Genetic Podocyte Lineage Reveals Progressive Podocytopenia with Parietal Cell Hyperplasia in a Murine Model of Cellular/Collapsing Focal Segmental Glomerulosclerosis
Genetic Podocyte Lineage Reveals Progressive Podocytopenia with Parietal Cell Hyperplasia in a Murine Model of Cellular/Collapsing Focal Segmental Glomerulosclerosis
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DOI：
10.2353/ajpath.2009.080789
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发表时间：
2009-05-01
影响因子：
6
通讯作者：
Nagata, Michio
中科院分区：
文献类型：
--
作者：
Suzuki, Taisei;Matsusaka, Taiji;Nagata, Michio
局灶节段性肾小球硬化（FSGS）是一种进行性肾脏疾病，典型的肾小球内脏细胞增生在FSGS的细胞/塌陷中观察到，是疾病进展的重要病理因素。然而，促进FSGS的细胞特征目前仍不清楚。为了确定细胞/衰竭FSGS中增生细胞的起源和表型改变，本研究使用了先前描述的p21缺陷小鼠内脏细胞增生的FSGS模型，并通过遗传标记鉴定足细胞谱系。p21缺陷肾病小鼠的尿蛋白水平、第5天的毛细血管外增生指数和第14天的肾小球硬化指数均显著高于野生型对照。足细胞和壁上皮细胞（PEC）标记物的X-gal染色和免疫组化显示进行性足细胞减少伴毛细血管塌陷伴PEC增生导致FSGS。在我们的研究中，未标记的细胞既不表达WT1也不表达巢蛋白。Ki-67是一种增殖标志物，很少与足细胞相关，但在PECs中高水平表达。末端脱氧核苷酸转移酶dUTP镍端标记染色和电子显微镜均未显示第5天和第14天足细胞明显凋亡的证据。这些发现表明，足细胞大量丢失和同时发生的PEC增生是一种实际的病理，可能有助于该小鼠模型中FSGS细胞/坍缩的进展。此外，这是首次证明p21在PEC细胞周期中的调节作用的研究。（美国病理学杂志2009,174.1675-1682;DOI: 10.2353/ajpath.2009.080789）
Focal segmental glomerulosclerosis (FSGS) is a progressive renal disease, and the glomerular visceral cell hyperplasia typically observed in cellular/collapsing FSGS is an important pathological factor in disease progression. However, the cellular features that promote FSGS currently remain obscure. To determine both the origin and phenotypic alterations in hyperplastic cells in cellular/collapsing FSGS, the present study used a previously described FSGS model in p21-deficient mice with visceral cell hyperplasia and identified the podocyte lineage by genetic tagging. The p21-deficient mice with nephropathy showed significantly higher urinary protein levels, extracapillary hyperplastic indices on day 5, and glomerular sclerosis indices on day 14 than wild-type controls. X-gal staining and immunohistochemistry for podocyte and parietal epithelial cell (PEC) markers revealed progressive podocytopenia with capillary collapse accompanied by PEC hyperplasia leading to FSGS. In our investigation, non-tagged cells expressed neither WT1 nor nestin. Ki-67, a proliferation marker, was rarely associated with podocytes but was expressed at high levels in PECs. Both terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and electron microscopy failed to show evidence of significant podocyte apoptosis on days 5 and 14. These findings suggest that extensive podocyte loss and simultaneous PEC hyperplasia is an actual pathology that may contribute to the progression of cellular/collapsing FSGS in this mouse model. Additionally, this is the first study to demonstrate the regulatory role of p21 in the PEC cell cycle. (Am J Pathol 2009,174.1675-1682; DOI: 10.2353/ajpath.2009.080789)