Estrada Chelsea C, Wilson Craig, Gujarati Nehaben, Ahmed Sumaya, Bronstein Robert, Daehn Ilse S, Revelo Monica P, Guo Yiqing, Mallipattu Sandeep K
Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, United States.
Division of Nephrology, Department of Medicine, Northport Veterans Affairs Medical Center, Northport, New York, United States.
Am J Physiol Renal Physiol. 2025 Feb 1;328(2):F190-F203. doi: 10.1152/ajprenal.00283.2024. Epub 2024 Dec 20.
Glomerular endothelial cell (GEnC) injury is a common feature across the wide spectrum of glomerular diseases. We recently reported that the endothelial-specific knockout of increases the susceptibility to GEnC injury and subsequent development of subacute thrombotic microangiopathy (TMA). However, the mechanism(s) mediating GEnCs response to injury in TMA are poorly understood. Single-nucleus RNA-sequencing demonstrated enrichment in pathways involved in angiogenesis, permeability, focal adhesion, dedifferentiation, and cytoskeletal organization in the endothelial cluster in mice with TMA. , a structural component of fenestral diaphragms, was highly enriched specifically in injured GEnCs. Induction of in cultured GEnCs increased proliferation, migration, and cell permeability with an accompanying loss of mature GEnC markers. Immunostaining for PLVAP in human kidney biopsies confirmed the increase in glomerular PLVAP in TMA, which correlated with a higher grade of glomerular injury. To date, this is the first study to show that the induction of in GEnCs shifts the cells to an immature state, which might exacerbate glomerular injury in TMA. This study investigated the mechanism(s) underlying glomerular endothelial cell (GEnC) injury in thrombotic microangiopathy (TMA). We identified plasmalemmal vesicle-associated protein (PLVAP) as specifically upregulated in injured GEnCs in TMA, which was accompanied by pathways involved in angiogenesis and loss of differentiation. Induction of increased proliferation and migration of GEnCs. Human kidney biopsies with TMA demonstrated an increase in glomerular PLVAP, which correlated with histological markers of GEnC injury, confirming its pathologic role in TMA.
肾小球内皮细胞（GEnC）损伤是各种肾小球疾病的共同特征。我们最近报道，内皮细胞特异性敲除会增加对GEnC损伤的易感性以及随后亚急性血栓性微血管病（TMA）的发生。然而，介导TMA中GEnC对损伤反应的机制尚不清楚。单核RNA测序表明，TMA小鼠的内皮细胞簇中参与血管生成、通透性、粘着斑、去分化和细胞骨架组织的途径富集。窗孔隔膜的结构成分PLVAP在受损的GEnC中高度富集。在培养的GEnC中诱导PLVAP可增加细胞增殖、迁移和细胞通透性，同时伴随着成熟GEnC标志物的丧失。对人类肾活检组织进行PLVAP免疫染色证实，TMA中肾小球PLVAP增加，这与更高等级的肾小球损伤相关。迄今为止，这是第一项表明在GEnC中诱导PLVAP会使细胞转变为未成熟状态的研究，这可能会加剧TMA中的肾小球损伤。本研究调查了血栓性微血管病（TMA）中肾小球内皮细胞（GEnC）损伤的潜在机制。我们发现，在TMA中受损的GEnC中，质膜囊泡相关蛋白（PLVAP）特异性上调，同时伴有血管生成和分化丧失相关的途径。诱导PLVAP可增加GEnC的增殖和迁移。TMA患者的肾活检显示肾小球PLVAP增加，这与GEnC损伤的组织学标志物相关，证实了其在TMA中的病理作用。
