Aberrant activation of Notch-1 signaling inhibits podocyte restoration after islet transplantation in a rat model of diabetic nephropathy.
Aberrant activation of Notch-1 signaling inhibits podocyte restoration after islet transplantation in a rat model of diabetic nephropathy.
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Notch-1信号的异常激活抑制糖尿病肾病大鼠模型胰岛移植后足细胞的恢复
DOI：
10.1038/s41419-018-0985-z
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发表时间：
2018-09-20
影响因子：
9
通讯作者：
Yang T
中科院分区：
文献类型：
--
作者：
He Y;Zhang M;Wu Y;Jiang H;Fu H;Cai Y;Xu Z;Liu C;Chen B;Yang T
信号转导异常在足细胞损伤过程中起重要作用，并被认为是引发许多肾小球疾病的关键事件。有新的证据表明，在胰岛移植后，在预防肾损伤和恢复足细胞方面有显着改善。然而，信号传导异常是否影响胰岛移植的治疗效果仍不清楚。本研究旨在探讨Notch-1信号通路激活对胰岛移植后肾损伤和足细胞修复的影响。分别在糖尿病肾病和高糖条件下进行体内和体外实验。高糖可诱导足细胞损伤，Jagged-1/FC和N-[N-（3，5-二氟苯乙酰基）-l-丙氨酰]-S-苯基甘氨酸丁酯（DAPT）可调节Notch-1通路相关基因的表达水平。将足细胞与胰岛共培养，以研究高糖条件下胰岛的保护作用。组织学染色和透射电镜观察肾小球足细胞的病理变化。这项研究的结果表明，在体内和体外功能性胰岛细胞显着降低足细胞中的Notch-1信号。与共培养组和移植组相比，高活化的Notch-1信号通路显著降低了胰岛对足细胞修复和肾损伤的影响。DAPT治疗后肾损害和足细胞损伤减轻。此外，在不同的处理下，凋亡和自噬之间的平衡是不同的。本研究中的所有数据表明，高活化的Notch-1信号可能影响高糖条件下胰岛移植对肾损伤和足细胞修复的治疗效果。凋亡和自噬之间的平衡也与足细胞的恢复程度密切相关。这一发现可能表明，体内微环境在胰岛移植后足细胞修复中起着关键作用，这为将来不同糖尿病肾病患者胰岛移植后的评估和靶向治疗提供了有希望的和个体化的。
Signaling abnormalities play important roles during podocyte injury and have been indicated as crucial events for triggering many glomerular diseases. There is emerging evidence demonstrating significant improvements in preventing renal injury and restoring podocytes after islet transplantation. However, whether signaling abnormalities affect the therapeutic efficacy of islet transplantation remain unclear. This study was established to investigate the impact of Notch-1 signaling activation on renal injury and podocyte restoration after islet transplantation. Experiments were performed in vivo and in vitro under conditions of diabetic nephropathy and high-glucose medium, respectively. Podocyte injury in vitro was induced by high-glucose concentration, and expression levels of genes associated with the Notch-1 pathway were also regulated by Jagged-1/FC andN-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycinet-butyl ester (DAPT). Podocytes were co-cultured with islets to investigate the protective effect of islets in high-glucose conditions. Histopathological staining and transmission electron microscopy were performed to assess pathological changes in podocytes in glomeruli. The results from this study showed that Notch-1 signaling in podocytes was significantly decreased by functional islet cells in vivo and in vitro. Compared with the co-cultured group and transplanted group, highly activated Notch-1 signaling significantly moderated the effect of islets in affecting podocyte restoration and renal injury. Renal damage and podocyte injury were alleviated after DAPT treatment. Furthermore, the balance between apoptosis and autophagy was diverse under different treatments. All the data in this study showed that highly activated Notch-1 signaling could affect the therapeutic efficacy of islet transplantation on renal injury and podocyte restoration in high-glucose conditions. The balance between apoptosis and autophagy was also closely associated with the degree of podocyte restoration. This finding may suggest that the in vivo microenvironment plays a critical role in podocyte restoration after islet transplantation, which provides a promising and individual assessment and targeting treatment for different diabetic nephropathy patients after islet transplantation into the future.
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影响因子：
13.6
作者：
Pichaiwong, Warangkana;Hudkins, Kelly L.;Alpers, Charles E.
通讯作者：
Alpers, Charles E.
元通蛋白促进糖尿病性肾病中的足细胞凋亡。
影响因子：
9
作者：
Liu WT;Peng FF;Li HY;Chen XW;Gong WQ;Chen WJ;Chen YH;Li PL;Li ST;Xu ZZ;Long HB
通讯作者：
Long HB
影响因子：
16.2
作者：
Fiorina, P;La Rosa, S;Secchi, A
通讯作者：
Secchi, A
影响因子：
16.6
作者：
Meakin PJ;Mezzapesa A;Benabou E;Haas ME;Bonardo B;Grino M;Brunel JM;Desbois-Mouthon C;Biddinger SB;Govers R;Ashford MLJ;Peiretti F
通讯作者：
Peiretti F
影响因子：
7.7
作者：
Cheung L;Le Tissier P;Goldsmith SG;Treier M;Lovell-Badge R;Rizzoti K
通讯作者：
Rizzoti K