Marshall Caroline B, Shankland Stuart J
Division of Nephrology, University of Washington, Seattle, WA 98195, USA.
Nephron Exp Nephrol. 2007;106(2):e51-9. doi: 10.1159/000101793. Epub 2007 Jun 6.
The glomerular visceral epithelial cell, or podocyte, is a highly specialized and terminally differentiated cell that is fundamental to the integrity of the glomerular filtration barrier and functions to prevent urinary protein leakage and to oppose intracapillary hydrostatic pressure. Common to many human kidney diseases and experimental animal models is a strong association between podocyte injury and the development of progressive kidney disease. Studies have shown that a decline in podocyte number strongly correlates with, and likely underlies, proteinuria and the progression to glomerulosclerosis. Maintenance of podocyte differentiation, essential to its normal structure and function, is challenged in the setting of glomerular injury, with very divergent outcomes dependent upon the inciting injury. In response to injury, podocytes may undergo several cell fates, including proliferation, de-differentiation, hypertrophy, apoptosis, or necrosis. Common to these potential outcomes of renal injury is their ultimate regulation at the level of the cell cycle. Positive regulators (cyclins and cyclin-dependent kinases) and negative regulators (cyclin-dependent kinase inhibitors) coordinate the cell cycle. There is now a large body of literature confirming the importance of cell cycle regulatory proteins in the cellular response to injury. Emerging lessons from mouse knockout experiments highlight that the cell cycle machinery operates differently in distinct cell types. Recent studies focusing on the roles of cell cycle regulatory proteins specifically in podocytes have provided important clues on how these proteins operate to constrain cell proliferation and preserve differentiation in health, and how they modulate the dysregulated phenotype in diseased states. In disease, both a failure to regenerate lost podocytes and an inappropriate proliferative response can have profound consequences for glomerular structure and function. Here, we will review the latest advances in understanding the roles of cell cycle regulatory proteins in diseases of the podocyte.
肾小球脏层上皮细胞，即足细胞，是一种高度特化且终末分化的细胞，对肾小球滤过屏障的完整性至关重要，其功能是防止尿蛋白泄漏并对抗毛细血管内静水压力。在许多人类肾脏疾病和实验动物模型中，足细胞损伤与进行性肾脏疾病的发展之间存在密切关联。研究表明，足细胞数量的减少与蛋白尿以及肾小球硬化的进展密切相关，并且可能是其基础。维持足细胞分化对于其正常结构和功能至关重要，但在肾小球损伤的情况下会受到挑战，其结果因引发损伤的不同而有很大差异。对损伤的反应中，足细胞可能经历几种细胞命运，包括增殖、去分化、肥大、凋亡或坏死。这些肾脏损伤潜在结果的共同之处在于它们最终在细胞周期水平上受到调控。正调控因子（细胞周期蛋白和细胞周期蛋白依赖性激酶）和负调控因子（细胞周期蛋白依赖性激酶抑制剂）协调细胞周期。现在有大量文献证实细胞周期调节蛋白在细胞对损伤的反应中的重要性。从小鼠基因敲除实验中得到的新认识突出表明，细胞周期机制在不同细胞类型中的运作方式不同。最近专注于细胞周期调节蛋白在足细胞中具体作用的研究，为这些蛋白如何在健康状态下限制细胞增殖和维持分化，以及在疾病状态下如何调节失调表型提供了重要线索。在疾病中，未能再生丢失的足细胞以及不适当的增殖反应都可能对肾小球结构和功能产生深远影响。在这里，我们将综述在理解细胞周期调节蛋白在足细胞疾病中的作用方面的最新进展。
