Department of Nephrology, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
J Am Soc Nephrol. 2010 Dec;21(12):2047-52. doi: 10.1681/ASN.2010010003. Epub 2010 Sep 16.
It is not clear whether interstitial fibroblasts or tubular epithelial cells are primarily responsible for the profibrotic effects of NF-κB activation during renal fibrogenesis. Here, we crossed mice carrying a conditional IκB dominant-negative transgene (IκBdN) with mice transgenic for cell-specific FSP1.Cre (FSP1(+) fibroblasts) or γGT.Cre (proximal tubular epithelia) and challenged all progeny with unilateral ureteral obstruction. We determined NF-κB activation by nuclear localization of phosphorylated p65 ((p)p65) in renal tissues after 7 days. We observed inhibition of NF-κB activation in interstitial cells and tubular epithelia in obstructed kidneys of FSP1.Cre;IκBdN and γGT.Cre;IκBdN mice, respectively, compared with IκBdN controls (P < 0.05). Deposition of extracellular matrix, however, was significantly lower in the obstructed kidneys of FSP1.Cre;IκBdN mice but not in γGT.Cre;IκBdN mice (P < 0.05). In addition, levels of mRNA encoding the profibrotic PAI-1, fibronectin-EIIIA, and type I (α1) procollagen were significantly lower in obstructed kidneys of FSP1.Cre;IκBdN mice compared with γGT.Cre;IκBdN mice (P < 0.05). Taken together, these data support a profibrotic role for fibroblasts, but not proximal tubular epithelial cells, in modulating NF-κB activation during renal fibrogenesis.
在肾纤维化过程中，NF-κB 激活的致纤维化效应主要是由间质成纤维细胞还是肾小管上皮细胞负责，目前尚不清楚。在这里，我们将携带条件性 IκB 显性失活转基因（IκBdN）的小鼠与 FSP1.Cre 转基因（FSP1(+)成纤维细胞）或 γGT.Cre 转基因（近端肾小管上皮细胞）小鼠杂交，并对所有后代进行单侧输尿管梗阻处理。在梗阻后 7 天，通过肾组织中磷酸化 p65（（p)p65）的核定位来确定 NF-κB 的激活情况。与 IκBdN 对照相比，我们分别观察到 FSP1.Cre；IκBdN 和 γGT.Cre；IκBdN 小鼠的梗阻肾脏中，间质细胞和肾小管上皮细胞中的 NF-κB 激活受到抑制（P < 0.05）。然而，FSP1.Cre；IκBdN 小鼠的梗阻肾脏中细胞外基质的沉积显著低于 γGT.Cre；IκBdN 小鼠（P < 0.05）。此外，FSP1.Cre；IκBdN 小鼠的梗阻肾脏中编码致纤维化 PAI-1、纤维连接蛋白-EIIIA 和 I 型（α1）前胶原的 mRNA 水平显著低于 γGT.Cre；IκBdN 小鼠（P < 0.05）。总之，这些数据支持成纤维细胞在调节 NF-κB 激活方面发挥致纤维化作用，而近端肾小管上皮细胞则没有。
