Alterations in Protein Translation and Carboxylic Acid Catabolic Processes in
Diabetic Kidney Disease.
Authors Collins KS, Eadon MT, Cheng YH, Barwinska D, Melo Ferreira R, McCarthy TW,
Janosevic D, Syed F, Maier B, El-Achkar TM, Kelly KJ, Phillips CL, Hato T,
Sutton TA, Dagher PC
Submitted By Submitted Externally on 6/13/2022
Status Published
Journal Cells
Year 2022
Date Published 3/1/2022
Volume : Pages 11 : Not Specified
PubMed Reference 35406730
Abstract 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.