scholarly journals Hyperphosphatemia Contributes to Inflammation and Iron Dysregulation in Models of Normal and Impaired Renal Function

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2238-2238
Author(s):  
Brian Czaya ◽  
Beatrice Richter ◽  
Christopher Yanucil ◽  
Isaac Campos ◽  
Kylie Heitman ◽  
...  
Keyword(s):  
Renal Function ◽  
Inflammatory Cytokines ◽  
Systemic Inflammation ◽  
Iron Metabolism ◽  
Impaired Renal Function ◽  
Conflicts Of Interest ◽  
Experimental Studies ◽  
Dependent Manner ◽  
Primary Mouse ◽  
Iron Dysregulation

Background Fibroblast growth factor (FGF) 23 is a phosphaturic hormone that targets the kidney to promote urinary phosphate excretion. In patients with chronic kidney disease (CKD), serum concentrations of phosphate (Pi) and FGF23 gradually increase as renal function declines and associate with various pathologies, including systemic inflammation and anemia. Our previous studies revealed FGF23 contributes to inflammation by directly targeting hepatocytes via FGF receptor 4 (FGFR4) and inducing phospholipase Cγ (PLCγ) signaling and the expression of inflammatory cytokines. Experimental studies have shown Pi can accelerate CKD-associated pathologies, but direct effects of Pi on the liver are not well described. Here we compare the effects of Pi versus FGF23 on hepatocytes and determine their respective contributions to inflammation and anemia in the context of CKD. Methods We subject mice with global deletion of FGFR4 and wild-type littermates to increasing dietary Pi load (0.7%, 2.0%, or 3.0%) or an adenine-rich diet (used as a CKD model) in order to examine systemic inflammation and alterations in iron metabolism in the setting of normal and impaired renal function. In addition, we study primary mouse hepatocytes treated with FGF23 and increasing Pi concentrations and examine the activation of downstream signaling events and expression levels of specific target genes. Furthermore, we determine if co-treatment with inhibitors of Pi uptake and downstream signal mediators block the observed effects. Results A 3% Pi diet as well as an adenine-rich diet promote inflammation and iron dysregulation in mice. These effects are exacerbated in FGFR4 knockout mice. In cultured hepatocytes, expression of inflammatory cytokines, hepcidin and FGF23 are induced by Pi in a dose-dependent manner. Furthermore, Pi activates NFkB signaling and the inhibition of Pi uptake and of NFkB protects from Pi-induced effects. Conclusion We postulate that in CKD, gradual elevations in serum Pi promote inflammation and anemia by targeting the liver to induce gene programs which regulate the inflammatory response and iron metabolism. Our study indicates these Pi effects may be independent of FGF23. Pharmacological approaches targeting hyperphosphatemia or hepatic Pi actions might alleviate various CKD-associated pathologies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Longitudinal Plasma Measures of Trimethylamine N‐Oxide and Risk of Atherosclerotic Cardiovascular Disease Events in Community‐Based Older Adults

2021 ◽  
Author(s):  
Yujin Lee ◽  
Ina Nemet ◽  
Zeneng Wang ◽  
Heidi T. M. Lai ◽  
Marcia C. de Oliveira Otto ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Renal Function ◽  
Impaired Renal Function ◽  
Proportional Hazards ◽  
Dietary Habits ◽  
Experimental Studies ◽  
Cox Proportional Hazards ◽  
Atherosclerotic Cardiovascular Disease ◽  
Community Based ◽  
Stable Isotope Dilution

