Abstract
Smad3 deficiency prevents the development of type 2 diabetic nephropathy; however, the underlying molecular mechanisms remain unknown. In this study, we aimed to identify Smad3-related genes involved in the pathogenesis of diabetic kidney disease. High-throughput RNA sequencing was performed to profile the whole transcriptome in the diabetic kidney of Smad3 WT-db/db, Smad3 KO-db/db, Smad3(+/-) db/db and their littermate control db/m mice at 20 weeks. The gene ontology, pathways and alternative splicing of differentially expressed protein-coding genes and long non-coding RNAs related to Smad3 in diabetic kidney were analysed. Compared to Smad3 WT-db/db mice, Smad3 KO-db/db mice exhibited an alteration of genes associated with RNA splicing and metabolism, whereas heterozygosity deletion of Smad3 (Smad3(+/-) db/db mice) significantly altered genes related to cell division and cell cycle. Notably, three protein-coding genes (Upk1b, Psca and Gdf15) and two lncRNAs (NONMMUG023520.2 and NONMMUG032975.2) were identified to be Smad3-dependent and to be associated with the development of diabetic nephropathy. By using whole transcriptome RNA sequencing, we identified novel Smad3 transcripts related to the development of diabetic nephropathy. Thus, targeting these transcripts may represent a novel and effective therapy for diabetic nephropathy.