Establishment of a 3D hyperuricemia model based on cultured human liver organoids
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE189228 | GEO | 2023/12/01
REPOSITORIES: GEO
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Project description:Increased plasma uric acid (hyperuricemia) has been associated with worse outcomes for chronic kidney disease (CKD). But some attempts to control uric acid (UA) in large-cohort clinical trials did not produce clinically meaningful benefits for CKD. Some studies suggest that only hyperuricemia with crystals, but not asymptomatic hyperuricemia promotes the progression of CKD. Salt-sensitivity (SS) in blood pressure is a prevalent trait that is sexually dimorphic and results in kidney damage. But the connection between hyperuricemia and SS hypertension (HTN) is still unclear. Here we tested the connection between the two using both male and female Dahl SS rats, a well-establish model of SS HTN. We hypothesized that mild asymptomatic hyperuricemia is beneficial in controlling the progression of SS HTN. A uricase inhibitor, oxonic acid (2%) (Oxo) was used to induce hyperuricemia and high-salt (HS) (4% NaCl) diet was used to induce SS HTN. After 3 weeks, in response to oxonic acid supplementation, both sexes showed a significant increase of UA in plasma compared to their respective HS-only controls (Males: 0.63 ±0.07 vs. 2.17 ±0.34; Females: 0.78 ±0.15 vs. 2.04 ±0.35 mg/dl, HS vs. HS/oxo). Interestingly, only male HS/oxo rats showed a significant increase in uricosuria (Males: 0.23 ±0.03 vs. 0.45 ±0.06; Femaels: 0.26 ±0.06 vs. 0.26 ±0.001 UA/Cre, HS vs. HS/oxo). Moreover, the mild hyperuricemia was associated with a significant attenuation of the progression and magnitude of the mean arterial pressure in male but not female rats (Males: 157 ±3 vs. 136 ±3; Females: 155 ±6 vs. 154 ±5 mmHg, HS vs. HS/oxo). Xanthine oxidase (XO) is one of the enzymes that produce UA, and its activity has been shown to affect HTN as well. Therefore, we examined the level of XO activity in the plasma after the treatment. While there was no difference in the activity based on the diet within each sex, females had significantly lower levels of XO activity compared to males in each of the diets. To further investigate the beneficial phenotype seen in male rats, we evaluate changes in the progression of renal pathology. The HS/oxo group compared to the HS group had a lower kidney weight/body weight ratio and lower protein cast accumulation, indicating lower kidney damage. Furthermore, the HS/Oxo treated males had less oxidative damage in their tubules than the HS-only males. Bulk-RNA seq done on the male kidneys revealed that attenuated HTN phenotype was associated with an increased expression in Mas1 (MAS receptor), Klk-1 (Kallikrein-1), and Pcsk6 (PCSK6 enzyme) which can all lead to the activation of different vasodilatory pathways. Our study showed that in male but not female Dahl SS rats, asymptomatic mild hyperuricemia accompanied by hyperuricosuria ameliorates the progression of SS HTN and protects kidneys from further damage. Thus, our findings challenge the notion of hyperuricemia being inherently detrimental to health and highlight that this is an oversimplified view of UA’s role in disease.
2024-07-10 | GSE269511 | GEO
Project description:Approximately 15% of US adults have circulating levels of uric acid above its solubility limit, which is causally linked to the inflammatory disease gout. In most mammals, uric acid elimination is facilitated by the enzyme uricase. However, human uricase is a pseudogene, having been inactivated early in hominid evolution. Though it has long been known that a substantial amount of uric acid is eliminated in the gut, the role of the gut microbiota in hyperuricemia has not been studied. Here we identify a gene cluster, widely distributed in the gut microbiome, that encodes a pathway for uric acid degradation. Stable isotope tracing demonstrates that gut bacteria metabolize uric acid to xanthine or short chain fatty acids such as acetate, lactate and butyrate. Ablation of the microbiota in uricase-deficient mice causes profound hyperuricemia, and anaerobe-targeted antibiotics increase the risk of gout in humans. These data reveal a role for the gut microbiota in uric acid excretion and highlight the potential for microbiome-targeted therapeutics in hyperuricemia.
2023-06-16 | GSE206419 | GEO
Project description:Hyperuricemia is an essential risk factor in chronic kidney disease (CKD), while urate-lowering therapy to prevent or delay CKD is controversial. Alternatively activated macrophages in response to local microenvironment play diverse roles in kidney diseases. Here, we aim to investigate whether and how macrophage integrin αM (ITGAM) contributes to hyperuricemia-related CKD. In vivo, we explored dynamic characteristics of renal tissue in C57BL/6J mice with hyperuricemia-related CKD. By incorporating transcriptomics and phosphoproteomics data, we analyzed gene expression profile, hub genes and potential pathways. In vitro, we validated bioinformatic findings under different conditions with interventions corresponding to core nodes. We found that hyperuricemia-related CKD was characterized by elevated serum uric acid levels, impaired renal function, activation of macrophage alternative (M2) polarization, and kidney fibrosis. Integrated bioinformatic analyses revealed Itgam as the potential core gene and was associated with focal adhesion signaling. Notably, we confirmed the upregulated expression of macrophage ITGAM, activated pathway, and macrophage M2 polarization in injured kidneys. In vitro, through silencing Itgam, inhibiting p-FAK or p-AKT1 phosphorylation, and concurrent inhibiting of p-FAK while activating p-AKT1 all contributed to the modulation of macrophage M2 polarization. Our results indicated targeting macrophage ITGAM might be a promising therapeutic approach for preventing CKD.
