Severe Nephrotoxic Nephritis following Conditional and Kidney-Specific Knockdown of Stanniocalcin-1
Severe Nephrotoxic Nephritis following Conditional and Kidney-Specific Knockdown of Stanniocalcin-1
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DOI：
10.1371/journal.pone.0138440
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发表时间：
2015-09-22
期刊：
影响因子：
3.7
通讯作者：
Sheikh-Hamad, David
中科院分区：
文献类型：
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作者：
Huang, Luping;Lou, Yahuan;Sheikh-Hamad, David
背景炎症是肾毒性肾炎的标志。Stanniocalcin-1(STC1)是一种促进生存的因子，它抑制巨噬细胞，稳定内皮屏障功能，减少白细胞的跨内皮细胞迁移；一致地，转基因(TG)过表达STC1对肾毒性肾炎具有保护作用。在此，我们试图确定条件和肾脏特异性敲除STC1后的肾毒性肾炎的表型。方法利用超声微泡技术将表达CRE的shRNA(STC1shRNA的70%在4d内被敲除)和杂乱的shRNA(对照)分别表达STC1shRNA和杂乱的shRNA(对照组)。结果两组小鼠在注射抗GBM抗体后10d的血肌酐、蛋白尿、蛋白尿和尿量无明显差异，但肾特异性STC1基因敲除组小鼠出现严重的肾毒性肾炎，表现为严重的肾小管坏死、肾小球透明/坏死和大量管型形成，而对照组小鼠表现为轻度肾小管损伤和新月体肾炎。令人惊讶的是，在STC1基因敲除的肾脏中，细胞因子/趋化因子的表达以及T细胞和巨噬细胞的浸润也减少了。结论肾特异性基因敲除后的肾毒性肾炎以肾小管和肾小球严重坏死为特征，可能是由于STC1介导的促生存因子丢失所致，而炎症反应的缺乏可能与细胞因子/趋化因子/生长因子的释放减少有关。
BackgroundInflammation is the hallmark of nephrotoxic nephritis. Stanniocalcin-1 (STC1), a pro-survival factor, inhibits macrophages, stabilizes endothelial barrier function, and diminishes transendothelial migration of leukocytes; consistently, transgenic (Tg) overexpression of STC1 protects from nephrotoxic nephritis. Herein, we sought to determine the phenotype of nephrotoxic nephritis after conditional and kidney-specific knockdown of STC1.MethodsWe used Tg mice that, express either STC1 shRNA (70% knockdown of STC1 within 4d) or scrambled shRNA (control) upon delivery of Cre-expressing plasmid to the kidney using ultrasound microbubble technique. Sheep anti-mouse GBM antibody was administered 4d after shRNA activation; and mice were euthanized 10 days later for analysis.ResultsSerum creatinine, proteinuria, albuminuria and urine output were similar 10 days after anti-GBM delivery in both groups; however, anti-GBM antibody delivery to mice with kidney-specific knockdown of STC1 produced severe nephrotoxic nephritis, characterized by severe tubular necrosis, glomerular hyalinosis/necrosis and massive cast formation, while control mice manifested mild tubular injury and crescentic glomerulonephritis. Surprisingly, the expression of cytokines/chemokines and infiltration with T-cells and macrophages were also diminished in STC1 knockdown kidneys. Staining for sheep anti-mouse GBM antibody, deposition of mouse C-3 and IgG in the kidney, and antibody response to sheep IgG were equal.Conclusionsnephrotoxic nephritis after kidney-specific knockdown of STC1 is characterized by severe tubular and glomerular necrosis, possibly due to loss of STC1-mediated pro-survival factors, and we attribute the paucity of inflammation to diminished release of cytokines/chemokines/growth factors from the necrotic epithelium.