Proteomic Analysis of Mouse Kidney Tissue Associates Peroxisomal Dysfunction with Early Diabetic Kidney Disease
Abstract
:1. Introduction
2. Results
2.1. Physiopathologic Characterization of Ins2Akita and db/db Mouse Models
2.2. Glomerular Proteome Profiles from Ins2Akita Mice Revealed Prominent Changes in Mitochondrial and Peroxisomal Proteins in Early and Late DKD
2.3. Validation of Findings in Late T2D DKD Animal Model and Cross-Omics Validation, Further Confirming Peroxisomal Changes in DKD
Description | Symbol | Ratio | Transcriptomics Expression (Nephroseq; in DKD vs. Controls) (Ref.) | Single-Cell Human Kidney Transcriptomics Expression (Wilson et al. [41]) | ||
---|---|---|---|---|---|---|
db/db vs. WT Kidney Cortex 6 Months | Ins2Akita vs. WT Glomeruli 2 Months | Ins2Akita vs. WT Glomeruli 4 Months | ||||
Nucleoside diphosphate-linked moiety X | NUDT19 | 0.236 | 0.25 | 0.23 | Decrease [40] | not detected |
Peroxisomal sarcosine oxidase | PIPOX | 0.406 | 0.567 | 0.615 | Decrease [39] | not detected |
Alpha-methylacyl-CoA racemase | AMACR | 0.185 | 0.52 | 0.56 | Decrease [39] | decrease |
2.4. IHC Validation of Peroxisomal Deregulation in Human DKD Patients
3. Discussion
4. Conclusions
5. Materials and Methods
5.1. Animals
5.2. Isolation of Glomeruli
5.3. Murine Kidney Histology
5.4. Biochemical Analysis
5.5. Sample Preparation for Proteomics
5.6. LC–MS/MS Analysis
5.7. MS Data Processing
5.8. Functional Analysis
5.9. Investigation through Transcriptomics Data Analysis
5.10. Clinical Material
5.11. Immunohistochemistry of Human DKD Specimens
5.12. Evaluation of Immunohistochemistry
5.13. Statistical Analysis of Proteomics Data
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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GO Term | Term p Value Corrected with BH | Group Genes |
---|---|---|
Cholesterol biosynthesis | 0.008 | Acat2, Lbr, Nsdhl |
Regulation of ornithine decarboxylase (ODC) | 0.011 | Nqo1, Psmd11, Psmd3 |
Metabolism of polyamines | 0.014 | Nqo1, Psmd11, Psmd3 |
Peroxisomal protein import | 9.05 × 10−10 | Acox1, Agps, Crot, Dao, Ehhadh, Nudt19, Pecr, Pipox, Scp2 |
Peroxisomal lipid metabolism | 9.54 × 10−10 | Acox1, Aldh3a2, Crot, Ehhadh, Nudt19, Pecr, Scp2 |
Protein localization | 1.14 × 10−9 | Acox1, Agps, Aldh3a2, Crot, Dao, Ehhadh, Nudt19, Pecr, Pipox, Scp2 |
Fatty acid metabolism | 1.31 × 10−6 | Acox1, Aldh3a2, Crot, Cyp4b1, Ehhadh, Ggt1, Nudt19, Pecr, Scp2 |
GO Term | Term p Value Corrected with BH | Group Genes |
---|---|---|
Metabolism of amino acids and derivatives | 1.41 × 10−7 | Aass, Acad8, Aldh4a1, Amt, Cth, Dmgdh, Gcat, Gcsh, Gldc, Gls, Glud1, Gstz1, Hibadh, Mccc1, Nqo1, Prodh, Sardh |
HDL remodeling | 0.0005 | Alb, Apoa1, Apoe |
Glyoxylate metabolism and glycine degradation | 0.0008 | Aldh4a1, Amt, Gcsh, Gldc |
Branched-chain amino acid catabolism | 0.002 | Acad8, Hibadh, Mccc1 |
The citric acid (TCA) cycle, respiratory electron and ATP synthesis by chemiosmotic coupling | 0.006 | Atp5h, Gstz1, Ndufb11, Ndufb6, Ndufb7, Ndufs5 |
Protein localization | 4.83 × 10−8 | Acot4, Acox1, Agps, Atad1, Crot, Dhrs4, Ehhadh, Ldhd, Nudt19, Pecr, Pipox |