2024-06-26 | GSE262687 | GEO
Project description:Background Currently, it is not possible to predict whether patients with hyperuricemia (HUA) will develop gout and how this progression may be affected by urate-lowering treatment (ULT). Our study aimed to evaluate differences in plasma lipidome between patients with asymptomatic HUA detected < 40 years (HUA<40) and > 40 years, gout patients with disease onset < 40 years (Gout<40) and > 40 years, and normouricemic healthy controls (HC).
Methods Plasma samples were collected from 94 asymptomatic HUA (77% HUA<40) subjects, 196 gout patients (59% Gout<40), and 53 HC. A comprehensive targeted lipidomic analysis was performed to semi-quantify 608 lipids in plasma. Univariate and multivariate statistics and advanced visualizations were applied.
Results Both HUA and gout patients showed alterations in lipid profiles with the most significant upregulation of phosphatidylethanolamines and downregulation of lysophosphatidylcholine plasmalogens/plasmanyls. More profound changes were observed in HUA<40 and Gout<40 without ULT. Multivariate statistics differentiated HUA<40 and Gout<40 groups from HC with an overall accuracy of > 95%.
Conclusion Alterations in the lipidome of HUA and Gout patients show a significant impact on lipid metabolism. The most significant glycerophospholipid dysregulation was found in HUA<40 and Gout<40 patients, together with a correction of this imbalance with ULT.
Keywords LC-MS, Lipidomics, Glycerophospholipids, Hyperuricemia, Gout, Urate-lowering treatment
Study was published and is accessible under this DOI: https://doi.org/10.1186/s13075-023-03204-6
Please cite as follows: Kvasni?ka, A., Friedecký, D., Brumarová, R. et al. Alterations in lipidome profiles distinguish early-onset hyperuricemia, gout, and the effect of urate-lowering treatment. Arthritis Res Ther 25, 234 (2023). https://doi.org/10.1186/s13075-023-03204-6
2023-10-11 | MSV000093082 | MassIVE
Project description:Sunflower (Helianthus annuus L.) calathide is becoming more well-known as a result of its anti-hyperuricemia bioactivity. Aiming at developing anti-hyperuricemic ingredients in sunflower calathide extract (SCE), we were fortunate to discover abietic acid (AA), identified from SCE, has the capacity to inhibit xanthine oxidase activity at low concentrations (IC50 = 10.60 µM and inhibition constant was 193.5 nM) that examined by inhibitor screening experiment in vitro and computer-simulated molecular docking. To further explore the anti-hyperuricemia effects, the UA-stimulated human embryonic kidney (HEK) 293T cells were evaluated as a conceivable model in the current study. The huge amounts of high-throughput sequencing data, which mapping to reference genome, were analyzed by bioinformatics approaches: Weighted Gene Co-Expression Network Analysis (WGCNA) along with Kyoto Encyclopedia of Genes and Genomes (KEGG). Interestingly, the purine metabolism-related genes expressed in the AA treatment were nearly opposite to that of the UA group, indicating negative feedback regulations that AA perhaps contributes to maintain urate homeostasis in the high UA-exposed kidney cellular environment. Here, we consider that HEK293T cells ought to be an achievable in vitro model for UA metabolism research because the PNPase, PRPS1, PRPS2, and RPIA, which participate in UA generation, widely expressed in the untreated 293T cells as well. And AA markedly suppressed the PNPase, PRPS2, and RPIA expressed in UA-stimulated 293T cells, implying inhibitions for UA biosynthesis. As a result, AA not only inhibited xanthine oxidase activity efficiently but also regulated genes PNPase, PRPS2, and RPIA. It is promising to be developed as an inhibitor against hyperuricemia. Therefore, abietic acid, which could be isolated from plants, has the potential for anti-hyperuricemia, and the current study provided a precedent for pharmacology analysis of natural ingredients.
2022-03-11 | GSE198133 | GEO
Project description:We performed label-free liquid chromatography MS/MS spectrometry analysis of urine samples from 26 HUA patients and 25 healthy controls, attempting to establish the possible protein links between hyperuricemia and these diseases by profiling urine proteome.
2019-12-24 | PXD016900 |
Project description:Objective: Our study aimed to evaluate differences in plasma lipidome between patients with asymptomatic hyperuricemia (HUA) detected < 40 years (HUA<40) and > 40 years, gout patients with disease onset < 40 years (Gout<40) and > 40 years, and normouricemic healthy controls.
