Accelerated podocyte detachment and progressive podocyte loss from glomeruli with age in Alport Syndrome.
Accelerated podocyte detachment and progressive podocyte loss from glomeruli with age in Alport Syndrome.
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DOI：
10.1016/j.kint.2017.05.017
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发表时间：
2017-12
影响因子：
19.6
通讯作者：
Wiggins RC
中科院分区：
文献类型：
--
作者：
Ding F;Wickman L;Wang SQ;Zhang Y;Wang F;Afshinnia F;Hodgin J;Ding J;Wiggins RC
足细胞耗竭是肾小球疾病进展的常见机制。由足细胞产生α3α4α5 （IV）胶原异源三聚体缺陷引起的Alport综合征肾小球病变，与尿中足细胞脱离率升高和肾小球足细胞数量减少有关，提示足细胞对肾小球基底膜粘附缺陷可能在推动肾小球进展中起作用。本研究采用95例阿尔波特综合征遗传表型队列[尿液研究]和41例存档活检[活检研究]来验证这一假设。足细胞脱离率（通过每肌酐或24小时排泄尿中表达的足细胞mRNA来测量）比对照组显著增加了11倍，并且在检测到蛋白尿或微量白蛋白尿之前。与此同时，Alport综合征肾小球平均每年丢失26个足细胞，而对照组肾小球平均每年丢失2.3个足细胞，与尿足细胞脱离率增加相对应，差异为11倍。出生时Alport综合征活组织检查显示每肾小球足细胞数正常（558个/肾小球），但预计足细胞加速丢失会在22岁左右导致终末期肾病。来自两个独立队列的活检数据显示肾小球足细胞损失率与足细胞脱离率增加11倍相似。活组织检查中足细胞数量和密度的减少与蛋白尿、肾小球硬化和肾功能下降有关。因此，Alport综合征的足细胞脱离率似乎从出生开始就增加，推动了进展过程，并可能有助于预测终末期肾脏疾病的时间和对治疗的反应。
Podocyte depletion is a common mechanism driving progression in glomerular diseases. Alport Syndrome glomerulopathy, caused by defective α3α4α5 (IV) collagen heterotrimer production by podocytes, is associated with an increased rate of podocyte detachment detectable in urine and reduced glomerular podocyte number suggesting that defective podocyte adherence to the glomerular basement membrane might play a role in driving progression. Here a genetically phenotyped Alport Syndrome cohort of 95 individuals [urine study] and 41 archived biopsies [biopsy study] were used to test this hypothesis. Podocyte detachment rate (measured by podocin mRNA in urine pellets expressed either per creatinine or 24 hour excretion) was significantly increased 11-fold above control, and prior to a detectably increased proteinuria or microalbuminuria. In parallel, Alport Syndrome glomeruli lose an average 26 podocytes per year versus control glomeruli that lose 2.3 podocytes per year, an 11-fold difference corresponding to the increased urine podocyte detachment rate. Podocyte number per glomerulus in Alport Syndrome biopsies is projected to be normal at birth (558/glomerulus) but accelerated podocyte loss was projected to cause end stage kidney disease by about 22 years. Biopsy data from two independent cohorts showed a similar estimated glomerular podocyte loss rate comparable to the measured 11-fold increase in podocyte detachment rate. Reduction in podocyte number and density in biopsies correlated with proteinuria, glomerulosclerosis and reduced renal function. Thus, the podocyte detachment rate appears to be increased from birth in Alport Syndrome, drives the progression process, and could potentially help predict time to end stage kidney disease and response to treatment.
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