526-P: Urine Tricarboxylic Acid Cycle Organic Anions and Progression of Diabetic Kidney Disease

Abstract Purpose of Review Diabetic kidney disease (DKD), a leading cause of end-stage kidney disease, is the result of metabolic network alterations in the kidney. Therefore, metabolomics is an effective tool for understanding its pathophysiology, finding key biomarkers, and developing a new treatment strategy. In this review, we summarize the application of metabolomics to DKD research. Recent Findings Alterations in renal energy metabolism including the accumulation of tricarboxylic acid cycle and glucose metabolites are observed in the early stage of DKD, and they finally lead to mitochondrial dysfunction in advanced DKD. Mitochondrial fission-fusion imbalance and dysregulated organelle crosstalk might contribute to this process. Moreover, metabolomics has identified several uremic toxins including phenyl sulfate and tryptophan derivatives as promising biomarkers that mediate DKD progression. Summary Recent advances in metabolomics have clarified the role of dysregulated energy metabolism and uremic toxins in DKD pathophysiology. Integration of multi-omics data will provide additional information for identifying critical drivers of DKD.

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CFAP45 is a Potential Predictor of Mitochondrial Dysfunction in Diabetic Kidney Disease

10.21203/rs.3.rs-277502/v1 ◽

2021 ◽

Author(s):

Yang Chen ◽

Min Shen ◽

Yun Shi ◽

Li Ji ◽

Yong Gu ◽

...

Keyword(s):

Kidney Disease ◽

Signaling Pathways ◽

Diabetic Kidney Disease ◽

Tricarboxylic Acid Cycle ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Pathway Enrichment Analysis ◽

Diabetic Kidney ◽

Expression Levels ◽

Potential Biomarker

Abstract Background: Cilia and Flagella Associated Protein 45 (CFAP45) is known to be involved in the regulation of ciliary motility. However, its potential role in diabetic kidney disease (DKD) remains unknown. This study demonstrated the role of CFAP45 in the development of DKD based on the Gene Expression Omnibus database.Methods: First, we investigated the expression of CFAP45 in a whole-genome expression microarray (GSE30122). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, as well as Gene Set Enrichment Analysis (GSEA), were then conducted to identify the key signaling pathways associated with CFAP45. The networks between transcript factors and hub genes were then constructed by Cytoscape software.Findings: The expression levels of CFAP45 mRNA were reduced in DKD samples as compared to normal samples. Receiver operating characteristic (ROC) curve analysis suggested the significant discriminatory power (area under curve [AUC] = 0.811) of CFAP45 between DKD and normal tissues. Low expression levels of CFAP45 were correlated with apoptosis, senescence and the induction of mast cell infiltration. Function enrichment analysis indicated that CFAP45 is involved in the most significant hallmarks of mitochondrial metabolism dysfunction, including glycolysis and gluconeogenesis, fatty acid metabolism and degradation, ubiquitin-dependent protein catabolic processes, the tricarboxylic acid cycle (TCA) cycle, the action of oxidoreductase on Nicotinamide adenine dinucleotide (NADH), and the peroxisome proliferator-activated receptor (PPAR) signaling pathways located in the mitochondrial matrix and the lysosomal membrane. The transcription factor SMAD4 was found to negatively regulate the PPAR γ coactivator 1α (PGC1α). Interpretation: CFAP45 may regulate mitochondrial metabolic activity by affecting the function of the primary cilium on the kidney epithelial cells. CFAP45 may serve as a potential biomarker for the diagnosis and treatment of DKD.

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