Protein kinase C α inhibition prevents peritoneal damage in a mouse model of chronic peritoneal exposure to high-glucose dialysate
Protein kinase C α inhibition prevents peritoneal damage in a mouse model of chronic peritoneal exposure to high-glucose dialysate
复制标题
蛋白激酶 Cα 抑制可防止长期腹膜暴露于高葡萄糖透析液的小鼠模型的腹膜损伤。
DOI：
10.1016/j.kint.2016.01.025
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发表时间：
2016-06-01
影响因子：
19.6
通讯作者：
Shushakova, Nelli
中科院分区：
文献类型：
--
作者：
Wang, Le;Balzer, Michael S.;Shushakova, Nelli
腹膜透析过程中长期暴露于市售葡萄糖腹膜透析液可诱导腹膜损伤，导致超滤失败。在这项研究中，蛋白激酶C（PKC）α的腹膜损伤的作用进行了研究，在腹膜透析的小鼠模型。我们使用了两种不同的方法：在C57 BL/6野生型小鼠和129/Sv遗传背景的PKC α缺陷小鼠中，通过腹腔内应用常规PKC抑制剂Go 6976阻断PKC α的生物活性。每天给予腹膜透析液5周诱导腹膜上调和PKC α活化，伴随腹膜间皮细胞的上皮-间充质转化、腹膜纤维化、新血管生成以及巨噬细胞和T细胞浸润，并伴有超滤能力降低。所有的病理变化都被PKC α阻断或缺乏所阻止。此外，用Go 6976和PKC α缺陷治疗导致促炎、促纤维化和促血管生成介质的强烈减少。在细胞培养实验中，Go 6976和PKC α缺乏的治疗都阻止了腹膜透析液诱导的小鼠腹膜间皮细胞MCP-1的释放，并改善了人腹膜间皮细胞中转化生长因子β 1诱导的上皮-间质转化和腹膜透析液诱导的MCP-1释放。因此，PKC α在腹膜透析液诱导的腹膜功能障碍的病理生理学中起着至关重要的作用，我们认为，其治疗抑制可能是腹膜透析患者有价值的治疗选择。
Chronic exposure to commercial glucose-based peritoneal dialysis fluids during peritoneal dialysis induces peritoneal membrane damage leading to ultrafiltration failure. In this study the role of protein kinase C (PKC) alpha in peritoneal membrane damage was investigated in a mouse model of peritoneal dialysis. We used 2 different approaches: blockade of biological activity of PKC alpha by intraperitoneal application of the conventional PKC inhibitor Go6976 in C57BL/6 wild-type mice and PKC alpha-deficientmice on a 129/Sv genetic background. Daily administration of peritoneal dialysis fluid for 5 weeks induced peritoneal upregulation and activation of PKC alpha accompanied by epithelial-to-mesenchymal transition of peritoneal mesothelial cells, peritoneal membrane fibrosis, neoangiogenesis, and macrophage and T cell infiltration, paralleled by reduced ultrafiltration capacity. All pathological changes were prevented by PKC alpha blockade or deficiency. Moreover, treatment with Go6976 and PKC alpha deficiency resulted in strong reduction of proinflammatory, profibrotic, and proangiogenic mediators. In cell culture experiments, both treatment with Go6976 and PKC alpha deficiency prevented peritoneal dialysis fluid-induced release of MCP-1 from mouse peritoneal mesothelial cells and ameliorated transforming growth factor-beta 1-induced epithelial-to-mesenchymal transition and peritoneal dialysis fluid-induced MCP-1 release in human peritoneal mesothelial cells. Thus, PKC alpha plays a crucial role in the pathophysiology of peritoneal membrane dysfunction induced by peritoneal dialysis fluids, and we suggest that its therapeutic inhibition might be a valuable treatment option for peritoneal dialysis patients.