Jiang Quan, Song Guiyu, He Liying, Li Xue, Jiang Bo, Wang Qianxun, Wang Shaoxun, Kim Catherine, Barkestani Mahsa Nouri, Lopez Roberto, Fan Matthew, Wanniarachchi Kujani, Quaranta Maya, Tian Xuefei, Mani Arya, Gonzalez Anjelica, Goodwin Julie E, Sessa William C, Ishibe Shuta, Jane-Wit Dan
Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Cardiology, West Haven VA Medical Center, West Haven, Connecticut, USA.
Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Cardiology, West Haven VA Medical Center, West Haven, Connecticut, USA; Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
Kidney Int. 2024 Sep;106(3):419-432. doi: 10.1016/j.kint.2024.05.007. Epub 2024 May 24.
ZFYVE21 is an ancient, endosome-associated protein that is highly expressed in endothelial cells (ECs) but whose function(s) in vivo 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 Zfyve21 reporter mice. These knockout mice developed accelerated aging phenotypes including reduced endothelial nitric oxide (ENOS) activity, failure to thrive, and kidney insufficiency. Kidneys from Zfyve21 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.
ZFYVE21是一种古老的、与内体相关的蛋白质，在内皮细胞（ECs）中高度表达，但其在体内的功能尚不清楚。在此，我们确定ZFYVE21是衰老肾脏中血管屏障功能的关键调节因子。在老年人类和小鼠肾脏的内皮细胞中，ZFYVE21水平显著下降。为了研究相关影响，我们构建了内皮细胞特异性Zfyve21报告基因小鼠。这些基因敲除小鼠出现了加速衰老的表型，包括内皮型一氧化氮合酶（ENOS）活性降低、生长发育不良和肾功能不全。Zfyve21内皮细胞小鼠的肾脏出现间质水肿和肾小球内皮细胞损伤。ZFYVE21介导的表型并非发育编程所致，因为成年期内皮细胞中ZFYVE21的缺失模拟了其在出生前的缺失，并且一氧化氮供体可使成年宿主的肾功能恢复正常。通过活细胞成像和人类肾脏器官培养，我们发现ZFYVE21以一种依赖于小GTP酶Rab5和蛋白激酶Akt的方式，降低了抑制性小窝蛋白-1的囊泡水平，并促进了高尔基体衍生的ENOS向核周Rab5囊泡群体的转移，从而在功能上维持ENOS活性。因此，我们的研究确定了一种ZFYVE21介导的维持ENOS活性的转运机制，并证明了该途径与衰老过程中维持肾功能的相关性。
