Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China.
College of Liberal Arts, University of Minnesota, USA.
Diabetes Res Clin Pract. 2020 Apr;162:108093. doi: 10.1016/j.diabres.2020.108093. Epub 2020 Feb 25.
This study aimed to detect the effect of angiotensin-converting enzyme (ACE) 2-modified mesenchymal stem cells (MSCs) on glomerular fibrosis in vitro and in vivo and investigate the underlying molecular mechanism.
MSCs transduced with the ACE2 gene (MSCs-ACE2) were cocultured with glomerular mesangial cells (GMCs) following Ang II stimulation. MSCs-ACE2 were transplanted into streptozotocin-induced diabetic rats. Physical, biochemical and morphological parameters were measured, and fibrotic indicators and renin-angiotensin system (RAS) components in GMCs and kidney tissues were assessed.
The transduction efficiency of MSCs was as high as 85%. The modified MSCs secreted soluble ACE2 protein into the culture medium. After transplantation into rats with diabetes, MSCs-ACE2 targeted injured kidneys and enhanced local expression of ACE2. Compared with MSC treatment alone, MSC-ACE2 treatment was superior in reducing albuminuria and improving glomerulosclerosis. In vitro and in vivo, MSCs-ACE2 were more beneficial than MSCs alone in decreasing Ang II and increasing Ang1-7, thereby inhibiting the detrimental effects of Ang II accumulation by downregulating collagen I and fibronectin (FN) expression and inhibiting the transforming growth factor (TGF-β)/Smad pathway.
MSCs modified with ACE2 therapy have additional benefits to the progression of diabetic nephropathy (DN) by inhibiting renal RAS activation and reducing glomerular fibrosis.
本研究旨在检测血管紧张素转换酶（ACE）2 修饰间充质干细胞（MSCs）对体外和体内肾小球纤维化的影响，并探讨其潜在的分子机制。
将携带 ACE2 基因的 MSCs（MSCs-ACE2）与 Ang II 刺激后的肾小球系膜细胞（GMCs）共培养。将 MSCs-ACE2 移植到链脲佐菌素诱导的糖尿病大鼠中。测量物理、生化和形态学参数，并评估 GMCs 和肾脏组织中的纤维化指标和肾素-血管紧张素系统（RAS）成分。
MSCs 的转导效率高达 85%。修饰后的 MSCs 将可溶性 ACE2 蛋白分泌到培养基中。在糖尿病大鼠移植后，MSCs-ACE2 靶向损伤的肾脏并增强局部 ACE2 的表达。与单独 MSC 治疗相比，MSC-ACE2 治疗在减少蛋白尿和改善肾小球硬化方面更具优势。在体外和体内，MSCs-ACE2 比单独的 MSCs 更有利于减少 Ang II 和增加 Ang1-7，从而通过下调胶原 I 和纤维连接蛋白（FN）的表达和抑制转化生长因子（TGF-β）/Smad 通路来抑制 Ang II 积聚的有害影响。
通过抑制肾 RAS 激活和减少肾小球纤维化，ACE2 修饰的 MSCs 对糖尿病肾病（DN）的进展具有额外的益处。
