Background

Several studies revealed alterations of single sphingolipid species, such as chain length-specific ceramides, in plasma and serum of patients with kidney diseases. Here, we investigated whether such alterations occur in kidney tissue from patients and mice suffering from renal fibrosis, the common endpoint of chronic kidney diseases.

Methods

Human fibrotic kidney samples were collected from nephrectomy specimens with hydronephrosis and/or pyelonephritis. Healthy parts from tumor nephrectomies served as nonfibrotic controls. Mouse fibrotic kidney samples were collected from male C57BL/6J mice treated with an adenine-rich diet for 14 days or were subjected to 7 days of unilateral ureteral obstruction (UUO). Kidneys of untreated mice and contralateral kidneys (UUO) served as respective controls. Sphingolipid levels were detected by LC-MS/MS. Fibrotic markers were analyzed by TaqMan® analysis and immunohistology.

Results

Very long-chain ceramides Cer d18:1/24:0 and Cer d18:1/24:1 were significantly downregulated in both fibrotic human kidney cortex and fibrotic murine kidney compared to respective control samples. These effects correlate with upregulation of COL1α1, COL3α1 and αSMA expression in fibrotic human kidney cortex and fibrotic mouse kidney.

Conclusion

We have shown that very long-chain ceramides Cer d18:1/24:0 and Cer d18:1/24:1 are consistently downregulated in fibrotic kidney samples from human and mouse. Our findings support the use of in vivo murine models as appropriate translational means to understand the involvement of ceramides in human kidney diseases. In addition, our study raises interesting questions about the possible manipulation of ceramide metabolism to prevent progression of fibrosis and the use of ceramides as potential biomarkers of chronic kidney disease.

中文翻译：

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人和小鼠纤维化肾脏中链长特异性神经酰胺的一致改变

背景

几项研究揭示了患有肾脏疾病的患者血浆和血清中单个鞘脂类物种的改变，例如链长特异性神经酰胺。在这里，我们调查了这种变化是否发生在患有慢性肾病的共同终点-肾纤维化的患者和小鼠的肾脏组织中。

方法

从患有肾积水和/或肾盂肾炎的肾切除标本中收集人纤维化肾脏样品。来自肿瘤肾切除术的健康部位用作非纤维化对照。从富含腺嘌呤饮食处理14天的雄性C57BL / 6J小鼠中收集小鼠纤维化肾脏样品，或对它们进行7天的单侧输尿管阻塞（UUO）。未经治疗的小鼠的肾脏和对侧肾脏（UUO）分别作为对照。通过LC-MS / MS检测鞘脂水平。通过分析和免疫组织学分析纤维化标记物。

结果

与相应的对照样品相比，在纤维化的人肾皮质和纤维化的鼠肾中，非常长链的神经酰胺Cer d18：1/24：0和Cer d18：1/24：1均显着下调。这些作用与纤维化人肾皮质和纤维化小鼠肾脏中COL1α1，COL3α1和αSMA表达的上调有关。

结论

我们已经显示，在人和小鼠的纤维化肾脏样品中，非常长链的神经酰胺Cer d18：1/24：0和Cer d18：1/24：1始终被下调。我们的研究结果支持使用体内鼠模型作为适当的翻译手段来了解神经酰胺在人类肾脏疾病中的参与。此外，我们的研究提出了有关可能的神经酰胺代谢控制以防止纤维化进展以及将神经酰胺用作慢性肾脏疾病潜在生物标志物的有趣问题。