Enrichment of apolipoprotein A-IV and apolipoprotein D in the HDL proteome is associated with HDL functions in diabetic kidney disease without dialysis.
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ABSTRACT:
SUBMITTER: Santana MFM
PROVIDER: S-EPMC7488728 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
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Project description:BackgroundDiabetic nephropathy (DN) is a late complication in both type 1 diabetes mellitus (T1DM) and T2DM. Already at an early stage of DN morphological changes occur at the cell surface and in the extracellular matrix where the majority of the proteins carry N-linked glycosylations. These glycosylated proteins are highly important in cell adhesion and cell-matrix processes but not much is known about how they change in DN or whether the distinct etiology of T1DM and T2DM could have an effect on their abundances.MethodWe enriched for the N-glycosylated kidney proteome in db/db mice dosed with insulin or vehicle, in streptozotocin-induced (STZ) diabetic mice and healthy control mice dosed with vehicle. Glycopeptides were analyzed with label-free shotgun mass spectrometry and differential protein abundances identified in both mouse models were compared using multivariate analyses.ResultsThe majority of the N-glycosylated proteins were similarly regulated in both mouse models. However, distinct differences between the two mouse models were for example seen for integrin-β1, a protein expressed mainly in the glomeruli which abundance was increased in the STZ diabetic mice while decreased in the db/db mice and for the sodium/glucose cotransporter-1, mainly expressed in the proximal tubules which abundance was increased in the db/db mice but decreased in the STZ diabetic mice. Insulin had an effect on the level of both glomerular and tubular proteins in the db/db mice. It decreased the abundance of G-protein coupled receptor-116 and of tyrosine-protein phosphatase non-receptor type substrate-1 away from the level in the healthy control mice.ConclusionsOur finding of differences in the N-glycosylation protein profiles in the db/db and STZ mouse models suggest that the etiology of DN could give rise to variations in the cell adhesion and cell-matrix composition in T1DM and T2DM. Thus, N-glycosylated protein differences could be a clue to dissimilarities in T1DM and T2DM at later stages of DN. Furthermore, we observed insulin specific regulation of N-glycosylated proteins both in the direction of and away from the abundances in healthy control mice.
| S-EPMC5065702 | biostudies-literature
Project description:BackgroundAll chronic kidney diseases in diabetic patients are not diabetic kidney diseases. The objective was to compare the clinical characteristics, survival and access to transplantation in diabetic patients starting dialysis and classified either as diabetic kidney disease (DKD) or non-diabetic kidney disease in diabetic patients (NDKD).MethodsWe used the nationwide French REIN registry to analyse baseline clinical characteristics at dialysis inception and outcomes defined as kidney transplantation, deaths and their causes. The probability of death or transplantation was analysed using a multivariate Cox model and the Fine and Gray competing for risk model (sdHT).ResultsWe included 65,136 patients from January 2009 to December 2015 with a median follow-up of 31 months. The cumulative incidence of kidney transplantation over eight years was 46.9% (44.8-48.9) in non-diabetic patients (ND), higher than the 19.3% (17.5-21.2) in the DKD group and 22.2% (18.4-26.7) in the NDKD group. The risk of death was significantly higher in the NDKD group than in the DKD group, even after accounting for the competing risk of transplantation (NDKD/sdHR 1.22; 95%CI 1.18-1.27; p < 0.005 vs. DKD/sdHR 1.12; 95%CI 1.08-1.16; p < 0.005 with adjustment for age, sex, major adverse cardiovascular events, cancer and chronic respiratory failure, compared to ND).ConclusionsIn diabetic patients starting dialysis, patients in the DKD group had reduced access to kidney transplantation. NDKD patients had a higher risk of mortality than DKD. The distinction between DKD and NDKD should be accounted for in the plan of care of diabetic patients starting dialysis.
| S-EPMC9258992 | biostudies-literature
Project description:Patients with chronic kidney disease (CKD) are at high risk for CVD. However, traditional lipid risk factors, including low HDL levels, cannot completely explain the increased risk. Altered HDL proteome is linked with both CVD and CKD, but the role of HDL proteins in incident CVD events in patients with CKD is unknown. In this prospective case-control study, we used targeted proteomics to quantify 31 HDL proteins in 92 subjects (46 incident new CVD and 46 one-to-one matched controls) at various stages of CKD. We tested associations of HDL proteins with incident CVD using matched logistic regression analysis. In the model fully adjusted for clinical confounders, lipid levels, C-reactive protein, and proteinuria, no significant associations were found for HDL-C, but we observed inverse associations between levels of HDL proteins paraoxonase/arylesterase 1 (PON1), paraoxonase/arylesterase 3 (PON3), and LCAT and incident CVD. Odds ratios (per 1 SD) were 0.38 (0.18-0.97, P = 0.042), 0.42 (0.20-0.92, P = 0.031), and 0.30 (0.11-0.83, P = 0.020) for PON1, PON3, and LCAT, respectively. Apolipoprotein A-IV remained associated with incident CVD in CKD patients in models adjusted for clinical confounders and lipid levels but lost significance with the addition of C-reactive protein and proteinuria to the model. In conclusion, levels of four HDL proteins, PON1, PON3, LCAT, and apolipoprotein A-IV, were found to be inversely associated with incident CVD events in CKD patients. Our observations indicate that HDLs' protein cargo, but not HDL-C levels, can serve as a marker-and perhaps mediator-for elevated CVD risk in CKD patients.
