National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, China.
School of Medicine, Southeast University, Nanjing, 210009, China.
Sci Rep. 2019 Jan 24;9(1):716. doi: 10.1038/s41598-018-36902-2.
Tubulointerstitial fibrosis impacts renal prognosis of focal segmental glomerulosclerosis (FSGS). Based on transcriptomic analysis, we found that the level of LOC105375913 was increased in tubular cells of FSGS patients. C3a induced the expression of LOC105375913, which promoted the expression of fibronectin and collagen I in tubular cells. Silence of snail reversed the level of fibronectin and collagen I in cells overexpressing LOC105375913. MiR-27b was predicted and confirmed to regulate the expression of snail in tubular cells, and LOC105375913 contained the response element of miR-27b. The competitive binding between LOC105375913 and miR-27b increased the level of snail and promoted fibrogenesis in tubular cells. Upstream, p38 and XBP-1s regulated the expression of LOC105375913. Inhibition of p38 or silence of XBP-1s decreased the level of LOC105375913, and suppressed the expression of snail, fibronectin and collagen I in tubular cells treated with C3a. Overexpression of LOC105375913 decreased the level of miR-27b, increased the level of snail and caused tubulointerstitial fibrosis in mice. In conclusion, the activation of C3a/p38/XBP-1s pathway induces the expression of LOC105375913 in tubular cells, and LOC105375913 increases the level of snail and induces tubulointerstitial fibrosis through competitive binding of miR-27b in tubular cells of FSGS patients.
肾小管间质纤维化影响局灶节段性肾小球硬化症 (FSGS) 的肾脏预后。基于转录组分析，我们发现 FSGS 患者肾小管细胞中 LOC105375913 的水平增加。C3a 诱导 LOC105375913 的表达，促进肾小管细胞中纤连蛋白和胶原 I 的表达。沉默 snail 逆转了过表达 LOC105375913 的细胞中纤连蛋白和胶原 I 的水平。miR-27b 被预测并证实可调节肾小管细胞中 snail 的表达，而 LOC105375913 含有 miR-27b 的反应元件。LOC105375913 和 miR-27b 之间的竞争结合增加了 snail 的水平，并促进了肾小管细胞中的纤维生成。在上游，p38 和 XBP-1s 调节 LOC105375913 的表达。抑制 p38 或沉默 XBP-1s 降低了 LOC105375913 的水平，并抑制了 C3a 处理的肾小管细胞中 snail、纤连蛋白和胶原 I 的表达。过表达 LOC105375913 降低了 miR-27b 的水平，增加了 snail 的水平，并导致 FSGS 小鼠的肾小管间质纤维化。总之，C3a/p38/XBP-1s 通路的激活诱导 FSGS 患者肾小管细胞中 LOC105375913 的表达，而 LOC105375913 通过肾小管细胞中 miR-27b 的竞争结合增加 snail 的水平并诱导肾小管间质纤维化。
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