Podocyte depletion and glomerulosclerosis have a direct relationship in the PAN-treated rat
Podocyte depletion and glomerulosclerosis have a direct relationship in the PAN-treated rat
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DOI：
10.1046/j.1523-1755.2001.060003957.x
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发表时间：
2001-09-01
影响因子：
19.6
通讯作者：
Wiggins, R
中科院分区：
文献类型：
--
作者：
Kim, YH;Goyal, M;Wiggins, R
背景足细胞是高度分化的肾小球上皮细胞，具有有限的分裂潜力。它们负责维持和支持肾小球基底膜，以促进有效的过滤。本研究的假设是嘌呤霉素氨基糖苷（PAN）处理的大鼠肾小球硬化的发展是否可归因于足细胞的减少。在Sprague-Dawley大鼠中注射PAN一次、两次或三次，间隔30天。使用免疫过氧化物酶组织化学和GLEPP 1（PTPRO）和WT-1的抗体对肾小球中的足细胞进行计数。使用逆转录-定量聚合酶链反应（RT-QPCR）测定尿液中的足细胞。肾小球面积用计算机形态测量法测量。在初步实验中，单次注射PAN导致肾小球足细胞计数减少25%。通过鉴定Bowman氏间隙中分离的足细胞、测量尿中nephrin和GLEPP 1 mRNA、肾小球的超微结构分析和鉴定肾小球中TUNEL阳性凋亡足细胞，获得了PAN注射后足细胞从肾小球丢失的额外独立确认。在第二个实验中，通过以30天的间隔注射一次、两次或三次PAN，实现了15%、31%和53%的连续足细胞消耗。缺乏足细胞的肾小球区域发展为肾小球硬化，并且随着足细胞的逐渐耗尽，该区域逐渐增加。足细胞消耗百分比和肾小球硬化面积之间的相关系数（r（2））值为0.99。该图的Y轴截距显示，当仅10%至20%的足细胞丢失时，肾小球硬化开始。这份报告支持越来越多的数据将肾小球硬化症与相对足细胞数量减少[每足细胞肾小球面积增加（GAPP）]直接联系起来。它提出了与足细胞损失的机制、预防足细胞耗竭的策略和预防肾小球疾病进展相关的重要问题。
Background. Podocytes are highly differentiated glomerular epithelial cells with limited potential to divide. They are responsible for maintaining and supporting the glomerular basement membrane so as to facilitate efficient filtration. The hypothesis tested was whether the development of glomerulosclerosis in the puromycin aminonucleoside (PAN)-treated rat could be attributed to podocyte depletion.Methods. PAN was injected in Sprague-Dawley rats once, twice, or three times at 30-day intervals. Podocytes were counted in glomeruli using immunoperoxidase histochemistry and antibodies to both GLEPP1 (PTPRO) and WT-1. Podocytes were assayed in urine using reverse transcription-quantitative polymerase chain reaction (RT-QPCR). Glomerular areas were measured by computerized morphometry.Results. In a preliminary experiment, a single injection of PAN caused a reduction in the glomerular podocyte count by 25%. Additional independent confirmation that podocytes were lost from glomeruli after PAN injection was obtained identifying detached podocytes in Bowman's space, measurement of nephrin and GLEPP1 mRNAs in urine, ultrastructural analysis of glomeruli, and identification of TUNEL-positive apoptotic podocytes in glomeruli. In a second experiment, sequential podocyte depletion by 15, 31, and 53% was achieved by the administration of one, two, or three injections of PAN at 30-day intervals. The region of the glomerulus devoid of podocytes developed glomerulosclerosis, and this area progressively increased as podocytes were progressively depleted. The correlation coefficient (r(2)) value for the relationship between percent podocyte depletion and glomerulosclerotic area was 0.99. The Y intercept of this plot showed that glomerulosclerosis was initiated when only 10 to 20% of podocytes were lost.Conclusion. This report supports the growing body of data linking glomerulosclerosis directly to a reduction in relative podocyte number [increased glomerular area per podocyte (GAPP)]. It raises important questions related to the mechanisms of podocyte loss, strategies for prevention of podocyte depletion, and the prevention of progression of glomerular diseases.