| S-EPMC8566900 | biostudies-literature
Project description:Residual kidney function contributes substantially to solute clearance in dialysis patients but cannot be assessed without urine collection. We used serum filtration markers to develop dialysis-specific equations to estimate urinary urea clearance without the need for urine collection. In our development cohort, we measured 24-hour urine clearances under close supervision in 44 patients and validated these equations in 826 patients from the Netherlands Cooperative Study on the Adequacy of Dialysis. For the development and validation cohorts, median urinary urea clearance was 2.6 and 2.4 ml/min, respectively. During the 24-hour visit in the development cohort, serum ?-trace protein concentrations remained in steady state but concentrations of all other markers increased. In the validation cohort, bias (median measured minus estimated clearance) was low for all equations. Precision was significantly better for ?-trace protein and ?2-microglobulin equations and the accuracy was significantly greater for ?-trace protein, ?2-microglobulin, and cystatin C equations, compared with the urea plus creatinine equation. Area under the receiver operator characteristic curve for detecting measured urinary urea clearance by equation-estimated urinary urea clearance (both 2 ml/min or more) were 0.821, 0.850, and 0.796 for ?-trace protein, ?2-microglobulin, and cystatin C equations, respectively; significantly greater than the 0.663 for the urea plus creatinine equation. Thus, residual renal function can be estimated in dialysis patients without urine collections.
| S-EPMC4834223 | biostudies-literature
Project description:BACKGROUND:Research on the human urine proteome may lay the foundation for the discovery of relevant disease biomarkers. Post-translational modifications (PTMs) have important effects on the functions of protein biomarkers. Identifying PTMs without enrichment adds no extra steps to conventional identification procedures for urine proteomics. The only difference is that this method requires software that can conduct unrestrictive identifications of PTMs. In this study, routine urine proteomics techniques were used to identify urine proteins. Unspecified PTMs were searched by MODa and PEAKS 6 automated software, followed by a manual search to screen out in vivo PTMs by removing all in vitro PTMs and amino acid substitutions. RESULTS:There were 75 peptides with 6 in vivo PTMs that were found by both MODa and PEAKS 6. Of these, 34 peptides in 18 proteins have novel in vivo PTMs compared with the annotation information of these proteins on the Universal Protein Resource website. These new in vivo PTMs had undergone methylation, dehydration, oxidation, hydroxylation, phosphorylation, or dihydroxylation. CONCLUSIONS:In this study, we identified PTMs of urine proteins without the need for enrichment. Our investigation may provide a useful reference for biomarker discovery in the future.
| S-EPMC3585864 | biostudies-literature
Project description:Hepatic fibrosis may ultimately result in organ failure and death, a reality compounded by the fact that most drugs for liver fibrosis appear to be effective only if given as a prophylactic or early treatment. In a dimethylnitrosamine-induced liver fibrotic model, aspartate aminotransferase/alanine aminotransferase levels could not precisely distinguish the differences between the initial stage of liver fibrosis and normal control, whereas histological examination indicated that dimethylnitrosamine treatment for two weeks has resulted in hepatic fibrogenesis. Comprehensive proteomics identified 12 proteins mainly associated with the interleukin 6-stimulated inflammatory pathway. Coordinately, cytokine profiles showed that dimethylnitrosamine administration would stimulate various signaling pathways leading to liver fibrosis. Of note, apolipoprotein A4 in serum samples obtained from patients in the early stage of liver fibrosis were significantly increased compared to the healthy controls (p<0.001) while the area under curve was 0.966. Moreover, increased apolipoprotein A4 significantly enhanced transforming growth factor beta 1-induced alpha smooth muscle actin expression. In this regard, overexpression of apolipoprotein A4 in early stage of liver fibrosis might magnify and imply the progression of hepatic fibrosis. These findings suggest that apolipoprotein A4 upregulation may correlate with hepatic fibrosis staging and that apolipoprotein A4 together with current biomarker can increase the sensitivity and specificity for the early detection of liver fibrosis in a high-throughput manner.
| S-EPMC5687660 | biostudies-literature
Project description:Chronic kidney disease is associated with an increased cardiovascular morbidity/mortality and the altered biological properties of HDL particles have been pointed out in this burden. We aimed to describe the proteome of HDL from non-diabetic hemodialysis patients and proteins which were up and down represented in HDL particles of HD patients compared to heathy controls. HDL were sampled from the plasma of 9 non-diabetic HD and 9 potential kidney-donors patients with a sequential potassium bromide stepwise density gradient ultracentrifugation. Samples were analyzed using an nano-RSLC coupled on line with a Q-Orbitrap.
