Establishment of reference values for the lysine acetylation marker Nɛ-acetyllysine in small volume human plasma samples by a multi-target LC–MS/MS method

Gessner, Arne; Mieth, Maren; Auge, Daniel; Chafai, Anja; Müller, Fabian; Fromm, Martin F.; Maas, Renke

doi:10.1007/s00726-019-02765-8

Cited by 7 publications

(2 citation statements)

References 45 publications

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“…As this PTM impacts protein function, an equilibrated balance between acetylation and deacetylation is required. Recently, aberrant lysine acetylation has been associated with CKD, metabolic syndrome and other diseases ( Gessner et al, 2019 ). In our data ( Figure 3E panel B), levels of N2-acetyl-lysine decrease with OE of Cpt1a and achieve an abundance near similar values to the WTCT group.…”

Section: Resultsmentioning

confidence: 99%

Impact of renal tubular Cpt1a overexpression on the kidney metabolome in the folic acid-induced fibrosis mouse model

Cuevas-Delgado

Miguel

Rupérez

et al. 2023

Front. Mol. Biosci.

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Background: Chronic kidney disease (CKD) is characterized by the progressive and irreversible deterioration of kidney function and structure with the appearance of renal fibrosis. A significant decrease in mitochondrial metabolism, specifically a reduction in fatty acid oxidation (FAO) in tubular cells, is observed in tubulointerstitial fibrosis, whereas FAO enhancement provides protection. Untargeted metabolomics offers the potential to provide a comprehensive analysis of the renal metabolome in the context of kidney injury.Methodology: Renal tissue from a carnitine palmitoyl transferase 1a (Cpt1a) overexpressing mouse model, which displays enhanced FAO in the renal tubule, subjected to folic acid nephropathy (FAN) was studied through a multiplatform untargeted metabolomics approach based on LC-MS, CE-MS and GC-MS analysis to achieve the highest coverage of the metabolome and lipidome affected by fibrosis. The expression of genes related to the biochemical routes showing significant changes was also evaluated.Results: By combining different tools for signal processing, statistical analysis and feature annotation, we were able to identify variations in 194 metabolites and lipids involved in many metabolic routes: TCA cycle, polyamines, one-carbon metabolism, amino acid metabolism, purine metabolism, FAO, glycerolipids and glycerophospholipids synthesis and degradation, glycosphingolipids interconversion, and sterol metabolism. We found several metabolites strongly altered by FAN, with no reversion induced by Cpt1a overexpression (v.g. citric acid), whereas other metabolites were influenced by CPT1A-induced FAO (v.g. glycine-betaine).Conclusion: It was implemented a successful multiplatform metabolomics approach for renal tissue analysis. Profound metabolic changes accompany CKD-associated fibrosis, some associated with tubular FAO failure. These results highlight the importance of addressing the crosstalk between metabolism and fibrosis when undertaking studies attempting to elucidate the mechanism of CKD progression.

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Section: Resultsmentioning

confidence: 99%

Impact of renal tubular Cpt1a overexpression on the kidney metabolome in the folic acid-induced fibrosis mouse model

Cuevas-Delgado

Miguel

Rupérez

et al. 2023

Front. Mol. Biosci.

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“…All samples were analyzed by a validated liquid-chromatography coupled to tandem mass-spectrometry assay adapted from a previously published method [24]. In brief, 20 µL of sample were mixed with 100 µL of acetonitrile containing deuterated internal standards of the analytes of interest.…”

Section: Analysis Of Plasma and Urine Samplesmentioning

confidence: 99%

Effects of treatment with SGLT-2 inhibitors on arginine-related cardiovascular and renal biomarkers

Gessner

Gemeinhardt

Bosch

et al. 2022

Cardiovasc Diabetol

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Background In patients with type 2 diabetes (T2D) sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve glycaemic control as well as cardiovascular and renal outcomes. Their effects on l-arginine (Arg) related risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA) and the protective biomarker L-homoarginine (hArg) linking T2D to cardiovascular and renal disease have not yet been reported. Methods Plasma and 24-h urine samples taken before and after 6 weeks of treatment were available from two prospective, randomized, double-blind, placebo-controlled, cross-over trials with empagliflozin (71 patients analyzed, NCT02471963) and dapagliflozin (59 patients analyzed, NCT02383238). In these samples, concentrations of hArg, Arg, ADMA, SDMA, and creatinine were determined by liquid-chromatography coupled to tandem mass-spectrometry. Additionally, intraindividual changes of the biomarkers in plasma were correlated with intraindividual changes of clinical parameters. Results Treatment with empagliflozin and dapagliflozin was associated with a reduction of plasma hArg by 17.5% and 13.7% (both p < 0.001), respectively, and increase in plasma SDMA concentration of 6.7% and 3.6%, respectively (p < 0.001 and p < 0.05), while plasma Arg and ADMA concentrations were not significantly altered. 24-h urinary excretion of ADMA was reduced by 15.2% after treatment with empagliflozin (p < 0.001) but not after dapagliflozin treatment, while excretion of the other markers was not significantly altered. Renal clearance of SDMA was reduced by 9.1% and 3.9% for both drugs (both p < 0.05). A reduction in ADMA clearance was observable after empagliflozin treatment only (− 15.5%, p < 0.001), but not after dapagliflozin. Renal clearance of hArg and Arg was not significantly altered. Treatment effects on l-arginine related biomarkers were not constantly correlated with effects on glycated hemoglobin, fasting plasma glucose, body mass index, and systolic blood pressure. Conclusions Treatment with SGLT-2 inhibitors has divergent effects on Arg-related biomarkers and could affect risk estimates associated with these markers. The observed effects are unlikely to explain the known cardiovascular and renal benefits of treatment with empagliflozin or dapagliflozin but still may indicate new therapeutic approaches in patients treated with SGLT-2 inhibitors. Trial registrationhttp://www.clinicaltrials.gov: NCT02471963 (registered 15th June 2015, retrospectively registered) and NCT02383238.

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Metabolomics tools for biomarker discovery: applications in chronic kidney disease

Cuevas-Delgado

Miguel

Lamas

et al. 2022

The Detection of Biomarkers

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Establishment of reference values for the lysine acetylation marker Nɛ-acetyllysine in small volume human plasma samples by a multi-target LC–MS/MS method

Cited by 7 publications

References 45 publications

Impact of renal tubular Cpt1a overexpression on the kidney metabolome in the folic acid-induced fibrosis mouse model

Impact of renal tubular Cpt1a overexpression on the kidney metabolome in the folic acid-induced fibrosis mouse model

Effects of treatment with SGLT-2 inhibitors on arginine-related cardiovascular and renal biomarkers

Metabolomics tools for biomarker discovery: applications in chronic kidney disease

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