Background Trimethylamine N‐oxide (TMAO) is a gut microbiota‐dependent metabolite of dietary choline, L‐carnitine, and phosphatidylcholine‐rich foods. On the basis of experimental studies and patients with prevalent disease, elevated plasma TMAO may increase risk of atherosclerotic cardiovascular disease (ASCVD). TMAO is also renally cleared and may interact with and causally contribute to renal dysfunction. Yet, how serial TMAO levels relate to incident and recurrent ASCVD in community‐based populations and the potential mediating or modifying role of renal function are not established. Methods and Results We investigated associations of serial measures of plasma TMAO, assessed at baseline and 7 years, with incident and recurrent ASCVD in a community‐based cohort of 4131 (incident) and 1449 (recurrent) older US adults. TMAO was measured using stable isotope dilution liquid chromatography–tandem mass spectrometry (laboratory coefficient of variation, <6%). Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, sudden cardiac death, or other atherosclerotic death) was centrally adjudicated using medical records. Risk was assessed by multivariable Cox proportional hazards regression, including time‐varying demographics, lifestyle factors, medical history, laboratory measures, and dietary habits. Potential mediating effects and interaction by estimated glomerular filtration rate (eGFR) were assessed. During prospective follow‐up, 1766 incident and 897 recurrent ASCVD events occurred. After multivariable adjustment, higher levels of TMAO were associated with a higher risk of incident ASCVD, with extreme quintile hazard ratio (HR) compared with the lowest quintile=1.21 (95% CI, 1.02–1.42; P ‐trend=0.029). This relationship appeared mediated or confounded by eGFR (eGFR‐adjusted HR, 1.07; 95% CI, 0.90–1.27), as well as modified by eGFR ( P ‐interaction <0.001). High levels of TMAO were associated with higher incidence of ASCVD in the presence of impaired renal function (eGFR <60 mL/min per 1.73 m 2 : HR, 1.56 [95% CI, 1.13–2.14]; P ‐trend=0.007), but not normal or mildly reduced renal function (eGFR ≥60 mL/min per 1.73 m 2 : HR, 1.03 [95% CI, 0.85–1.25]; P ‐trend=0.668). Among individuals with prior ASCVD, TMAO associated with higher risk of recurrent ASCVD (HR, 1.25 [95% CI, 1.01–1.56]; P ‐trend=0.009), without significant modification by eGFR. Conclusions In this large community‐based cohort of older US adults, serial measures of TMAO were associated with higher risk of incident ASCVD, with apparent modification by presence of impaired renal function and with higher risk of recurrent ASCVD.

Alda-1 Constrains TLR-Induced Cytokine Overproduction By Fanconi Anemia Macrophages By Enhancing ALDH1A1 Activity

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1000-1000
Author(s):  
Michael Garbati ◽  
Winifred Keeble ◽  
Wenjin Yang ◽  
Grover C. Bagby
Keyword(s):  
Inflammatory Cytokines ◽  
Small Molecule ◽  
Conflicts Of Interest ◽  
Fold Increase ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Monocytic Leukemia ◽  
Double Knockout ◽  
Hematopoietic Stem ◽  
Suppressive Function

Abstract Replication and survival of FA-deficient hematopoietic stem and progenitor cells (HSPC) are highly suppressed by exposure to inflammatory cytokines including TNFα, IL-1β, IFNγ, and MIP-1α. Additionally, FA macrophages exposed to specific toll-like receptor (TLR) ligands overproduce the very inflammatory cytokines that exhaust the stem cell pool. Recent evidence using double knockout mice suggests that aldehyde dehydrogenases (ALDH) may play a role in protecting FA HSPC but the mechanisms involved are unclear. We tested the hypothesis that the TLR-dependent overproduction of inflammatory cytokines in FA macrophages results from a loss of FA protein-dependent ALDH function. Control (T-shNT) or FANCC-deficient (T-shFC) THP-1 human monocytic leukemia cells were treated with Alda-1 (a small molecule ALDH agonist known to enhance the activity of both ALDH1A1 and ALDH2), before exposing them to the TLR-7/8 agonist R848 and quantifying the production of TNFα (ELISA of 24- culture supernatants). While R848 alone induced a 6-fold increase in TNFα production by the FANCC-deficient cells, Alda-1 suppressed TLR-induced TNFα production in a dose-dependent manner, by both T-shNT and T-shFC cells (Fig. 1). To identify the ALDH isoform that played a role in the suppression of TNFα production, we ectopically expressed ALDH1A1 or ALDH2 in T-shNT and T-shFC cells. Overexpression of ALDH2 had little effect on R848-induced TNFα production, but ALDH1A1 overexpression completely suppressed TNFα production by FANCC-deficient cells and suppressed (by approximately 50%) the production of TNFα by control cells (Fig. 2). Likewise, in loss-of-function studies, siRNA knockdown of ALDH1A1 (but not ALDH2) enhanced R848-induced production of TNFα (1.8-fold) in T-shNT cells but did not enhance TNFα overproduction in either FANCC-deficient (T-shFC) or FANCA-deficient (T-shFA [FANCA knockdown]) cells. Additionally, ALDH1A1 (but not ALDH2) mRNA was highly inducible in both THP-1 cells (by R848) and in Lin- Sca-1+ Kit+ murine marrow cells (by TNFα). While ALDH1A1 mRNA is expressed similarly in both T-shNT and T-shFC cells, our results indicate that in normal macrophages ALDH1A1 plays a role in the constraining TLR-induced TNF production but is significantly less functional in FANCC-deficient macrophages. In summary, (1) either pharmacological enhancement of ALDH function with Alda-1 or overexpression of ALDH1A1 is sufficient to restore the TLR-suppressive function of ALDH1A1 in FANCC-deficient macrophages, and (2) specific suppression of ALDH1A1, (but not ALDH2) induces an FA-like phenotype in control macrophages. We conclude that (1) optimal function of ALDH1A1 is FANCC- and FANCA-dependent in normal macrophages, (2) TLR-dependent overproduction of inflammatory cytokines by FA-deficient macrophages may result either from an increase in aldehyde load or the loss of a non-canonical signal-suppressive function of ALDH1A1, and (3) enhancement of ALDH activity using small molecule agonists such as Alda-1 may alleviate the FA macrophage/cytokine phenotype and thereby protect HSC from inflammation-induced exhaustion. Disclosures No relevant conflicts of interest to declare.

