RESUMO
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.
Assuntos
Envelhecimento , Caveolina 1 , Células Endoteliais , Rim , Camundongos Knockout , Óxido Nítrico Sintase Tipo III , Óxido Nítrico , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Animais , Humanos , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Células Endoteliais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rim/metabolismo , Caveolina 1/metabolismo , Caveolina 1/genética , Óxido Nítrico/metabolismo , Proteínas rab5 de Ligação ao GTP/metabolismo , Proteínas rab5 de Ligação ao GTP/genética , Camundongos , Masculino , Complexo de Golgi/metabolismo , Insuficiência Renal/metabolismo , Insuficiência Renal/fisiopatologia , Insuficiência Renal/genética , Doadores de Óxido Nítrico/farmacologia , Fenótipo , Camundongos Endogâmicos C57BLRESUMO
Atherosclerosis is a vascular disease in which inflammation plays a pivotal role. Receptor-mediated signaling pathways regulate vascular inflammation and the pathophysiology of atherosclerosis. Emerging evidence has revealed the role of the Wnt pathway in atherosclerosis progression. The Wnt pathway influences almost all stages of atherosclerosis progression, including endothelial dysfunction, monocyte infiltration, smooth muscle cell proliferation and migration, and plaque formation. Targeting the Wnt pathway to treat atherosclerosis represents a promising therapeutic approach that remains understudied. Blocking Wnt signaling utilizing small molecule inhibitors, recombinant proteins, and/or neutralizing antibodies ameliorates atherosclerosis in preclinical models. The Wnt pathway can be potentially manipulated through targeting Wnt ligands, receptors, co-receptors, and downstream signaling molecules. However, there are challenges associated with developing a real world therapeutic compound that targets the Wnt pathway. This review focuses on the role of Wnt signaling in atherosclerosis development, and the rationale for targeting this pathway for the treatment of atherosclerosis.