Altered lipid metabolism in the aging kidney identified by three layered omic analysis

Aging-related diseases and their comorbidities affect the life quality of a constantly growing proportion of our population. Age-associated changes of kidney structure and function are considerable contributors to the dramatically increased incidence of chronic kidney disease world-wide which has been identified to be a prominent cardiovascular risk factor. In order to detect molecular mechanisms involved in kidney aging we analyzed gene expression profiles of kidneys from adult and aged wild-type mice by a three-layered omics strategy. To this end, transcriptomic, proteomic and targeted lipidomic profiles of young and aged mice were generated and integrated. Transcriptome and proteome analyses revealed differential expression of genes involved primarily in lipid metabolism and immune response. Additional lipidomic analyses uncovered significant age-related differences in the total amount of phosphatidylethanolamines, phosphatidylcholines and sphingomyelins as well as in subspecies of phosphatidylserines and ceramides, while total ceramide levels remained unchanged. By integration of these datasets we identified Aldh1a1, a key enzyme in vitamin A metabolism specifically expressed in the medullary ascending limb, as one of the most prominent upregulated proteins in old kidneys. Moreover, ceramidase Asah1 was highly expressed in aged kidneys, consistent with a decrease in ceramide C16. In summary, our data suggest that changes in lipid metabolism are involved in the process of kidney aging and in the development of chronic kidney disease. 14 weeks females (4 replicates); 96 weeks females (5 replicates)衰老相关疾病及其合并症，正持续影响着全球占比不断提升的人群的生活质量。肾脏结构与功能的增龄性改变，是全球慢性肾脏病（chronic kidney disease, CKD）发病率大幅攀升的重要诱因，而慢性肾脏病已被证实为一类显著的心血管疾病风险因子。为探明肾脏衰老的分子机制，本研究采用三层组学（omics）策略，对成年与老年野生型小鼠的肾脏基因表达谱开展了分析。为此，我们获取并整合了年轻与老年小鼠的转录组（transcriptome）、蛋白质组（proteome）及靶向脂质组（targeted lipidome）谱学数据。转录组与蛋白质组分析显示，主要参与脂质代谢与免疫应答的基因存在差异表达现象。补充的脂质组学分析发现，老年小鼠体内磷脂酰乙醇胺（phosphatidylethanolamines）、磷脂酰胆碱（phosphatidylcholines）与鞘磷脂（sphingomyelins）的总含量，以及磷脂酰丝氨酸（phosphatidylserines）和神经酰胺（ceramides）的亚型均存在显著的增龄性差异，而神经酰胺的总水平未发生明显变化。通过整合上述多组学数据集，我们鉴定出Aldh1a1——一种在维生素A代谢中发挥关键作用、且特异性表达于肾小管髓质升支的酶——是老年肾脏中上调最为显著的蛋白质之一。此外，神经酰胺酶Asah1在老年小鼠肾脏中呈高表达，这与C16型神经酰胺的水平降低现象相符。综上，本研究数据表明，脂质代谢改变参与了肾脏衰老进程以及慢性肾脏病的发生发展。实验样本信息：14周龄雌性小鼠（4个生物学重复）；96周龄雌性小鼠（5个生物学重复）