Liapis Helen, Romagnani Paola, Anders Hans-Joachim
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri; Department of Internal Medicine (Renal), Washington University School of Medicine, St. Louis, Missouri.
Excellence Centre for Research, Transfer and High Education for the Development of de Novo Therapies (DENOTHE), Florence, Italy; Pediatric Nephrology Unit, Meyer Children's Hospital, Florence, Italy.
Am J Pathol. 2013 Nov;183(5):1364-1374. doi: 10.1016/j.ajpath.2013.06.033. Epub 2013 Sep 3.
Podocytes represent an essential component of the kidney's glomerular filtration barrier. They stay attached to the glomerular basement membrane via integrin interactions that support the capillary wall to withstand the pulsating filtration pressure. Podocyte structure is maintained by a dynamic actin cytoskeleton. Terminal differentiation is coupled with permanent exit from the cell cycle and arrest in a postmitotic state. Postmitotic podocytes do not have an infinite life span; in fact, physiologic loss in the urine is documented. Proteinuria and other injuries accelerate podocyte loss or induce death. Mature podocytes are unable to replicate and maintain their actin cytoskeleton simultaneously. By the end of mitosis, cytoskeletal actin forms part of the contractile ring, rendering a round shape to podocytes. Therefore, when podocyte mitosis is attempted, it may lead to aberrant mitosis (ie, mitotic catastrophe). Mitotic catastrophe implies that mitotic podocytes eventually detach or die; this is a previously unrecognized form of podocyte loss and a compensatory mechanism for podocyte hypertrophy that relies on post-G1-phase cell cycle arrest. In contrast, local podocyte progenitors (parietal epithelial cells) exhibit a simple actin cytoskeleton structure and can easily undergo mitosis, supporting podocyte regeneration. In this review we provide an appraisal of the in situ pathology of mitotic catastrophe compared with other proposed types of podocyte death and put experimental and renal biopsy data in a unified perspective.
足细胞是肾脏肾小球滤过屏障的重要组成部分。它们通过整合素相互作用附着于肾小球基底膜，这种相互作用支持毛细血管壁承受脉动性滤过压力。足细胞结构由动态的肌动蛋白细胞骨架维持。终末分化与细胞周期的永久退出以及细胞停滞于有丝分裂后状态相关联。有丝分裂后的足细胞没有无限的寿命；事实上，尿中生理性丢失是有记录的。蛋白尿和其他损伤会加速足细胞丢失或诱导其死亡。成熟足细胞无法同时进行复制并维持其肌动蛋白细胞骨架。在有丝分裂末期，细胞骨架肌动蛋白形成收缩环的一部分，使足细胞呈圆形。因此，当试图进行足细胞有丝分裂时，可能会导致异常有丝分裂（即有丝分裂灾难）。有丝分裂灾难意味着有丝分裂的足细胞最终会脱离或死亡；这是一种先前未被认识到的足细胞丢失形式，也是一种依赖于G1期后细胞周期停滞的足细胞肥大的代偿机制。相比之下，局部足细胞祖细胞（壁层上皮细胞）呈现简单的肌动蛋白细胞骨架结构，并且能够轻易地进行有丝分裂，支持足细胞再生。在本综述中，我们评估了有丝分裂灾难的原位病理学，并与其他提出的足细胞死亡类型进行了比较，同时将实验数据和肾活检数据置于统一的视角下。
