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.

Single-cell transcriptomics: A new tool for studying diabetic kidney disease

“…The acetyl-CoA metabolite was downregulated in db/db mice, consistent with the differential expression of the genes Acoxl and Acacb . These findings suggest that PT alterations and carboxylic acid catabolism during protein translation are key features of human and mouse DKD ( Collins et al, 2022 ).…”

“…A study on human and mouse DKD found carboxylic acid catabolic process, steroid hormone biosynthesis, glutathione metabolism, and biological oxidation were enriched in PT cells. Among these, the carboxylic acid catabolic process is the top pathway identified in mouse snRNA-seq and human datasets ( Collins et al, 2022 ). Spatially resolved metabolomics by mass spectrometry imaging revealed that increased glycolysis, mitochondrial dysfunction, AMPK inhibition, and lipid metabolism disorders occurred in a region-specific manner in the kidneys of rats with DKD ( Wang et al, 2021 ).…”

Kidney transcriptomics signature of prospective rapid diabetic kidney disease progression

“…60 This increase in mRNA translation could be caused by matrix accumulation and higher amounts of growth factors, both of which are prevalent in tubular injury and progressive DKD. 61 An imbalance brought about by an increase in protein synthesis and degradation can progress to ER stress, 60 which is one of the critical mechanisms in albumin-induced tubular injury. 62 Several limitations of this study should be acknowledged.…”

“…Translation pathways have been reported enriched in the proximal tubules of DKD kidney biopsies compared to controls. 60 This increase in mRNA translation could be caused by matrix accumulation and higher amounts of growth factors, both of which are prevalent in tubular injury and progressive DKD. 61 An imbalance brought about by an increase in protein synthesis and degradation can progress to ER stress, 60 which is one of the critical mechanisms in albumin-induced tubular injury.…”

Association of amino acids related to urea cycle with risk of diabetic nephropathy in two independent cross-sectional studies of Chinese adults

“…Diabetic nephropathy (DN) is a result of a complex interaction between metabolic processes, is a result of long-term tubular ( 5 , 6 ) and glomerular damage, and is an important cause of renal failure ( 7 ) and inflammatory and hemodynamic change ( 3 ). Its key risk factor is insulin resistance.…”