Small RNA sequencing reveals snoRNAs and piRNA-019825 as novel players in diabetic kidney disease

Introduction Micro- and macrovascular complications are common among persons with type 2 diabetes. Recently there has been growing interest to investigate the potential of circulating small non-coding RNAs (sncRNAs) as contributors to the development of diabetic complications. In this study we investigate to what extent circulating sncRNAs levels associate with prevalent diabetic kidney disease (DKD) in persons with type 2 diabetes. Methods Plasma sncRNAs levels were determined using small RNA-seq, allowing detection of miRNAs, snoRNAs, piRNAs, tRNA-fragments and various other sncRNA classes. We tested for differentially expressed sncRNAs in persons with type 2 diabetes, with DKD (n=69) or without DKD (n=405). In secondary analyses, we also tested the association with eGFR, albuminuria (UACR) and the plasma proteome. Results In total seven sncRNAs were negatively associated with prevalent DKD (all P FDR ≤0.05). Including one microRNA (miR-143-5p), five snoRNAs (U8, SNORD118, SNORD24, SNORD107, SNORD87) and a piRNA (piR-019825|DQ597218). Proteomic analyses showed that the seven sncRNAs, and especially the piRNA piR-019825, were associated with plasma levels of 24 proteins of which several have known associations with kidney function including TNF sR-I (TNFRFS1A), DAN (NBL1) and cystatin C (CST3). Conclusion We have identified novel small non-coding RNAs, primarily from classes other than microRNAs, that are associated with diabetic kidney disease. Our results shows that the involvement of small non-coding RNAs in DKD goes beyond the already known microRNAs and also involves other classes of sncRNA, in particular snoRNAs and the piRNA piR-019825, that have never been studied before in relation to kidney function.