Institute of Nephrology, Zhong Da Hospital, Southeast University, Nanjing 210009, China.
J Cell Biochem. 2011 Jun;112(6):1585-92. doi: 10.1002/jcb.23074.
Inflammatory cell infiltration plays a key role in the pathogenesis of tubulointerstitial damage in chronic renal diseases. In addition to secreting the profibrotic cytokines, monocytes themselves have been demonstrated to be directly associated with renal fibrogenesis. However, how infiltrating monocytes interact with resident cells and the underlying mechanisms remain elusive. In this study we investigated the effects of monocytes on phenotypic changes of human proximal tubular HK-2 cells. The typical epithelial cell morphology of HK-2 cells disappeared after co-culture with monocytes, accompanied by decreased E-cadherin expression, and increased α-SMA and fibronectin expression, suggesting that HK-2 cells undergo epithelial-mesenchymal transition (EMT). Further analysis revealed that the effects were dependent on direct contact of the two types of cells as conditioned medium had no effects. Interestingly, administration of CD18 antibody directly inhibited this process. Furthermore, by microarray and RT-PCR we found that NF-kB signaling may play a role in this process and blockade of this signaling pathway in HK-2 cells could inhibit ICAM-1 expression and EMT phenotypes. Taken together, these findings suggest that monocytes infiltration could directly induce EMT of HK-2 cells via upregulation ICAM-1 through NF-kB signaling pathway.
炎症细胞浸润在慢性肾脏病的肾小管间质损伤发病机制中起着关键作用。除了分泌促纤维化细胞因子外，单核细胞本身已被证明与肾纤维化直接相关。然而，浸润的单核细胞如何与固有细胞相互作用以及潜在的机制仍不清楚。在这项研究中，我们研究了单核细胞对人近端肾小管 HK-2 细胞表型变化的影响。HK-2 细胞与单核细胞共培养后，典型的上皮细胞形态消失，同时 E-钙黏蛋白表达降低，α-SMA 和纤连蛋白表达增加，提示 HK-2 细胞发生上皮-间充质转化（EMT）。进一步分析表明，这种作用依赖于两种细胞的直接接触，因为条件培养基没有作用。有趣的是，CD18 抗体的给药直接抑制了这一过程。此外，通过微阵列和 RT-PCR，我们发现 NF-κB 信号通路可能在这个过程中起作用，并且在 HK-2 细胞中阻断这个信号通路可以抑制 ICAM-1 表达和 EMT 表型。总之，这些发现表明，单核细胞浸润可以通过 NF-κB 信号通路上调 ICAM-1 直接诱导 HK-2 细胞 EMT。