CCL5 Released from Platelets Increases Megakaryocyte Maturation and Proplatelet Formation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1162-1162
Author(s):  
Kellie R Machlus ◽  
Kelly Elizabeth Johnson ◽  
Rajesh Kulenthirarajan ◽  
Saleh El-Husayni ◽  
Jodi A Forward ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Inflammatory Cytokines ◽  
Conflicts Of Interest ◽  
Physiological Stress ◽  
Ccr5 Antagonist ◽  
Dependent Manner ◽  
Platelet Production ◽  
Platelet Releasate ◽  
Proplatelet Formation ◽  
Receptor Ccr5

Abstract Background: In times of physiological stress (i.e. myocardial infarction, infection, inflammation, malignancy), platelet count can transiently elevate. What initiates this reactive thrombocytosis is poorly understood. Platelets store inflammatory cytokines that are released upon activation, including abundant amounts of chemokine ligand 5 (CCL5). Aim: We hypothesize that CCL5 could self-regulate platelet production through a positive feedback mechanism targeting megakaryocytes (MKs). We aim to establish that platelet-derived CCL5 drives up-regulation of platelet production by enhancing MK maturation and proplatelet formation. Methods: Primary murine fetal liver-derived MKs were treated with CCL5, Maraviroc (CCR5 antagonist) and/or platelet releasate; their number and ploidy were quantified by flow cytometry and proplatelet formation quantified in ImageJ. CCL5 and its receptor CCR5 were characterized in MKs and platelets using western blot, flow cytometry and immunofluorescence. CCL5 concentration was quantified with ELISA. Results: Intriguingly, we found that adding the releasate from TRAP-activated platelets to MKs increased proplatelet production by 47%. Platelets store inflammatory cytokines that are released upon activation, including CCL5 (RANTES); after TRAP activation, platelets release over 25 ng/mL of CCL5. We hypothesized that CCL5 could regulate platelet production by binding to its receptor, CCR5, on MKs. Maraviroc, a specific CCR5 antagonist, diminished the effect of platelet releasate on proplatelet production by 95%, suggesting the CCL5 derived from platelets was sufficient to drive increased platelet production through MK CCR5. Interestingly, CCL5 was abundantly present in both MKs and platelets, but CCR5 expression was restricted to MKs. To confirm this effect was mediated by CCL5 in the releasate, we cultured MKs with recombinant human CCL5. Recombinant CCL5 increased MK proplatelet production by 50%, consistent with the results seen after addition of platelet releasate. In addition, the CCL5-treated MKs had significantly higher ploidy; 65% fewer MKs were 2N while 76% more were 16N. Pretreating the MK cultures with Maraviroc prior to exposure to CCL5 reversed the augmented proplatelet formation and ploidy, indicating that CCL5 increased MK ploidy and subsequent proplatelet formation in a CCR5-dependent manner. To determine the mechanism by which the CCL5/CCR5 interaction mediates its effects, we treated MKs with CCL5 and probed signaling pathways downstream of CCR5. Interestingly, preliminary data suggest that CCR5 activation induces Akt phosphorylation, a pathway previously shown to be important for MK ploidy and maturation. Conclusions: CCL5 increases MK ploidy and subsequent proplatelet formation in a CCR5-dependent manner. We propose that CCL5 may act in addition to TPO to increase platelet counts during times of physiological stress. Disclosures No relevant conflicts of interest to declare.

Assessment of possible nephrotoxicity from iohexol in patients with normal and impaired renal function

1998 ◽  
Vol 39 (4) ◽  
pp. 362-367 ◽  
Author(s):  
Stefan Lundqvist ◽  
G. Holmberg ◽  
G. Jakobsson ◽  
F. Lithner ◽  
K. Skinningsrud ◽  
...  
Keyword(s):  
Renal Function ◽  
Impaired Renal Function

scholarly journals High-dose Glycerol Monolaurate Up-Regulated Beneficial Indigenous Microbiota without Inducing Metabolic Dysfunction and Systemic Inflammation: New Insights into Its Antimicrobial Potential

