Similar Biophysical Abnormalities in Glomeruli and Podocytes from Two Distinct Models
Similar Biophysical Abnormalities in Glomeruli and Podocytes from Two Distinct Models
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DOI：
10.1681/asn.2017050475
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发表时间：
2018-05-01
影响因子：
13.6
通讯作者：
Miller, R. Tyler
中科院分区：
文献类型：
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作者：
Embry, Addie E.;Liu, Zhenan;Miller, R. Tyler
背景 FSGS 是一种导致肾小球功能丧失的足细胞损伤模式。足细胞支持其他足细胞和肾小球毛细血管结构，抵抗血流动力学力，形成狭缝隔膜，并具有允许这些功能的机械特性。然而，疾病中肾小球和足细胞的生物物理特征仍不清楚。方法使用显微压痕、原子力显微镜、免疫荧光显微镜、定量RT-PCR和三维胶原凝胶收缩测定，研究了慢性（Tg26小鼠[HIV蛋白表达]）和急性（鱼精蛋白给药[细胞骨架重排]）足细胞损伤模型中肾小球和足细胞的生物物理和结构特性。结果与野生型相比尽管胶原蛋白含量增加，但随着疾病进展，Tg26 肾小球逐渐变得更加变形。 Tg26足细胞细胞骨架紊乱，粘着斑明显异常，粘着力较弱；他们无法对机械信号做出反应，并且在三维胶原蛋白凝胶中施加最小的牵引力。鱼精蛋白治疗对肾小球和足细胞有相似但较温和的影响。结论 Tg26足细胞结构完整性降低导致肾小球毛细血管变形性增加，限制毛细血管对抗血流动力学的能力，可能导致足细胞进一步损伤。由于缺乏足细胞维持所需的正常生物物理信号，正常足细胞机械完整性的丧失可能会伤害邻近的足细胞。 Tg26模型中足细胞机械行为的严重缺陷可以解释为什么Tg26肾小球逐渐软化，尽管胶原沉积增加，并且可能是与严重足细胞损伤相关的肾小球疾病快速发展的基础。在较轻的损伤（鱼精蛋白）中，会发生类似的过程，但持续时间较长。
Background FSGS is a pattern of podocyte injury that leads to loss of glomerular function. Podocytes support other podocytes and glomerular capillary structure, oppose hemodynamic forces, form the slit diaphragm, and have mechanical properties that permit these functions. However, the biophysical characteristics of glomeruli and podocytes in disease remain unclear.Methods Using microindentation, atomic force microscopy, immunofluorescence microscopy, quantitative RT-PCR, and a three-dimensional collagen gel contraction assay, we studied the biophysical and structural properties of glomeruli and podocytes in chronic (Tg26 mice [HIV protein expression]) and acute (protamine administration [cytoskeletal rearrangement]) models of podocyte injury.Results Compared with wild-type glomeruli, Tg26 glomeruli became progressively more deformable with disease progression, despite increased collagen content. Tg26 podocytes had disordered cytoskeletons, markedly abnormal focal adhesions, and weaker adhesion; they failed to respond to mechanical signals and exerted minimal traction force in three-dimensional collagen gels. Protamine treatment had similar but milder effects on glomeruli and podocytes.Conclusions Reduced structural integrity of Tg26 podocytes causes increased deformability of glomerular capillaries and limits the ability of capillaries to counter hemodynamic force, possibly leading to further podocyte injury. Loss of normal podocyte mechanical integrity could injure neighboring podocytes due to the absence of normal biophysical signals required for podocyte maintenance. The severe defects in podocyte mechanical behavior in the Tg26 model may explain why Tg26 glomeruli soften progressively, despite increased collagen deposition, and may be the basis for the rapid course of glomerular diseases associated with severe podocyte injury. In milder injury (protamine), similar processes occur but over a longer time.