Metabolite profiling of CKD progression in the chronic renal insufficiency cohort study

JCI Insight, Год журнала: 2022, Номер 7(20)

Опубликована: Сен. 1, 2022

BACKGROUNDMetabolomic profiling in individuals with chronic kidney disease (CKD) has the potential to identify novel biomarkers and provide insight into pathogenesis.METHODSWe examined association between blood metabolites CKD progression, defined as subsequent development of end-stage renal (ESRD) or estimated glomerular filtrate rate (eGFR) halving, 1,773 participants Chronic Renal Insufficiency Cohort (CRIC) study, 962 African-American Study Kidney Disease Hypertension (AASK), 5,305 Atherosclerosis Risk Communities (ARIC) study.RESULTSIn CRIC, more than half measured were associated progression minimally adjusted Cox proportional hazards models, but number strength associations markedly attenuated by serial adjustment for covariates, particularly eGFR. Ten significantly fully models CRIC; 3 these also significant AASK ARIC, highlighting markers filtration (pseudouridine), histamine metabolism (methylimidazoleacetate), azotemia (homocitrulline). Our findings highlight N-acetylserine a marker tubular function, observed CRIC ARIC.CONCLUSIONOur demonstrate application metabolomics causal pathways progression.FUNDINGThis study was supported NIH (U01 DK106981, U01 DK106982, DK085689, R01 DK108803, DK124399).

Язык: Английский

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Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury

JCI Insight, Год журнала: 2022, Номер 7(18)

Опубликована: Авг. 23, 2022

Energy metabolism failure in proximal tubule cells (PTCs) is a hallmark of chronic kidney injury. We combined transcriptomic, metabolomic, and lipidomic approaches experimental models patient cohorts to investigate the molecular basis progression allograft injury initiated by ischemia/reperfusion (IRI). The urinary metabolome transplant recipients with who experienced severe IRI was substantially enriched long chain fatty acids (FAs). identified renal FA-related gene signature low levels carnitine palmitoyltransferase 2 (Cpt2) acyl-CoA synthetase medium family member 5 (Acsm5) high 4 (Acsl4 Acsl5) associated IRI, transition injury, established disease mouse recipients. findings were consistent presence Cpt2–Acsl4+Acsl5+Acsm5– PTCs failing recover from as single-nucleus RNA-Seq. In vitro experiments indicated that ER stress contributed CPT2 repression, which, turn, promoted lipids' accumulation, drove profibrogenic epithelial phenotypic changes, activated unfolded protein response. through inhibition lipid accumulation engaged an auto-amplification loop leading lipotoxicity self-sustained cellular stress. Thus, imprints persistent FA disturbance tubule, sustaining

Язык: Английский

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Molecular mechanism of renal lipid accumulation in diabetic kidney disease

Journal of Cellular and Molecular Medicine, Год журнала: 2024, Номер 28(11)

Опубликована: Июнь 1, 2024

Abstract Diabetic kidney disease (DKD) is a leading cause of end stage renal with unmet clinical demands for treatment. Lipids are essential cell survival; however, cells have limited capability to metabolize overloaded lipids. Dyslipidaemia common in DKD patients and ectopic lipid accumulation associated progression. Unveiling the molecular mechanism involved regulation crucial exploring potential therapeutic targets. In this review, we focused on underlying cholesterol, oxysterol fatty acid metabolism disorder context DKD. Specific regulators different compartment TREM2 macrophages, lipid‐related macrophages DKD, were discussed. The role sodium‐glucose transporter 2 inhibitors improving was summarized.

