In-depth transcriptomic analyses investigating molecular mechanisms underlying diabetic retinopathy (smallRNA)

Diabetic Retinopathy (DR) is among the major global causes for vision loss. With the rise in diabetes prevalence, an increase in DR incidence is expected. Current understanding of both the molecular etiology and pathways involved in the initiation and progression of DR is limited. Here we analyzed mRNA and miRNA expression profiles of 80 human post-mortem retinal samples from 80 patients diagnosed with various stages of DR. We found differentially expressed transcripts to be predominantly associated with late stage DR and pathways such as hippo and gap junction signaling. A multivariate regression model identified transcripts with progressive changes throughout disease stages, which in turn displayed significant overlap with sphingolipid and cGMP−PKG signaling. Combined analysis of miRNA and mRNA expression further uncovered disease-relevant miRNA/mRNA associations as potential mechanisms of post-transcriptional regulation. Finally, integrating human retinal single cell RNA-Sequencing data revealed a continuous loss of retinal ganglion cells, and Müller cell mediated changes in histidine and β-alanine signaling. Our findings offer an unprecedented insight into the development of DR and provide potential avenues for future therapeutic intervention. Post-mortem human eyes from 43 donors were obtained through the Iowa Lions Eye Bank (Coralville, IA) after written informed consent of the next-of-kin was obtained. Preservation of eyes occurred within 6 hours post-mortem. From each donor group (healthy control, diabetic, NPPR, and NPDR/PDR + DME), 10 tissue samples were collected from the macula region as well as the retinal periphery. All tissue samples were taken with a 6mm biopsy punch, snap frozen in liquid nitrogen, and preserved at -80C until use. Submitter states that raw data can't be provided due to patient privacy concerns. Raw data will be uploaded to dbGaP.