Zhang Lei, Han Changsong, Ye Fei, He Yan, Jin Yinji, Wang Tianzhen, Wu Yiqi, Jiang Yang, Zhang Fengmin, Jin Xiaoming
Department of Pathology, Harbin Medical University, Harbin 150081, China.
Department of Microbiology, Harbin Medical University, Harbin 150081, China.
Int J Mol Sci. 2017 Feb 12;18(2):390. doi: 10.3390/ijms18020390.
Glomerular fibrosis has been shown to be closely related to the progression and prognosis of IgA nephropathy (IgAN). However, mechanism underlying IgAN glomerular fibrosis remains unclear. Recently, our study showed that plasma gelsolin (pGSN) was decreased in the serum of an IgAN mouse model and that pGSN deposition was found in the glomeruli. Another cytokine, TGF-β1, which is closely related to glomerular fibrosis, was also found to be highly expressed in the glomeruli. In the present study, we report that pGSN induces glomerular fibrosis through the TGF-β1/Smads signal transduction pathway. This is supported by the following findings: human mesangial cells (HMCs) show remarkable morphological changes and proliferation in response to co-stimulation with pGSN and polymeric IgA1 (pIgA1) from IgAN patients compared to other controls. Moreover, ELISA assays showed that more TGF-β1 secretion was found in HMCs supernatants in the co-stimulation group. Further experiments showed increased TGF-β1, Smad3, p-Smad2/3, Smad4, and collagen 1 and decreased Smad7 expression in the co-stimulation group. Our present study implied that the synergistic effect of pGSN and pIgA induced glomerular fibrosis via the TGF-β1/Smads signal transduction pathway. This might be a potential mechanism for the glomerular fibrosis observed in IgAN patients.
肾小球纤维化已被证明与IgA肾病（IgAN）的进展和预后密切相关。然而，IgAN肾小球纤维化的潜在机制仍不清楚。最近，我们的研究表明，在IgAN小鼠模型的血清中血浆凝溶胶蛋白（pGSN）减少，并且在肾小球中发现了pGSN沉积。另一种与肾小球纤维化密切相关的细胞因子转化生长因子-β1（TGF-β1），也被发现在肾小球中高表达。在本研究中，我们报告pGSN通过TGF-β1/Smads信号转导通路诱导肾小球纤维化。以下发现支持了这一点：与其他对照组相比，人系膜细胞（HMCs）在与pGSN和来自IgAN患者的聚合IgA1（pIgA1）共同刺激下显示出明显的形态变化和增殖。此外，ELISA分析表明，在共同刺激组的HMCs上清液中发现更多的TGF-β1分泌。进一步的实验表明，在共同刺激组中TGF-β1、Smad3、磷酸化Smad2/3、Smad4和胶原蛋白1表达增加，而Smad7表达减少。我们目前的研究表明，pGSN和pIgA的协同作用通过TGF-β1/Smads信号转导通路诱导肾小球纤维化。这可能是IgAN患者中观察到的肾小球纤维化的潜在机制。
