Background: MicroRNAs (miRNAs) are involved in gene regulation and play important roles in the etiology of various diseases including diabetic kidney disease. The objective of this study was to determine miRNAs profile and their target proteins associated with risk of progression to end-stage renal disease (ESRD) in diabetes.
Methods: Using HTG edge sequence platform, 2,083 miRNAs were measured in baseline plasma specimens of patients with renal impairment (CKD stage 3 and 4). We also measured 1,029 protein levels using SomaScan proteomics platform to assess the target proteins of candidate miRNAs. We studied 375 patients with diabetes: 239 patients with type 1 diabetes as our exploratory panel and 136 patients with type 2 diabetes as our replication panel.
Results: We identified 19 circulating miRNAs that were strongly associated with progression to ESRD in both T1D and T2D. Among them, 4 representative miRNAs were selected. In pathway analysis, Axon guidance (AG) was the most significant pathway enriched by genes targeted by the representative miRNAs. Our proteomics platform included 41 AG proteins and 6 of them were identified to be associated with ESRD in T1D and T2D. Mediation analysis revealed that 10-83% of the miRNAs effect on ESRD is mediated through axon guidance proteins, namely 2 Ephrin ligands and 4 Ephrin receptors.
Conclusions: Our results suggest that certain miRNAs play a significant etiological role in progression of diabetic kidney disease to ESRD mediated by axon guidance proteins. These miRNAs and AG proteins have the potential to be used as novel therapeutic targets and prognostic biomarkers.
E. Satake: None. J. Skupien: None. Z.I. Md Dom: None. H. Kobayashi: None. K. Ihara: None. M.G. Pezzolesi: None. M. Niewczas: None. A. Krolewski: None.
National Institutes of Health; Novo Nordisk Foundation; Sunstar Foundation