Peroxisomal protein import | 7.25 × 10−8 | Acot4, Acox1, Agps, Crot, Dhrs4, Ehhadh, Nudt19, Pecr, Pipox |
Peroxisomal lipid metabolism | 1.93 × 10−6 | Clasp2, Clip1, Dync1i2, Pafah1b1, Smc3 |
Fatty acid metabolism | 0.0007 | Acot4, Acox1, Crot, Cyp4b1, Ehhadh, Nudt19, Pecr, Ptgs1 |
Beta-oxidation of very long-chain fatty acids | 0.0007 | Acot4, Acox1, Ehhadh |
Accession | Name | pval_INS2vs.WT2 | Ratio_INS2vs.WT2 | pval_INS4vs.WT4 | Ratio_INS4vs.WT4 | Related to Diabetes | Kidney Expression and/or Function |
---|---|---|---|---|---|---|---|
D3Z7P3 | Glutaminase kidney isoform, mitochondrial OS | 0.000311 | 2.94 | 0.000311 | 2.33 | YES | YES |
Q91W43 | Glycine dehydrogenase (decarboxylating), mitochondrial | 0.000311 | 2.16 | 0.000155 | 2.88 | YES | YES |
P02535 | Keratin, type I cytoskeletal 10 | 0.00124 | 4.12 | 0.000155 | 3.62 | NO | NO |
O88986 | 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial | 0.00214 | 3.54 | 0.00295 | 2.57 | YES | YES |
Q99K67 | Alpha-aminoadipic semialdehyde synthase, | 0.00218 | 1.76 | 0.00295 | 2.57 | YES | YES |
P26645 | Myristoylated alanine-rich C-kinase substrate | 0.00314 | 2.21 | 0.00986 | 2.58 | NO | YES |
P01029 | Complement C4-B | 0.00897 | 5.57 | 0.00295 | 4.42 | NO | NO |
Q99L43 | Phosphatidate cytidylyltransferase 2 | 0.0125 | 2.12 | 0.00295 | 1.92 | NO | YES |
P27546 | Microtubule-associated protein 4 | 0.0128 | 6.06 | 0.0148 | 1.73 | NO | YES |
Q02013 | Aquaporin-1 | 0.0128 | 2.23 | 0.00187 | 2.24 | NO | YES |
Q9JKV5 | Secretory carrier-associated membrane protein 4 | 0.0173 | 2.065 | 0.033 | 2.59 | NO | YES |
P01872 | Ig mu chain C region | 0.0231 | 4.94 | 0.00147 | 14.0 | NO | NO |
Q3U9G9 | Lamin-B receptor | 0.0231 | 3.59 | 0.00817 | 2.284 | NO | NO |
O09111 | NADH dehydrogenase [ubiquinone] 1 beta | 0.0289 | 1.898 | 0.00699 | 1.94 | YES | |
Q8BGA8 | Acyl-coenzyme A synthetase ACSM5, mitochondrial | 0.0289 | 1.52 | 0.000622 | 1.95 | NO | YES |
P11276 | Fibronectin | 0.0292 | 3.05 | 0.000554 | 103 | YES | YES |
O35682 | Myeloid-associated differentiation marker | 0.0321 | 2.85 | 0.00699 | 2.25 | NO | NO |
O70251 | Elongation factor 1-beta | 0.0321 | 1.76 | 0.00135 | 2.30 | NO | YES |
Q9ESD7 | Dysferlin | 0.0321 | 2.16 | 0.00377 | 4.55 | NO | YES |
Q8CFA2 | Aminomethyltransferase, mitochondrial | 0.04 | 2.17 | 0.00295 | 2.95 | YES | YES |
Q64669 | NAD(P)H dehydrogenase [quinone] 1 | 0.043 | 6.96 | 0.01 | 1.60 | NO | YES |
Accession | Name | pval_INS2vs.WT2 | Ratio_INS2vs.WT2 | pval_INS4vs.WT4 | Ratio_INS4vs.WT4 | Related to Diabetes | Kidney Expression and/or Function |
---|---|---|---|---|---|---|---|
Q99MZ7 | Peroxisomal trans-2-enoyl-CoA reductase | 0.000311 | 0.485 | 0.00466 | 0.565 | NO | YES |
Q9DBM2 | Peroxisomal bifunctional enzyme | 0.000311 | 0.453 | 0.01 | 0.664 | NO | YES |
O09174 | Alpha-methylacyl-CoA racemase | 0.000622 | 0.52 | 0.00187 | 0.56 | YES | YES |
P11930 | Nucleoside diphosphate-linked moiety X motif | 0.000622 | 0.2499 | 0.000311 | 0.23 | NO | YES |
Q61847 | Meprin A subunit beta | 0.000622 | 0.408 | 0.00187 | 0.455 | YES | YES |
Q9DC50 | Peroxisomal carnitine O-octanoyltransferase | 0.00124 | 0.413 | 0.0122 | 0.296 | YES | YES |
