RT Journal Article
SR Electronic
T1 Alterations in protein translation and carboxylic acid catabolic processes in diabetic kidney disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.18.440341
DO 10.1101/2021.04.18.440341
A1 Kimberly S. Collins
A1 Michael T. Eadon
A1 Ying-Hua Cheng
A1 Daria Barwinska
A1 Ricardo Melo Ferreira
A1 Thomas W. McCarthy
A1 Danielle Janosevic
A1 Farooq Syed
A1 Bernhard Maier
A1 Tarek M. El-Achkar
A1 Katherine J. Kelly
A1 Carrie L. Phillips
A1 Takashi Hato
A1 Timothy A. Sutton
A1 Pierre C. Dagher
YR 2021
UL http://biorxiv.org/content/early/2021/04/19/2021.04.18.440341.abstract
AB Diabetic kidney disease (DKD) remains the leading cause of end stage kidney disease despite decades of study. Alterations in the glomerulus and kidney tubules both contribute to the pathogenesis of DKD although the majority of investigative efforts have focused on the glomerulus. We sought to examine the differential expression signature of human DKD in the glomerulus and proximal tubule and corroborate our findings in the db/db mouse model of diabetes. A transcriptogram network analysis of RNAseq data from laser microdissected (LMD) human glomerulus and proximal tubule of DKD and reference nephrectomy samples revealed enriched pathways including rhodopsin-like receptors, olfactory signaling, and ribosome (protein translation) in the proximal tubule of human DKD biopsy samples. The translation pathway was also enriched in the glomerulus. Increased translation in diabetic kidneys was validated using polyribosomal profiling in the db/db mouse model of diabetes. Using single nuclear RNA sequencing (snRNAseq) of kidneys from db/db mice, we prioritized additional pathways identified in human DKD. The top overlapping pathway identified in the murine snRNAseq proximal tubule clusters and the human LMD proximal tubule compartment was carboxylic acid catabolism. Using ultra-performance liquid chromatography-mass spectrometry, the fatty acid catabolism pathway was also found to be dysregulated in the db/db mouse model. The Acetyl-CoA metabolite was down-regulated in db/db mice, aligning with the human differential expression of the genes ACOX1 and ACACB. In summary, our findings demonstrate that proximal tubular alterations in protein translation and carboxylic acid catabolism are key features in both human and murine DKD.Competing Interest StatementThe authors have declared no competing interest.