Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
School of Pharmacy, Wenzhou Medical University, Wenzhou, 325000, China.
Cell Death Dis. 2018 Sep 20;9(10):950. doi: 10.1038/s41419-018-0985-z.
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 and N-[N-(3,5-Difluorophenacetyl)-L-alanyl]- S-phenylglycine t-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.
信号异常在 podocyte 损伤中起着重要作用，并被认为是触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，预防肾损伤和恢复 podocyte 具有显著效果。然而，信号异常是否会影响胰岛移植的治疗效果尚不清楚。本研究旨在探讨 Notch-1 信号激活对胰岛移植后肾损伤和 podocyte 恢复的影响。在糖尿病肾病和高糖培养基的条件下分别进行了体内和体外实验。体外通过高糖浓度诱导 podocyte 损伤，并通过 Jagged-1/FC 和 N-[N-(3,5-二氟苯乙酰基)-L-丙氨酰]-S-苯甘氨酸叔丁酯（DAPT）调节与 Notch-1 通路相关的基因表达水平。将 podocyte 与胰岛共培养，以研究胰岛在高糖条件下的保护作用。进行组织病理学染色和透射电子显微镜检查，以评估肾小球中 podocyte 的病理变化。本研究结果表明，体内和体外的功能性胰岛细胞均可显著降低 podocyte 中的 Notch-1 信号。与共培养组和移植组相比，高度激活的 Notch-1 信号显著减弱了胰岛对 podocyte 恢复和肾损伤的影响。DAPT 处理后肾损伤和 podocyte 损伤减轻。此外，不同处理下的细胞凋亡和自噬平衡也不同。本研究的所有数据表明，高度激活的 Notch-1 信号可影响胰岛移植对高糖条件下肾损伤和 podocyte 恢复的治疗效果。细胞凋亡和自噬的平衡也与 podocyte 恢复程度密切相关。这一发现可能表明，胰岛移植后体内微环境在 podocyte 恢复中起着关键作用，为未来不同糖尿病肾病患者的胰岛移植后提供了有前景的个体化评估和靶向治疗。
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