Notch activation differentially regulates renal progenitors proliferation and differentiation toward the podocyte lineage in glomerular disorders.
Notch activation differentially regulates renal progenitors proliferation and differentiation toward the podocyte lineage in glomerular disorders.
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DOI：
10.1002/stem.492
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发表时间：
2010-09
期刊：
影响因子：
5.2
通讯作者：
Romagnani, Paola
中科院分区：
文献类型：
--
作者：
Lasagni, Laura;Ballerini, Lara;Angelotti, Maria Lucia;Parente, Eliana;Sagrinati, Costanza;Mazzinghi, Benedetta;Peired, Anna;Ronconi, Elisa;Becherucci, Francesca;Bani, Daniele;Gacci, Mauro;Carini, Marco;Lazzeri, Elena;Romagnani, Paola
肾小球疾病占终末期肾病的90%。足细胞丢失是进展为肾小球硬化的常见决定因素。成熟的足细胞不能增殖，但最近的证据表明，它们可以被鲍曼囊内定位的肾前体细胞取代。在这里，我们证明了人肾前体细胞中Notch的激活刺激进入细胞周期的S期和细胞分裂，而它的下调是向足细胞分化所必需的。事实上，Notch通路的持续激活诱导足细胞越过G2/M检查点，导致细胞骨架破坏和有丝分裂灾难而死亡。Noch在健康成人肾脏的肾小球中几乎不表达，而在肾小球疾病患者的肾祖细胞和足细胞中观察到强烈的上调。相应地，抑制局灶性节段性肾小球硬化小鼠模型中的Notch通路可以改善肾小球损伤初期的蛋白尿和减少足细胞的丢失，同时随着蛋白尿和肾小球硬化的加重，在肾小球损伤的再生期诱导祖细胞增殖减少。综上所述，这些结果表明，肾小球疾病的严重程度取决于Notch调节的足细胞死亡和肾前体细胞再生之间的平衡。干细胞，2010；28：1674-1685。
Glomerular diseases account for 90% of end-stage kidney disease. Podocyte loss is a common determining factor for the progression toward glomerulosclerosis. Mature podocytes cannot proliferate, but recent evidence suggests that they can be replaced by renal progenitors localized within the Bowman's capsule. Here, we demonstrate that Notch activation in human renal progenitors stimulates entry into the S-phase of the cell cycle and cell division, whereas its downregulation is required for differentiation toward the podocyte lineage. Indeed, a persistent activation of the Notch pathway induced podocytes to cross the G2/M checkpoint, resulting in cytoskeleton disruption and death by mitotic catastrophe. Notch expression was virtually absent in the glomeruli of healthy adult kidneys, while a strong upregulation was observed in renal progenitors and podocytes in patients affected by glomerular disorders. Accordingly, inhibition of the Notch pathway in mouse models of focal segmental glomerulosclerosis ameliorated proteinuria and reduced podocyte loss during the initial phases of glomerular injury, while inducing reduction of progenitor proliferation during the regenerative phases of glomerular injury with worsening of proteinuria and glomerulosclerosis. Taken altogether, these results suggest that the severity of glomerular disorders depends on the Notch-regulated balance between podocyte death and regeneration provided by renal progenitors. Stem Cells 2010; 28:1674–1685.
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影响因子：
19.6
作者：
KRIZ, W;HAHNEL, B;ELGER, H
通讯作者：
ELGER, H
Notch 激活静止心肌细胞的细胞周期重入和进展。
DOI：
10.1083/jcb.200806104
发表时间：
2008-10-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Campa VM;Gutiérrez-Lanza R;Cerignoli F;Díaz-Trelles R;Nelson B;Tsuji T;Barcova M;Jiang W;Mercola M
通讯作者：
Mercola M
DOI：
10.1159/000209207
发表时间：
2009
期刊：
Nephron. Experimental nephrology
影响因子：
--
作者：
Niranjan T;Murea M;Susztak K
通讯作者：
Susztak K
DOI：
10.1084/jem.20021897
发表时间：
2003-06-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lasagni L;Francalanci M;Annunziato F;Lazzeri E;Giannini S;Cosmi L;Sagrinati C;Mazzinghi B;Orlando C;Maggi E;Marra F;Romagnani S;Serio M;Romagnani P
通讯作者：
Romagnani P
影响因子：
19.6
作者：
NAGATA, M;KRIZ, W
通讯作者：
KRIZ, W