Q5FW60 | Major urinary protein 20 | 0.00215 | only in wt | 0.0324 | only in wt | NO | NO |
Q64462 | Cytochrome P450 4B1 | 0.00218 | 0.387 | 0.00109 | 0.473 | NO | NO |
Q91WU0 | Carboxylesterase 1F | 0.00373 | 0.387 | 0.00466 | 0.579 | NO | YES |
Q9D826 | Peroxisomal sarcosine oxidase | 0.005905 | 0.566932 | 0.0499 | 0.615 | YES | YES |
Q9R0H0 | Peroxisomal acyl-coenzyme A oxidase 1 | 0.00591 | 0.599 | 0.00109 | 0.496 | YES | YES |
P16015 | Carbonic anhydrase 3 | 0.00721 | only in wt | 0.0071 | 0.119 | NO | NO |
Q3UBX0 | Transmembrane protein 109 | 0.014 | 0.590 | 0.0289 | 0.289 | NO | YES |
Q8C0I1 | Alkyldihydroxyacetonephosphate synthase, peroxisomal | 0.0157 | 0.297 | 0.000682 | 0.08254 | YES | YES |
P03930 | ATP synthase protein 8 | 0.0173 | 0.353 | 0.0287 | 0.0285 | NO | NO |
P28825 | Meprin A subunit alpha | 0.0205 | 0.326 | 0.000155 | 0.424 | YES | YES |
Q3UNX5 | Acyl-coenzyme A synthetase ACSM3, mitochondrial | 0.0289 | 0.431 | 0.00257 | 0.203 | NO | YES |
Q9DCC4 | Pyrroline-5-carboxylate reductase 3 | 0.0356 | 0.537 | 0.0204 | 0.287 | NO | YES |
GO Term | Group p Value Corrected with BH | Group Genes |
---|---|---|
Cellular amino acid catabolic process | 2.51 × 10−6 | Aass, Amt, Gcat, Gldc, Gls |
Alpha-amino acid catabolic process | 2.83 × 10−6 | Aass, Amt, Gcat, Gldc, Gls |
Response to mercury ion | 0.0004 | Aqp1, Cds2, Dysf, Fn1, Krt10 |
Cellular response to osmotic stress | 0.00208 | Aqp1, Cds2, Dysf |
Fatty acid catabolic process | 2.36 × 10−7 | Acox1, Ces1f, Crot, Ehhadh, Pipox, Pycrl |
Isoprenoid catabolic process | 0.0218 | Amacr |
Ether lipid biosynthetic process | 0.0275 | Agps |
Trans-2-enoyl-CoA reductase (NADPH) activity | 0.029 | Pecr |
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Tserga, A.; Pouloudi, D.; Saulnier-Blache, J.S.; Stroggilos, R.; Theochari, I.; Gakiopoulou, H.; Mischak, H.; Zoidakis, J.; Schanstra, J.P.; Vlahou, A.; et al. Proteomic Analysis of Mouse Kidney Tissue Associates Peroxisomal Dysfunction with Early Diabetic Kidney Disease. Biomedicines 2022, 10, 216. https://doi.org/10.3390/biomedicines10020216
Tserga A, Pouloudi D, Saulnier-Blache JS, Stroggilos R, Theochari I, Gakiopoulou H, Mischak H, Zoidakis J, Schanstra JP, Vlahou A, et al. Proteomic Analysis of Mouse Kidney Tissue Associates Peroxisomal Dysfunction with Early Diabetic Kidney Disease. Biomedicines. 2022; 10(2):216. https://doi.org/10.3390/biomedicines10020216
Chicago/Turabian StyleTserga, Aggeliki, Despoina Pouloudi, Jean Sébastien Saulnier-Blache, Rafael Stroggilos, Irene Theochari, Harikleia Gakiopoulou, Harald Mischak, Jerome Zoidakis, Joost Peter Schanstra, Antonia Vlahou, and et al. 2022. "Proteomic Analysis of Mouse Kidney Tissue Associates Peroxisomal Dysfunction with Early Diabetic Kidney Disease" Biomedicines 10, no. 2: 216. https://doi.org/10.3390/biomedicines10020216
APA StyleTserga, A., Pouloudi, D., Saulnier-Blache, J. S., Stroggilos, R., Theochari, I., Gakiopoulou, H., Mischak, H., Zoidakis, J., Schanstra, J. P., Vlahou, A., & Makridakis, M. (2022). Proteomic Analysis of Mouse Kidney Tissue Associates Peroxisomal Dysfunction with Early Diabetic Kidney Disease. Biomedicines, 10(2), 216. https://doi.org/10.3390/biomedicines10020216