Язык: Английский

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Metabolomics in diabetic nephropathy: Unveiling novel biomarkers for diagnosis (Review)

Molecular Medicine Reports, Год журнала: 2024, Номер 30(3)

Опубликована: Июль 3, 2024

Diabetic nephropathy (DN) also known as diabetic kidney disease, is a major microvascular complication of diabetes and leading cause end‑stage renal disease (ESRD), which affects the morbidity mortality patients with diabetes. Despite advancements in care, current diagnostic methods, such determination albuminuria estimated glomerular filtration rate, are limited sensitivity specificity, often only identifying damage after considerable morphological changes. The present review discusses potential metabolomics an approach for early detection management DN. Metabolomics study metabolites, small molecules produced by cellular processes, may provide more sensitive specific tool compared traditional methods. For purposes this review, systematic search was conducted on PubMed Google Scholar recent human studies published between 2011 2023 that used diagnosis has demonstrated metabolic biomarkers to ability detect broad spectrum metabolites high specificity allow earlier better DN, potentially reducing progression ESRD. Furthermore, pathway analysis assesses pathophysiological mechanisms underlying On whole, By providing in‑depth understanding alterations associated could significantly improve detection, enable timely interventions reduce healthcare burdens condition.

Язык: Английский

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Lysophosphatidylcholine: Potential Target for the Treatment of Chronic Pain

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(15), С. 8274 - 8274

Опубликована: Июль 27, 2022

The bioactive lipid lysophosphatidylcholine (LPC), a major phospholipid component of oxidized low-density lipoprotein (Ox-LDL), originates from the cleavage phosphatidylcholine by phospholipase A2 (PLA2) and is catabolized to other substances different enzymatic pathways. LPC exerts pleiotropic effects mediated its receptors, G protein-coupled signaling Toll-like ion channels activate several second messengers. Lysophosphatidylcholine (LPC) increasingly considered key marker/factor positively in pathological states, especially inflammation atherosclerosis development. Current studies have indicated that injury nervous tissues promotes oxidative stress peroxidation, as well excessive accumulation LPC, enhancing membrane hyperexcitability induce chronic pain, which may be recognized one hallmarks pain. However, findings lipidomic been lacking context In this review, we focus some detail on sources, biochemical pathways, signal-transduction system. Moreover, outline detection methods for accurate analysis each individual species reveal pathophysiological implication makes it an interesting target biomarkers development medicine regarding

Язык: Английский

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Potential progression biomarkers of diabetic kidney disease determined using comprehensive machine learning analysis of non-targeted metabolomics

Scientific Reports, Год журнала: 2022, Номер 12(1)

Опубликована: Сен. 29, 2022

Abstract Diabetic kidney disease is the main cause of end-stage renal worldwide. The prediction clinical course patients with diabetic remains difficult, despite identification potential biomarkers; therefore, novel biomarkers are needed to predict progression disease. We conducted non-targeted metabolomics using plasma and urine whose estimated glomerular filtration rate was between 30 60 mL/min/1.73 m 2 . analyzed how changed over time (up months) detect rapid decliners function. Conventional logistic analysis suggested that only one metabolite, urinary 1-methylpyridin-1-ium (NMP), a promising biomarker. then applied deep learning method identify physiological parameters in an explainable manner. narrowed down 3388 variables 50 two regression models, piecewise linear handcrafted regression, both which examined utility biomarker combinations. Our analysis, based on method, identified systolic blood pressure albumin-to-creatinine ratio, six metabolites, three unidentified metabolites including NMP, as biomarkers. This research suggests machine can could otherwise escape conventional statistical method.

Язык: Английский

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Advances in understanding and treating diabetic kidney disease: focus on tubulointerstitial inflammation mechanisms

Frontiers in Endocrinology, Год журнала: 2023, Номер 14

Опубликована: Окт. 4, 2023

Diabetic kidney disease (DKD) is a serious complication of diabetes that can lead to end-stage disease. Despite its significant impact, most research has concentrated on the glomerulus, with little attention paid tubulointerstitial region, which accounts for majority volume. DKD’s lesions are characterized by inflammation, fibrosis, and loss function, recent studies indicate these may occur earlier than glomerular lesions. Evidence shown inflammatory mechanisms in tubulointerstitium play critical role development progression Apart from renin-angiotensin-aldosterone blockade, Sodium-Glucose Linked Transporter-2(SGLT-2) inhibitors new types mineralocorticoid receptor antagonists have emerged as effective ways treat DKD. Moreover, researchers proposed potential targeted therapies, such inhibiting pro-inflammatory cytokines modulating T cells macrophages, among others. These therapies demonstrated promising results preclinical clinical trials, suggesting their DKD-induced effectively. Understanding immune-inflammatory underlying developing could significantly improve treatment management This review summarizes latest advances this field, highlighting importance focusing inflammation DKD outcomes.