2020-05-26 | PXD013301 | Pride
Project description:Introduction: High-density lipoprotein (HDL) particles are heterogeneous and their proteome is complex and distinct from HDL cholesterol. However, it is largely unknown whether HDL proteins are associated with cardiovascular protection. Areas covered: HDL isolation techniques and proteomic analyses are reviewed. A list of HDL proteins reported in 37 different studies was compiled and the effects of different isolation techniques on proteins attributed to HDL are discussed. Mass spectrometric techniques used for HDL analysis and the need for precise and robust methods for quantification of HDL proteins are discussed. Expert opinion: Proteins associated with HDL have the potential to be used as biomarkers and/or help to understand HDL functionality. To achieve this, large cohorts must be studied using precise quantification methods. Key factors in HDL proteome quantification are the isolation methodology and the mass spectrometry technique employed. Isolation methodology affects what proteins are identified in HDL and the specificity of association with HDL particles needs to be addressed. Shotgun proteomics yields imprecise quantification, but the majority of HDL studies relied on this approach. Few recent studies used targeted tandem mass spectrometry to quantify HDL proteins, and it is imperative that future studies focus on the application of these precise techniques.
| S-EPMC6802954 | biostudies-literature
Project description:Diabetes is associated with a number of metabolic and cardiovascular risk factors that contribute to a high rate of microvascular and macrovascular complications. The risk factors and mechanisms that contribute to the development of micro- and macrovascular disease in diabetes are not fully explained. In this study, we employed mass spectrometric analysis using tandem LC-MS/MS to generate a proteomic profile of protein abundance and post-translational modifications (PTM) in the aorta and kidney of diabetic rats. In addition, systems biology analyses were employed to identify key protein markers that can provide insights into molecular pathways and processes that are differentially regulated in the aorta and kidney of type 1 diabetic rats. Our results indicated that 188 (111 downregulated and 77 upregulated) proteins were significantly identified in the aorta of diabetic rats compared to normal controls. A total of 223 (109 downregulated and 114 upregulated) proteins were significantly identified in the kidney of diabetic rats compared to normal controls. When the protein profiles from the kidney and aorta of diabetic and control rats were analyzed by principal component analysis, a distinct separation of the groups was observed. In addition, diabetes resulted in a significant increase in PTM (oxidation, phosphorylation, and acetylation) of proteins in the kidney and aorta and this effect was partially reversed by insulin treatment. Ingenuity pathway analysis performed on the list of differentially expressed proteins depicted mitochondrial dysfunction, oxidative phosphorylation and acute phase response signaling to be among the altered canonical pathways by diabetes in both tissues. The findings of the present study provide a global proteomics view of markers that highlight the mechanisms and putative processes that modulate renal and vascular injury in diabetes.
| S-EPMC5679573 | biostudies-literature
Project description:Human high-density lipoproteins (HDLs) are a complex mixture of structurally related nanoparticles that perform distinct physiological functions. We previously showed that human HDL containing apolipoprotein A-I (APOA1) but not apolipoprotein A-II (APOA2), designated LpA-I, is composed primarily of two discretely sized populations. Here, we isolated these particles directly from human plasma by antibody affinity chromatography, separated them by high-resolution size-exclusion chromatography and performed a deep molecular characterization of each species. The large and small LpA-I populations were spherical with mean diameters of 109 Å and 91 Å, respectively. Unexpectedly, isotope dilution MS/MS with [15N]-APOA1 in concert with quantitation of particle concentration by calibrated ion mobility analysis demonstrated that the large particles contained fewer APOA1 molecules than the small particles; the stoichiometries were 3.0 and 3.7 molecules of APOA1 per particle, respectively. MS/MS experiments showed that the protein cargo of large LpA-I particles was more diverse. Human HDL and isolated particles containing both APOA1 and APOA2 exhibit a much wider range and variation of particle sizes than LpA-I, indicating that APOA2 is likely the major contributor to HDL size heterogeneity. We propose a ratchet model based on the trefoil structure of APOA1 whereby the helical cage maintaining particle structure has two "settings"-large and small-that accounts for these findings. This understanding of the determinants of HDL particle size and protein cargo distribution serves as a basis for determining the roles of HDL subpopulations in metabolism and disease states.
| S-EPMC8385444 | biostudies-literature