Alterations in protein translation and carboxylic acid catabolic processes in diabetic kidney disease

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.

Metabolic predictors of phenotypic traits can replace and complement measured clinical variables in transcriptome-wide association studies

“…The top-ranked enriched pathways for low eGFR are related to translation. Since low eGFR is an indicator of kidney disease, this is in line with studies reporting increased translational activity to several kidney diseases [30,31]. For diabetes and metabolic syndrome, which is a risk factor for diabetes, 16 out of the top 20 significantly enriched pathways were found for both outcomes.…”

Metabolomic predictors of phenotypic traits can replace and complement measured clinical variables in population-scale expression profiling studies

“…The top-ranked enriched pathways for low eGFR are related to translation. Since low eGFR is an indicator of kidney disease, this is in line with studies reporting increased translational activity to several kidney diseases [17,18]. For diabetes and metabolic syndrome, which is a risk factor for diabetes, 16 out of the top 20 significantly enriched pathways were found for both outcomes.…”

Identification of AGXT2, SHMT1, and ACO2 as important biomarkers of acute kidney injury by WGCNA

“…GO, and KEGG analyses were performed to reveal the role of candidate genes in the pathogenesis of AKI. GO analysis (Fig 4A ) revealed that candidate biomarker genes in biological processes were mainly enriched in the alpha-amino acid biosynthetic process [17][18][19] and the carboxylic acid biosynthetic process [20]; The molecular functions were mainly enriched in vitamin B and vitamin binding [21,22], amino acid binding [23,24] S-methyltransferase activity [25,26]; The cellular components were significantly enriched in brush border [27,28], apical plasma membrane [29,30], apical part of cell [31]. In addition, as shown in Fig 4B, KEGG analysis indicated that candidate genes were mainly enriched in Glycine, serine and threonine metabolism [32,33] Cysteine and methionine metabolism [34] and Biosynthesis of amino acids [35,36].…”