Deficiency of endothelial nitric oxide signaling pathway exacerbates peritoneal fibrosis in mice
Deficiency of endothelial nitric oxide signaling pathway exacerbates peritoneal fibrosis in mice
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DOI：
10.1007/s10157-014-1029-3
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发表时间：
2015-08-01
影响因子：
2.3
通讯作者：
Kashihara, Naoki
中科院分区：
文献类型：
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作者：
Kadoya, Hiroyuki;Satoh, Minoru;Kashihara, Naoki
长期腹膜透析（PD）会导致腹膜功能障碍和结构改变，最终导致腹膜纤维化。内皮型一氧化氮合酶（eNOS）-NO信号通路参与器官纤维化的进展。然而，它仍然是未知的，是否NO信号转导参与了腹膜纤维化的过程。我们评估了eNOS-NO信号通路在腹膜纤维化发展中的作用，以及刺激可溶性鸟苷酸环化酶（sGC）（NO的下游效应物）是否可以减轻腹膜纤维化。小鼠在第0天经历机械腹膜剥离诱导的腹膜纤维化。在腹膜剥离后3、7、14和28天，处死小鼠。在一些eNOSKO小鼠中，通过腹膜内注射施用sGC刺激剂Bay 41-2272在WT小鼠中，在第3天和第7天在中皮下区域中观察到肉芽肿组织形成。第7天后，腹膜厚度逐渐降低，腹膜组织得到修复，在第28天仅留下轻微的纤维化。然而，在腹膜剥离后28天，eNOSKO小鼠比WT小鼠表现出更多的腹膜纤维化进展。在eNOSKO小鼠中，在增厚的腹膜中的波形蛋白的表达在第7天后延长。用Bay 41-2272治疗显著减弱了eNOSKO小鼠中腹膜波形蛋白的表达和纤维化。eNOS-NO信号通路的破坏通过延迟伤口愈合而加剧了腹膜纤维化。sGC刺激可能是预防腹膜纤维化的有用疗法。
Long-term peritoneal dialysis (PD) causes peritoneal dysfunction and structural alterations, eventually leading to peritoneal fibrosis. The endothelial nitric oxide synthase (eNOS)-NO signaling pathway contributes to the progression of organ fibrosis. However, it remains unknown whether NO signaling is involved in the process of peritoneal fibrosis. We evaluated the role of the eNOS-NO signaling pathway in the development of peritoneal fibrosis and whether stimulation of soluble guanylate cyclase (sGC), a downstream effector of NO, could attenuate peritoneal fibrosis.We used wild-type (WT) and eNOS-deficient mice (eNOSKO). The mice underwent mechanical peritoneal stripping-induced peritoneal fibrosis at day 0. At 3, 7, 14, and 28 days after peritoneal stripping, the mice were killed. In some eNOSKO mice, the sGC stimulator Bay 41-2272 was administered by intraperitoneal injection.In WT mice, granulomatous tissue formation was observed in the submesothelial area at days 3 and 7. After day 7, the peritoneal membrane thickness gradually decreased and peritoneal tissue was repaired with leaving only slight fibrosis at day 28. However, eNOSKO mice demonstrated more progression of peritoneal fibrosis than WT mice at 28 days after peritoneal stripping. Expression of vimentin in the thickened peritoneum was prolonged after day 7 in eNOSKO mice. Treatment with Bay 41-2272 significantly attenuated peritoneal vimentin expression and fibrosis in the eNOSKO mice.Disruption of the eNOS-NO signaling pathway exacerbates peritoneal fibrosis by delaying wound healing. sGC stimulation may be a useful therapy for prevention of peritoneal fibrosis.