Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis.
Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis.
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DOI：
10.1038/ki.2012.20
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发表时间：
2012-07
影响因子：
19.6
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中科院分区：
文献类型：
--
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慢性肾脏疾病（CKD）仍然是发达国家的主要死亡原因之一，急性肾损伤（阿基）现在被认为是其发展的主要风险因素。了解急性损伤后导致CKD的因素受到目前阿基动物模型的限制，这些模型同时靶向各种肾细胞类型，如上皮细胞、内皮细胞和炎症细胞。在这里，我们开发了一种小鼠模型的肾损伤，使用Six 2-Cre-LoxP技术选择性地激活表达的猴白喉毒素受体的肾上皮细胞来源于后肾间充质。通过调整白喉毒素的时间和剂量，建立了高度选择性的肾小管损伤模型，以确定孤立性上皮损伤的急性和慢性后果。白喉毒素诱导的亚致死性肾小管上皮细胞损伤仅限于近端小管的S1和S2段，而不是广泛存在于后肾间充质来源的上皮细胞系中。急性损伤后立即发生炎性细胞浸润和强烈的肾小管细胞增殖，导致单次毒素损伤后完全恢复。与此形成鲜明对比的是，以一周的间隔对肾上皮细胞进行三次损伤导致了适应不良的修复，其中间质毛细血管损失、纤维化和肾小球硬化与间质纤维化的程度高度相关。因此，选择性上皮损伤可驱动间质纤维化、毛细血管稀疏和潜在的肾小球硬化的形成，证实了受损的肾小管上皮在CKD发病机制中的直接作用。
Chronic kidney disease (CKD) remains one of the leading causes of death in the developed world and acute kidney injury (AKI) is now recognized as a major risk factor in its development. Understanding the factors leading to CKD after acute injury are limited by current animal models of AKI which concurrently target various kidney cell types such as epithelial, endothelial and inflammatory cells. Here we developed a mouse model of kidney injury using the Six2-Cre-LoxP technology to selectively activate expression of the simian diphtheria toxin receptor in renal epithelia derived from the metanephric mesenchyme. By adjusting the timing and dose of diphtheria toxin a highly selective model of tubular injury was created to define the acute and chronic consequences of isolated epithelial injury. The diphtheria toxin-induced sublethal tubular epithelial injury was confined to the S1 and S2 segments of the proximal tubule rather than being widespread in the metanephric mesenchyme derived epithelial lineage. Acute injury was promptly followed by inflammatory cell infiltration and robust tubular cell proliferation leading to complete recovery after a single toxin insult. In striking contrast, three insults to renal epithelial cells at one week intervals resulted in maladaptive repair with interstitial capillary loss, fibrosis and glomerulosclerosis which was highly correlated with the degree of interstitial fibrosis. Thus, selective epithelial injury can drive the formation of interstitial fibrosis, capillary rarefaction and potentially glomerulosclerosis, substantiating a direct role for damaged tubule epithelium in the pathogenesis of CKD.
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影响因子：
3
作者：
Grgic, Ivica;Duffield, Jeremy S.;Humphreys, Benjamin D.
通讯作者：
Humphreys, Benjamin D.
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Rabb, Hamid
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6
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Hishida, A
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48
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Waisman, A