Methods: Plasma samples were collected from 94 asymptomatic HUA (77% HUA<40) subjects, 196 gout patients (59% Gout<40), and 70 normouricemic controls. A comprehensive targeted lipidomic analysis was performed to semi-quantify 608 lipids in plasma. Univariate and multivariate statistics and advanced visualizations were applied.
Results: Both HUA and gout patients showed similar changes in lipid profiles with the highest upregulation of phosphatidylethanolamines (median fold-changes and p-values were 2.9/3.4 and p=1.5x10-16/p=5.5x10-21 for HUA/Gout, respectively) and downregulation of lysophosphatidylcholine plasmalogens/plasmanyls (median fold-changes and p-values were 0.3/0.5 and p=4.8x10-21/p=2.2x10-21 for HUA/Gout, respectively). More profound changes were observed in HUA<40 and Gout<40. Moreover, a shift in the lipid profile towards controls was apparent in HUA<40 and Gout<40 during urate-lowering treatment. Multivariate statistics differentiated HUA<40 and Gout<40 groups from controls with an overall accuracy of > 94%.
Conclusion: The changes in the lipidome of HUA and Gout patients show a significant impact on lipid metabolism and a severe pathobiochemical effect, with no relationship with common determinants such as body mass index, metabolic syndrome, or pathogenic variants in major urate transporter ABCG2. The most significant glycerophospholipid dysregulation was found in HUA<40 and Gout<40 patients, together with a correction of this imbalance with urate-lowering treatment.
2023-03-30 | MSV000091596 | MassIVE
Project description:Mild hyperuricemia and salt-sensitive hypertension
| PRJNA1122323 | ENA
Project description:Background Currently, it is not possible to predict whether patients with hyperuricemia (HUA) will develop gout and how this progression may be affected by urate-lowering treatment (ULT). Our study aimed to evaluate differences in plasma lipidome between patients with asymptomatic HUA detected < 40 years (HUA<40) and > 40 years, gout patients with disease onset < 40 years (Gout<40) and > 40 years, and normouricemic healthy controls (HC).
Methods Plasma samples were collected from 94 asymptomatic HUA (77% HUA<40) subjects, 196 gout patients (59% Gout<40), and 53 HC. A comprehensive targeted lipidomic analysis was performed to semi-quantify 608 lipids in plasma. Univariate and multivariate statistics and advanced visualizations were applied.
Results Both HUA and gout patients showed alterations in lipid profiles with the most significant upregulation of phosphatidylethanolamines and downregulation of lysophosphatidylcholine plasmalogens/plasmanyls. More profound changes were observed in HUA<40 and Gout<40 without ULT. Multivariate statistics differentiated HUA<40 and Gout<40 groups from HC with an overall accuracy of > 95%.
Conclusion Alterations in the lipidome of HUA and Gout patients show a significant impact on lipid metabolism. The most significant glycerophospholipid dysregulation was found in HUA<40 and Gout<40 patients, together with a correction of this imbalance with ULT.
Keywords LC-MS, Lipidomics, Glycerophospholipids, Hyperuricemia, Gout, Urate-lowering treatment
Study was published and is accessible under this DOI: https://doi.org/10.1186/s13075-023-03204-6
Please cite as follows: Kvasni?ka, A., Friedecký, D., Brumarová, R. et al. Alterations in lipidome profiles distinguish early-onset hyperuricemia, gout, and the effect of urate-lowering treatment. Arthritis Res Ther 25, 234 (2023). https://doi.org/10.1186/s13075-023-03204-6
2023-10-11 | MSV000093082 | GNPS
Project description:Mechanisms underlying human hepatocyte growth in development and regeneration are incompletely understood. In vitro, human fetal hepatocytes (FH) can be robustly grown as organoids, while adult primary human hepatocyte (PHH) organoids remain difficult to expand, suggesting different growth requirements between fetal and adult hepatocytes. Here, we characterize hepatocyte organoid outgrowth using temporal transcriptomic and phenotypic approaches. FHs initiate reciprocal transcriptional programs involving increased proliferation and repressed lipid metabolism upon initiation of organoid growth. We exploited these insights to design maturation conditions for FH organoids, resulting in acquisition of mature hepatocyte morphological traits and increased expression of functional markers. During PHH organoid outgrowth in the same culture condition, the adult transcriptomes initially mimic the fetal transcriptomic signatures, but PHHs rapidly acquire disbalanced proliferation-lipid metabolism dynamics, resulting in steatosis and halted organoid growth. IL6 supplementation, as emerged from the fetal dataset, and simultaneous activation of the metabolic regulator FXR, prevents steatosis and promotes PHH proliferation, resulting in improved expansion of the derived organoids. Single-cell RNA sequencing analyses reveal preservation of their fetal and adult hepatocyte identities in the respective organoid cultures. Our findings uncover mitogen requirements and metabolic differences determining proliferation of hepatocytes changing from development to adulthood.
2024-04-30 | GSE264261 | GEO