Podocyte. depletion causes glomerulosclerosis: Diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene
Podocyte. depletion causes glomerulosclerosis: Diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene
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DOI：
10.1681/asn.2005010055
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发表时间：
2005-10-01
影响因子：
13.6
通讯作者：
Wiggins, RC
中科院分区：
文献类型：
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作者：
Wharram, BL;Goyal, M;Wiggins, RC
糖尿病（1型和2型）和IgA肾病的肾小球损伤和蛋白尿与人类足细胞消耗的程度有关。为了确定足细胞耗竭与肾小球硬化之间的因果关系，研制了一种在足细胞中特异性表达人白喉毒素受体的转基因大鼠菌株。啮齿动物同源物不作为白喉毒素（DT）受体，从而使啮齿动物对DT具有抗性。将DT注射到转基因大鼠而非野生型大鼠体内可引起肾小球足细胞的剂量依赖性耗竭。足细胞耗损引起的肾小球损伤分为三个阶段：第1阶段，0 ~ 20%耗损表现为肾小球系膜扩张、短暂性蛋白尿和肾功能正常；第2期，21 - 40%衰竭表现为肾小球系膜扩张，囊膜粘连（粘连），局灶节段性肾小球硬化，轻度持续性蛋白尿，肾功能正常；3期，40%足细胞减少，表现为段性到全局性肾小球硬化，伴持续高级别蛋白尿和肾功能下降。足细胞耗竭的这些病理生理后果与糖尿病肾小球硬化中足细胞耗竭、肾小球硬化和蛋白尿的程度相似。该模型系统有力地支持足细胞耗竭可能是人类肾小球疾病导致肾小球硬化和肾功能进行性丧失的主要机制。
Glomerular injury and proteinuria in diabetes (types 1 and 2) and IgA nephropathy is related to the degree of podocyte depletion in humans. For determining the causal relationship between podocyte depletion and glomerulosclerosis, a transgenic rat strain in which the human diphtheria toxin receptor is specifically expressed in podocytes was developed. The rodent homologue does not act as a diphtheria toxin (DT) receptor, thereby making rodents resistant to DT. Injection of DT into transgenic rats but not wild-type rats resulted in dose-dependent podocyte depletion from glomeruli. Three stages of glomerular injury caused by podocyte depletion were identified: Stage 1, 0 to 20% depletion showed mesangial expansion, transient proteinuria and normal renal function; stage 2, 21 to 40% depletion showed mesangial expansion, capsular adhesions (synechiae), focal segmental glomerulosclerosis, mild persistent proteinuria, and normal renal function; and stage 3, >40% podocyte depletion showed segmental to global glomerulosclerosis with sustained high-grade proteinuria and reduced renal function. These pathophysiologic consequences of podocyte depletion parallel similar degrees of podocyte depletion, glomerulosclerosis, and proteinuria seen in diabetic glomerulosclerosis. This model system provides strong support for the concept that podocyte depletion could be a major mechanism driving glomerulosclerosis and progressive loss of renal function in human glomerular diseases.