The RNA m6A reader YTHDF2 depletion phenocopies high glucose induced-cellular stress response in diabetic kidney disease

RNA modification, especially the m6A RNA methylation, has been increasingly associated with several physiological and pathophysiological processes. The proteins that help in establishment of the modification and its removal along with the reader proteins that facilitate the functional outcome, together play an important regulatory role in disease manifestation. Diabetic kidney disease (DKD) is one such example, which is categorized as a multifactorial disorder that involves complex metabolic, oxidative, inflammatory, and fibrotic alterations, mediated through genetic, epigenetic and signalling cascades. However, the contribution of m6A-associated RNA regulators in DKD manifestation is relatively less explored. In this study, using HFD+STZ-induced diabetic mice and high glucose-treated renal cell models, we identified the m6A reader protein, Ythdf2 as a consistently downregulated candidate. YTHDF2 depletion in the renal cell line altered cellular viability, proliferation and increased oxidative stress under high-glucose conditions. Click-IT EU labeling further revealed altered RNA processing effects following YTHDF2 depletion and glucose stress. In corroboration with the above observations in animal and cell line models, independent human DKD transcriptomic datasets demonstrated conserved inflammatory and fibrotic signatures as well as reduced YTHDF2 expression in DKD glomeruli. The YTHDF2 downregulation was found to be inversely correlated with several disease-associated inflammatory and fibrotic genes. Together, these findings identify YTHDF2 dysregulation as a potential post-transcriptional mechanism associated with cellular stress and disease-associated molecular programs in DKD.