Abstract
Background: The absence of efficient inhibitors for diabetic kidney disease (DKD) progression reflects the gaps in our understanding of DKD molecular pathogenesis. Methods: A comprehensive proteomic analysis was performed on the glomeruli and kidney cortex of diabetic mice with the subsequent validation of findings in human biopsies and omics datasets, aiming to better understand the underlying molecular biology of early DKD development and progression. Results: LC–MS/MS was employed to analyze the kidney proteome of 2 DKD models: Ins2Akita (early and late DKD) and db/db mice (late DKD). The abundance of detected proteins was defined. Pathway analysis of differentially expressed proteins in the early and late DKD versus the respective controls predicted dysregulation in DKD hallmarks (peroxisomal lipid metabolism and β-oxidation), supporting the functional relevance of the findings. Comparing the observed protein changes in early and late DKD, the consistent upregulation of 21 and downregulation of 18 proteins was detected. Among these were downregulated peroxisomal and upregulated mitochondrial proteins. Tissue sections from 16 DKD patients were analyzed by IHC confirming our results. Conclusion: Our study shows an extensive differential expression of peroxisomal proteins in the early stages of DKD that persists regardless of the disease severity, providing new perspectives and potential markers of diabetic kidney dysfunction.
Highlights
Our study indicated decreased levels of alpha-methylacyl-CoA racemase (AMACR), which is involved in the bile acid biosynthesis pathway
Level in animal models or human tissue, had to a good extent been observed at the mRNA level in animal models or human supporting, as a step further, theirfurther, role at an early time in diabetic kidney disease (DKD)
Interest since most of the peroxisome studies in are focused mainlyinonDKD. This is of great interest since most of the peroxisome studies the mitochondrial oxidative and the role ofoxidative peroxisomal catalase
Summary
Diabetic patients are at high risk of developing DKD, cardiovascular disease (CVD), neuropathy and retinopathy [1]. The prevalence of DKD is increasing and is associated with a heavy societal and financial burden [4] and therapeutic inertia, creating a major problem in DKD and diabetes 4.0/). Biomedicines 2022, 10, 216 treatment [5]. The absence of efficient inhibitors for diabetic kidney disease (DKD) progression reflects the gaps in our understanding of DKD molecular pathogenesis. Methods: A comprehensive proteomic analysis was performed on the glomeruli and kidney cortex of diabetic mice with the subsequent validation of findings in human biopsies and omics datasets, aiming to better understand the underlying molecular biology of early DKD development and progression
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