ZFYVE21 is an ancient, endosome-associated protein that is highly expressed in endothelial cells (ECs) but whose function(s) are undefined. Here, we identified ZFYVE21 as an essential regulator of vascular barrier function in the aging kidney. ZFYVE21 levels significantly decline in ECs in aged human and mouse kidneys. To investigate attendant effects, we generated EC-specific reporter mice. These knockout mice developed accelerated aging phenotypes including reduced endothelial nitric oxide (ENOS) activity, failure to thrive, and kidney insufficiency. Kidneys from EC mice showed interstitial edema and glomerular EC injury. ZFYVE21-mediated phenotypes were not programmed developmentally as loss of ZFYVE21 in ECs during adulthood phenocopied its loss prenatally, and a nitric oxide donor normalized kidney function in adult hosts. Using live cell imaging and human kidney organ cultures, we found that in a GTPase Rab5- and protein kinase Akt-dependent manner, ZFYVE21 reduced vesicular levels of inhibitory caveolin-1 and promoted transfer of Golgi-derived ENOS to a perinuclear Rab5 vesicular population to functionally sustain ENOS activity. Thus, our work defines a ZFYVE21- mediated trafficking mechanism sustaining ENOS activity and demonstrates the relevance of this pathway for maintaining kidney function with aging.

中文翻译：

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ZFYVE21 在衰老过程中促进肾脏内皮一氧化氮信号传导和血管屏障功能


ZFYVE21 是一种古老的内体相关蛋白，在内皮细胞 (EC) 中高度表达，但其功能尚不清楚。在这里，我们确定 ZFYVE21 是衰老肾脏中血管屏障功能的重要调节剂。老年人和小鼠肾脏 EC 中的 ZFYVE21 水平显着下降。为了研究随之而来的影响，我们生成了 EC 特异性报告小鼠。这些基因敲除小鼠出现了加速衰老的表型，包括内皮一氧化氮（ENOS）活性降低、生长迟缓和肾功能不全。 EC 小鼠的肾脏显示间质水肿和肾小球 EC 损伤。 ZFYVE21 介导的表型并未在发育过程中被编程，因为成年期 EC 中 ZFYVE21 的缺失在表型上复制了其在产前的缺失，并且一氧化氮供体使成年宿主的肾功能正常化。使用活细胞成像和人肾器官培养，我们发现 ZFYVE21 以 GTPase Rab5 和蛋白激酶 Akt 依赖性方式降低抑制性 Caveolin-1 的囊泡水平，并促进高尔基体衍生的 ENOS 转移到核周 Rab5 囊泡群体，从而功能上维持 ENOS 活性。因此，我们的工作定义了维持 ENOS 活性的 ZFYVE21 介导的运输机制，并证明了该途径与维持肾功能随衰老的相关性。