Язык: Английский

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Lysophospholipids and their producing enzymes: Their pathological roles and potential as pathological biomarkers

Pharmacology & Therapeutics, Год журнала: 2023, Номер 246, С. 108415 - 108415

Опубликована: Апрель 13, 2023

Язык: Английский

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Dynamic modulations of urinary sphingolipid and glycerophospholipid levels in COVID-19 and correlations with COVID-19-associated kidney injuries

Journal of Biomedical Science, Год журнала: 2022, Номер 29(1)

Опубликована: Ноя. 10, 2022

Among various complications of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome 2 (SARS-CoV-2), renal complications, namely COVID-19-associated kidney injuries, are related to the mortality COVID-19.In this retrospective cross-sectional study, we measured sphingolipids and glycerophospholipids, which have been shown possess potent biological properties, using liquid chromatography-mass spectrometry in 272 urine samples collected longitudinally from 91 COVID-19 subjects 95 control without infectious diseases, elucidate pathogenesis injuries.The urinary levels C18:0, C18:1, C22:0, C24:0 ceramides, sphingosine, dihydrosphingosine, phosphatidylcholine, lysophosphatidylcholine, lysophosphatidic acid, phosphatidylglycerol decreased, while those phosphatidylserine, lysophosphatidylserine, phosphatidylethanolamine, lysophosphatidylethanolamine increased patients with mild COVID-19, especially during early phase (day 1-3), suggesting that these modulations might reflect direct effects infection SARS-CoV-2. Generally, sphingomyelin, dihydrosphingosine L-phosphate, lysophosphatidylethanolamine, phosphatidylglycerol, lysophosphatidylglycerol, phosphatidylinositol, lysophosphatidylinositol increased, later phase, their result injuries accompanying COVID-19.Considering properties an understanding will help us understand mechanisms causing as well general may prompt researchers develop laboratory tests for predicting maximum severity and/or novel reagents suppress COVID-19.

Язык: Английский

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Inhibition of ChREBP ubiquitination via the ROS/Akt-dependent downregulation of Smurf2 contributes to lysophosphatidic acid-induced fibrosis in renal mesangial cells

Journal of Biomedical Science, Год журнала: 2022, Номер 29(1)

Опубликована: Май 10, 2022

Mesangial cell fibrosis, a typical symptom of diabetic nephropathy (DN), is major contributor to glomerulosclerosis. We previously reported that the pharmacological blockade lysophosphatidic acid (LPA) signaling improves DN. Although LPA implicated in renal underlying molecular mechanisms remain unclear. Here, role carbohydrate-responsive element-binding protein (ChREBP) LPA-induced fibrosis and were investigated.Eight-week-old wild-type db/db mice intraperitoneally injected with vehicle or an LPAR1/3 antagonist, ki16425 (10 mg/kg), for 8 weeks on daily basis, following which sacrificed expression was analyzed. SV40 MES13 cells treated presence absence ki16425, ChREBP fibrotic factors, including fibronectin, TGF-β, IL-1β, examined. The response investigated by overexpression knockdown. involvement Smad ubiquitination regulatory factor-2 (Smurf2), E3 ligase, factors Smurf2 To identify molecules regulating LPA, inhibitors such as A6370 (Akt1/2 kinase inhibitor) Ly 294002 (PI3K used.The increased mice, reduced treatment ki16425. Treatment induced cells, positively correlated. decreased knockdown, respectively. production reactive oxygen species (ROS) mediated via Traf4-mediated ubiquitination. ubiquitinated-ChREBP Additionally, knockdown significantly factors. inhibition Akt suppressed alterations Smurf2.Collectively, results demonstrated ROS/Akt-dependent downregulation subsequent increase might be one induces mesangial

Язык: Английский

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