JDRF Danielle Alberti Memorial Centre for Diabetes Complications,Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria,Australia.
Diabetes. 2011 Jun;60(6):1779-88. doi: 10.2337/db10-1110. Epub 2011 Apr 26.
Diabetic nephropathy is associated with dedifferentiation of podocytes, losing the specialized features required for efficient glomerular function and acquiring a number of profibrotic, proinflammatory, and proliferative features. These result from tight junction and cytoskeletal rearrangement, augmented proliferation, and apoptosis.
Experiments were performed in conditionally immortalized human podocytes developed by transfection with the temperature-sensitive SV40-T gene. Cells were then cultured in the presence of transforming growth factor (TGF)-β1 or angiotensin II in the presence or absence of a selective inhibitor of the TGF-β type I receptor kinase, SB-431542. Gene and protein expression were then examined by real-time RT-PCR and immunofluorescence, and correlated with changes observed in vivo in experimental diabetes.
Treatment of cells with TGF-β1 resulted in dynamic changes in their morphology, starting with retraction and shortening of foot processes and finishing with the formation of broad and complex tight junctions between adjacent podocytes. This dedifferentiation was also associated with dose- and time-dependent reduction in the expression of glomerular epithelial markers (nephrin, p-cadherin, zonnula occludens-1) and increased expression of mesenchymal markers (α-smooth muscle actin, vimentin, nestin), matrix components (fibronectin, collagen I, and collagen IV α3), cellular proliferation, and apoptosis. The induction of diabetes in mice was also associated with similar changes in morphology, protein expression, and proliferation in glomerular podocytes.
In response to TGF-β and other TGF-dependent stimuli, mature podocytes undergo dedifferentiation that leads to effacement of foot processes, morphologic flattening, and increased formation of intercellular tight junctions. This simplification of their phenotype to a more embryonic form is also associated with reentry of mature podocytes into the cell cycle, which results in enhanced proliferation and apoptosis. These "pathoadaptive" changes are seen early in the diabetic glomerulus and ultimately contribute to albuminuria, glomerulosclerosis, and podocytopenia.
糖尿病肾病与足细胞去分化有关，失去了高效肾小球功能所需的特殊特征，并获得了许多促纤维化、促炎和增殖的特征。这些特征是由紧密连接和细胞骨架重排、增殖增强和细胞凋亡引起的。
实验在通过温度敏感 SV40-T 基因转染而条件性永生化的人足细胞中进行。然后，在转化生长因子 (TGF)-β1 或血管紧张素 II 的存在下，在 TGF-β 型 I 受体激酶的选择性抑制剂 SB-431542 的存在或不存在下培养细胞。然后通过实时 RT-PCR 和免疫荧光检查基因和蛋白质表达，并与实验性糖尿病体内观察到的变化相关联。
TGF-β1 处理细胞导致其形态发生动态变化，首先是足突回缩和缩短，最后相邻足细胞之间形成广泛而复杂的紧密连接。这种去分化也与肾小球上皮标记物（nephrin、p-cadherin、zonnula occludens-1）表达的剂量和时间依赖性降低以及间充质标记物（α-平滑肌肌动蛋白、波形蛋白、巢蛋白）、基质成分（纤连蛋白、胶原 I 和胶原 IV α3）、细胞增殖和凋亡的增加有关。在小鼠中诱导糖尿病也与肾小球足细胞的形态、蛋白质表达和增殖的类似变化有关。
响应 TGF-β 和其他 TGF 依赖性刺激，成熟的足细胞经历去分化，导致足突消失、形态变平以及细胞间紧密连接的形成增加。这种表型向更胚胎形式的简化也与成熟足细胞重新进入细胞周期有关，导致增殖和凋亡增加。这些“病理适应性”变化在糖尿病肾小球早期出现，最终导致白蛋白尿、肾小球硬化和足细胞减少。
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