State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, P.R. China.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, P.R. China; State Key Laboratory of Analytical Chemistry for Life Sciences, Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing University, Nanjing, Jiangsu, P.R. China.
Kidney Int. 2019 Sep;96(3):674-688. doi: 10.1016/j.kint.2019.04.012. Epub 2019 May 10.
Tubular epithelial cell-derived profibrotic factors are known as the driving force in renal fibrosis for their roles in activating the surrounding fibroblast. However, the mechanisms driving their expressions remain undefined. Here, we find that kidney human epidermal growth factor receptor 2 (HER2), a member of the epidermal growth factor receptor family, significantly increased in unilateral ureteral obstruction-induced renal fibrosis, in type 1 and type 2 diabetic nephropathy, and in kidney biopsies from patients with renal fibrosis. Notably, the upregulation of HER2 mainly occurred in proximal tubular epithelial cells (PTECs). In vivo, the ectopic expression of HER2 in these cells was sufficient to activate the interstitial fibroblast and initiate interstitial fibrosis, whereas inhibiting HER2 reduced the accumulation of myofibroblasts and the extent of renal fibrosis in the mouse obstruction model and in streptozotocin (STZ)-induced diabetic mice. We also generated a tubular epithelial cell subline stably expressing HER2 and performed transcriptome RNA sequence analysis. This showed that sustained HER2 expression significantly induced the expression of profibrotic connective tissue growth factor (CTGF). Mechanistically, the induction of CTGF depended on the HER2-mediated activation of Stat3 in the tubular epithelium. In vitro, the incubation of kidney fibroblasts with culture medium from HER2-overexpressed tubular epithelial cells promoted fibroblast proliferation and activation, whereas silencing CTGF impeded the profibrotic effects of the tubular epithelial cell preconditioned media. Thus, our results highlight the significance of HER2 in tubular injury and characterize its role in promoting surrounding fibroblast activation and renal fibrosis in a paracrine manner.
管状上皮细胞衍生的促纤维化因子被认为是肾纤维化的驱动力，因为它们在激活周围成纤维细胞方面发挥作用。然而，驱动其表达的机制仍不清楚。在这里，我们发现肾脏人表皮生长因子受体 2（HER2），表皮生长因子受体家族的一员，在单侧输尿管梗阻诱导的肾纤维化、1 型和 2 型糖尿病肾病以及肾纤维化患者的肾活检中显著增加。值得注意的是，HER2 的上调主要发生在近端肾小管上皮细胞（PTECs）中。在体内，这些细胞中 HER2 的异位表达足以激活间质成纤维细胞并启动间质纤维化，而抑制 HER2 减少了小鼠梗阻模型和成纤维细胞中肌成纤维细胞的积累和肾纤维化的程度。我们还生成了稳定表达 HER2 的管状上皮细胞亚系，并进行了转录组 RNA 序列分析。这表明持续的 HER2 表达显著诱导了促纤维化结缔组织生长因子（CTGF）的表达。在机制上，CTGF 的诱导依赖于 HER2 介导的管状上皮细胞中 Stat3 的激活。在体外，用过表达 HER2 的管状上皮细胞的培养基孵育肾成纤维细胞可促进成纤维细胞的增殖和激活，而沉默 CTGF 则阻碍了管状上皮细胞预处理培养基的促纤维化作用。因此，我们的结果强调了 HER2 在管状损伤中的重要性，并描述了它在旁分泌方式促进周围成纤维细胞激活和肾纤维化中的作用。
