Severity and Frequency of Proximal Tubule Injury Determines Renal Prognosis
Severity and Frequency of Proximal Tubule Injury Determines Renal Prognosis
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DOI：
10.1681/asn.2015060647
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发表时间：
2016-08-01
影响因子：
13.6
通讯作者：
Yanagita, Motoko
中科院分区：
文献类型：
--
作者：
Takaori, Koji;Nakamura, Jin;Yanagita, Motoko
AKI 会增加罹患 CKD 的风险，但 AKI 与 CKD 之间的联系机制仍不清楚。由于近曲小管损伤是 AKI 的主要特征，因此我们推测近曲小管损伤会引发 CKD 的特征。我们建立了一种新型小鼠模型，通过诱导近端小管中不同程度的白喉毒素（DT）受体表达来诱导近端小管特异性可调节损伤。对表达 DT 受体的小鼠施用高剂量 DT 始终会导致严重的近端小管特异性损伤，并伴有间质纤维化和促红细胞生成素生成减少。单次注射低剂量DT引起的轻度近端肾小管损伤会引发可逆性纤维化，而重复的轻度损伤会导致持续的间质纤维化、炎症、肾小球硬化和管状肾小球。 DT 引起的近端小管特异性损伤也引发远端小管损伤。此外，受损的肾小管细胞与成纤维细胞共培养可刺激细胞外基质和炎症基因的诱导。这些结果支持近远端小管串扰以及肾小管细胞和成纤维细胞之间串扰的存在。总体而言，我们的数据提供的证据表明，近端小管损伤会引发 CKD 的几个特征，并且近端小管损伤的严重程度和频率决定着 CKD 的进展。
AKI increases the risk of developing CKD, but the mechanisms linking AKI to CKD remain unclear. Because proximal tubule injury is the mainstay of AKI, we postulated that proximal tubule injury triggers features of CKD. We generated a novel mouse model to induce proximal tubule-specific adjustable injury by inducing the expression of diphtheria toxin (DT) receptor with variable prevalence in proximal tubules. Administration of high-dose DT in mice expressing the DT receptor consistently caused severe proximal tubule-specific injury associated with interstitial fibrosis and reduction of erythropoietin production. Mild proximal tubule injury from a single injection of low-dose DT triggered reversible fibrosis, whereas repeated mild injuries caused sustained interstitial fibrosis, inflammation, glomerulosclerosis, and atubular glomeruli. DT-induced proximal tubule-specific injury also triggered distal tubule injury. Furthermore, injured tubular cells cocultured with fibroblasts stimulated induction of extracellular matrix and inflammatory genes. These results support the existence of proximal-distal tubule crosstalk and crosstalk between tubular cells and fibroblasts. Overall, our data provide evidence that proximal tubule injury triggers several features of CKD and that the severity and frequency of proximal tubule injury determines the progression to CKD.