Transplantation of Apoptosis-Resistant Endothelial Progenitor Cells Improves Renal Function in Diabetic Kidney Disease.
Transplantation of Apoptosis-Resistant Endothelial Progenitor Cells Improves Renal Function in Diabetic Kidney Disease.
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DOI：
10.1161/jaha.120.019365
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发表时间：
2021-04-06
影响因子：
5.4
通讯作者：
Sen S
中科院分区：
文献类型：
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作者：
Kundu N;Nandula SR;Asico LD;Fakhri M;Banerjee J;Jose PA;Sen S
糖尿病肾病与肾小球硬化和肾灌注不良有关。毛细血管形成增加和灌注改善可能有助于停止或逆转损伤。移植抗凋亡p53沉默内皮祖细胞（p53sh - EPCs）可能有助于改善血管化和肾脏灌注，并且可能比其他干细胞（如小鼠间充质间质细胞（mMSC））更有益。在链脲霉素诱导的1型糖尿病C57Bl/6小鼠中，在8至10周时证实出现高血糖和蛋白尿，随后在每个肾胶囊下移植30万个p53sh‐EPCs， Null‐EPCs（对照）或mMSC。每周收集尿液检测肌酐和蛋白水平。直接动脉插管测血压，肾超声测肾灌注。取肾进行组织学和mRNA表达分析。在p53sh - EPC -移植小鼠中，蛋白/肌酐（AUC）的降低高于无EPC（1.8倍，P=0.03）或无mMSC（1.6倍，P=0.04, n=4）移植小鼠。血管生成标志物，如内皮一氧化氮合酶（1.7倍，P=0.06），在p53sh - EPC移植后与无EPC相比上调。然而，与p53sh - EPC -移植小鼠相比，mMSC -移植小鼠的血管内皮生长因子- A表达降低（7倍，P=0.0004）。与空白EPC或mMSC相比，移植p53sh - EPC后，肾切片的Isolectin - B4染色显示肾小球硬化得到改善。此外，与未移植EPC的小鼠相比，移植p53sh - EPC的小鼠平均和峰值肾血流速（分别为1.3倍，P=0.01, 1.4倍，P=0.001）增加。抗凋亡p53sh EPC移植可通过减少蛋白尿、改善肾灌注和肾小球结构而有益于糖尿病肾病的治疗。
Diabetic kidney disease is associated with glomerulosclerosis and poor renal perfusion. Increased capillary formation and improved perfusion may help to halt or reverse the injury. Transplanting apoptosis‐resistant p53‐silenced endothelial progenitor cells (p53sh‐EPCs) may help improve vascularization and renal perfusion and could be more beneficial than another stem cell such as the mouse mesenchymal stromal cell (mMSC). Hyperglycemia and proteinuria were confirmed at 8 to 10 weeks in streptozotocin‐induced type1 diabetic C57Bl/6 mice, followed by transplantation of 0.3 million p53sh‐EPCs, Null‐EPCs (control), or mMSC under each kidney capsule. Urine was collected weekly for creatinine and protein levels. Blood pressure was measured by direct arterial cannulation and renal perfusion was measured by renal ultrasound. The kidneys were harvested for histology and mRNA expression. Reduction of protein/creatinine (AUC) was observed in p53sh‐EPC‐transplanted mice more than null‐EPC (1.8‐fold, P=0.03) or null‐mMSC (1.6‐fold, P=0.04, n=4) transplanted mice. Markers for angiogenesis, such as endothelial nitric oxide synthase (1.7‐fold, P=0.06), were upregulated post p53sh‐EPC transplantation compared with null EPC. However, vascular endothelial growth factor‐A expression was reduced (7‐fold, P=0.0004) in mMSC‐transplanted mice, compared with p53sh‐EPC‐transplanted mice. Isolectin‐B4 staining of kidney section showed improvement of glomerular sclerosis when p53sh‐EPC was transplanted, compared with null‐EPC or mMSC. In addition, mean and peak renal blood velocity (1.3‐fold, P=0.01, 1.4‐fold, P=0.001, respectively) were increased in p53sh‐EPC‐transplanted mice, relative to null‐EPC transplanted mice. Apoptosis‐resistant p53sh EPC transplantation could be beneficial in the treatment of diabetic kidney disease by decreasing proteinuria, and improving renal perfusion and glomerular architecture.