Eckes Timon, Trautmann Sandra, Djudjaj Sonja, Beyer Sandra, Patyna Sammy, Schwalm Stephanie, Gauer Stefan, Thomas Dominique, Schaefer Liliana, Boor Peter, Koch Alexander, Pfeilschifter Josef
Institute of General Pharmacology and Toxicology, University Hospital, Goethe University Frankfurt am Main, Germany.
Institute of Clinical Pharmacology, University Hospital, Goethe University Frankfurt am Main, Germany.
Biochim Biophys Acta Mol Cell Biol Lipids. 2021 Jan;1866(1):158821. doi: 10.1016/j.bbalip.2020.158821. Epub 2020 Oct 1.
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.
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.
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.
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.
多项研究揭示了肾病患者血浆和血清中单一鞘脂种类的改变，如特定链长的神经酰胺。在此，我们研究了在患有肾纤维化（慢性肾病的常见终点）的患者和小鼠的肾组织中是否发生此类改变。
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样本。来自肿瘤肾切除术的健康部分用作非纤维化对照。从小鼠纤维化肾样本中收集雄性C57BL/6J小鼠，这些小鼠接受富含腺嘌呤的饮食14天或进行7天的单侧输尿管梗阻（UUO）。未处理小鼠的肾脏和对侧肾脏（UUO）分别用作对照。通过液相色谱-串联质谱法检测鞘脂水平。通过TaqMan®分析和免疫组织学分析纤维化标志物。
与各自的对照样本相比，在纤维化的人肾皮质和纤维化的小鼠肾中，极长链神经酰胺Cer d18:1/24:0和Cer d18:1/24:1均显著下调。这些效应与纤维化的人肾皮质和纤维化的小鼠肾中COL1α1、COL3α1和αSMA表达的上调相关。
我们已经表明，极长链神经酰胺Cer d18:1/24:0和Cer d18:1/24:1在人和小鼠的纤维化肾样本中持续下调。我们的研究结果支持使用体内小鼠模型作为合适的转化手段，以了解神经酰胺在人类肾脏疾病中的作用。此外，我们的研究提出了关于可能操纵神经酰胺代谢以预防纤维化进展以及使用神经酰胺作为慢性肾病潜在生物标志物的有趣问题。
