用，对于巨蛋白的快速循环内吞作用也很重要。在肾脏中，megalin 与 v-ATP 酶和（P）RR 一起对于 RAS 成分的内吞摄取及其细胞内加工至关重要。在大脑中，（P）RR、v-ATP 酶和 megalin 是发育过程中和成人中的重要调节因子。这三种蛋白质都与 XLMR、XMRE、X 连锁帕金森病和癫痫、帕金森病伴认知障碍、痉挛、智力障碍和阿尔茨海默病等疾病有关，这些疾病的特征是神经元功能受损和/或神经元丢失。本综述侧重于 Atp6ap2 的相关影响，而不一定将它们归入 RAS。从机制上讲，许多效应可以用 Atp6ap2 对 v-ATP 酶组装和功能的作用来很好地解释。此外，讨论了可溶性（P）RR 类似物作为新治疗选择的应用。

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Functions of the (pro)renin receptor (Atp6ap2) at molecular and system levels: pathological implications in hypertension, renal and brain development, inflammation, and fibrosis

The (pro)renin receptor [(P)RR, Atp6ap2] was initially discovered as a membrane-bound binding partner of prorenin and renin. A soluble (P)RR has additional paracrine effects and is involved in metabolic syndrome and kidney damage. Meanwhile it is clear that most of the effects of the (P)RR are independent of prorenin. In the kidney, (P)RR plays an important role in renal dysfunction by activating proinflammatory and profibrotic molecules. In the brain, (P)RR is expressed in cardiovascular regulatory nuclei and is linked to hypertension. (P)RR is known to be an essential component of the v-ATPase as a key accessory protein and plays an important role in kidney, brain and heart via regulating the pH of the extracellular space and intracellular compartments. V-ATPase and (P)RR together act on WNT and mTOR signalling pathways, which are responsible for cellular homeostasis and autophagy. (P)RR through its role in v-ATPase assembly and function is also important for fast recycling endocytosis by megalin. In the kidney, megalin together with v-ATPase and (P)RR is crucial for endocytic uptake of components of the RAS and their intracellular processing. In the brain, (P)RR, v-ATPases and megalin are important regulators both during development and in the adult. All three proteins are associated with diseases such as XLMR, XMRE, X-linked parkinsonism and epilepsy, cognitive disorders with Parkinsonism, spasticity, intellectual disability, and Alzheimer’s Disease which are characterized by impaired neuronal function and/or neuronal loss. The present review focusses on the relevant effects of Atp6ap2 without assigning them necessarily to the RAS. Mechanistically, many effects can be well explained by the role of Atp6ap2 for v-ATPase assembly and function. Furthermore, application of a soluble (P)RR analogue as new therapeutic option is discussed.

更新日期：2021-10-02

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