Deletion of connective tissue growth factor ameliorates peritoneal fibrosis by inhibiting angiogenesis and inflammation
Deletion of connective tissue growth factor ameliorates peritoneal fibrosis by inhibiting angiogenesis and inflammation
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DOI：
10.1093/ndt/gfx317
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发表时间：
2018-06-01
影响因子：
6.1
通讯作者：
Yokoi, Hideki
中科院分区：
文献类型：
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作者：
Toda, Naohiro;Mori, Kiyoshi;Yokoi, Hideki
背景结缔组织生长因子（CTGF/CCN 2）调节其他生长因子的信号传导并促进纤维化。CTGF在患有腹膜纤维化的小鼠和人类中增加。CTGF的抑制还没有作为腹膜纤维化的潜在治疗靶点进行研究，因为系统性CTGF敲除小鼠在围产期死亡。为了研究CTGF在成年小鼠腹膜纤维化中的作用，我们通过将CTGF floxed小鼠与RosaCreER（T2）小鼠杂交来产生CTGF条件性敲除（cKO）小鼠。我们给Rosa-CTGF cKO小鼠施用他莫昔芬以删除全身的CTGF基因。我们通过腹膜内注射葡萄糖酸氯己定（CG）诱导野生型和Rosa-CTGF cKO小鼠的腹膜纤维化。在野生型小鼠中诱导腹膜纤维化增加CTGF表达并产生腹膜严重增厚。相比之下，CG处理的Rosa-CTGF cKO小鼠表现出腹膜增厚减少。腹膜平衡试验显示，CG处理的野生型小鼠中的过度腹膜小溶质转运通过CTGF缺失而正常化。CG处理的Rosa-CTGF cKO小鼠在腹膜中表现出减少的α SMA-、Ki 67-、CD 31-和MAC-2-阳性细胞数量。腹膜mRNA分析显示CG处理的Rosa-CTGF cKO小鼠表现出Cd 68、Acta 2（α SMA）、Pecam 1（CD 31）和Vegfa的表达降低。这些结果表明，CTGF的缺乏可以减少腹膜增厚，并通过减少腹膜纤维化中的血管生成和炎症来帮助维持腹膜功能。这些结果表明，CTGF在腹膜纤维化的进展中起重要作用。
Background. Connective tissue growth factor (CTGF/CCN2) regulates the signalling of other growth factors and promotes fibrosis. CTGF is increased in mice and humans with peritoneal fibrosis. Inhibition of CTGF has not been examined as a potential therapeutic target for peritoneal fibrosis because systemic CTGF knockout mice die at the perinatal stage.Methods. To study the role of CTGF in peritoneal fibrosis of adult mice, we generated CTGF conditional knockout (cKO) mice by crossing CTGF floxed mice with RosaCreER(T2) mice. We administered tamoxifen to Rosa-CTGF cKO mice to delete the CTGF gene throughout the body. We induced peritoneal fibrosis by intraperitoneal injection of chlorhexidine gluconate (CG) in wild-type and Rosa-CTGF cKO mice.Results. Induction of peritoneal fibrosis in wild-type mice increased CTGF expression and produced severe thickening of the peritoneum. In contrast, CG-treated Rosa-CTGF cKO mice exhibited reduced thickening of the peritoneum. Peritoneal equilibration test revealed that the excessive peritoneal small-solute transport in CG-treated wild-type mice was normalized by CTGF deletion. CG-treated Rosa-CTGF cKO mice exhibited a reduced number of alpha SMA-, Ki67-, CD31- and MAC-2-positive cells in the peritoneum. Analyses of peritoneal mRNA showed that CG-treated Rosa-CTGF cKO mice exhibited reduced expression of Cd68, Acta2 (alpha SMA), Pecam1 (CD31) and Vegfa.Conclusions. These results indicate that a deficiency of CTGF can reduce peritoneal thickening and help to maintain peritoneal function by reducing angiogenesis and inflammation in peritoneal fibrosis. These results suggest that CTGF plays an important role in the progression of peritoneal fibrosis.