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1981 ◽  
Author(s):  
Qiufen Mo ◽  
Aikun Fu ◽  
Lingli Deng ◽  
Minjie Zhao ◽  
Yang Li ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Systemic Inflammation ◽  
Body Weight Gain ◽  
High Dose ◽  
Dependent Manner ◽  
Glucose And Lipid Metabolism ◽  
Glycerol Monolaurate ◽  
Indigenous Microbiota ◽  
Anti Inflammatory ◽  
Dose Dependent

Glycerol monolaurate (GML) has potent antimicrobial and anti-inflammatory activities. The present study aimed to assess the dose-dependent antimicrobial-effects of GML on the gut microbiota, glucose and lipid metabolism and inflammatory response in C57BL/6 mice. Mice were fed on diets supplemented with GML at dose of 400, 800 and 1600 mg kg−1 for 4 months, respectively. Results showed that supplementation of GML, regardless of the dosages, induced modest body weight gain without affecting epididymal/brown fat pad, lipid profiles and glycemic markers. A high dose of GML (1600 mg kg−1) showed positive impacts on the anti-inflammatory TGF-β1 and IL-22. GML modulated the indigenous microbiota in a dose-dependent manner. It was found that 400 and 800 mg kg−1 GML improved the richness of Barnesiella, whereas a high dosage of GML (1600 mg kg−1) significantly increased the relative abundances of Clostridium XIVa, Oscillibacter and Parasutterella. The present work indicated that GML could upregulate the favorable microbial taxa without inducing systemic inflammation and dysfunction of glucose and lipid metabolism.

Impaired renal function is an independent risk factor for complications after surgery for femoral neck fracture

2021 ◽  
pp. 112070002110285
Author(s):  
Pradip Ramamurti ◽  
Safa C Fassihi ◽  
David Sacolick ◽  
Alex Gu ◽  
Chapman Wei ◽  
...  
Keyword(s):  
Renal Function ◽  
Risk Factor ◽  
Femoral Neck ◽  
Femoral Neck Fracture ◽  
Impaired Renal Function ◽  
Independent Risk Factor ◽  
Femoral Neck Fractures ◽  
Stage 4 ◽  
Ckd Stage ◽  
Neck Fracture

Background: The metabolic abnormalities that occur secondary to chronic kidney disease (CKD) increase the risk of femoral neck fractures compared to the general population. The purpose of this study is to determine whether impaired renal function is an independent risk factor for complications after surgery for femoral neck fracture. Methods: The ACS-NSQIP database was reviewed for patients who underwent total hip arthroplasty, hemiarthroplasty and open reduction internal fixation (ORIF) for femoral neck fractures between 2007 and 2018. Patients were split into cohorts based on calculated estimated glomerular filtration rate. Demographic information, comorbidities, and 30-day complications were analysed with univariate and multivariate analyses using chi-square, Fischer’s exact and analysis of variance testing. Results: The total number of patients for the study was 163,717. Patients with CKD stage 4 and 5 had an increased rate of any complication (39.1 and 36.7% respectively) compared with higher eGFRs ( p  < 0.001). Similarly, 30-day mortality was increased at 6.0% and 6.7% for both stage 4 and 5 ( p  < 0.001). By multivariate regression, those with CKD Stage 4 and 5 were at increased risk for any complication compared to patients with a normal preoperative eGFR of 90–120 ( p  < 0.001). Conclusions: This study demonstrated that patients with CKD Stage 4 and 5 are at increased risks of all complications, including death, renal, pulmonary and thromboembolic disease. Therefore, these patients should be cared for from a multidisciplinary approach with close attention to postoperative medications and fall prevention to help mitigate the risk of complications in the immediate postoperative period.

scholarly journals Iron Dysregulation and Inflammagens Related to Oral and Gut Health Are Central to the Development of Parkinson’s Disease

Biomolecules ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 30
Author(s):  
Marthinus Janse van Vuuren ◽  
Theodore Albertus Nell ◽  
Jonathan Ambrose Carr ◽  
Douglas B. Kell ◽  
Etheresia Pretorius
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Systemic Inflammation ◽  
Cell Damage ◽  
Vascular Dysfunction ◽  
Iron Chelation ◽  
Gut Health ◽  
Novel Treatments ◽  
Randomized Controlled Clinical Trials ◽  
Iron Dysregulation

Neuronal lesions in Parkinson’s disease (PD) are commonly associated with α-synuclein (α-Syn)-induced cell damage that are present both in the central and peripheral nervous systems of patients, with the enteric nervous system also being especially vulnerable. Here, we bring together evidence that the development and presence of PD depends on specific sets of interlinking factors that include neuroinflammation, systemic inflammation, α-Syn-induced cell damage, vascular dysfunction, iron dysregulation, and gut and periodontal dysbiosis. We argue that there is significant evidence that bacterial inflammagens fuel this systemic inflammation, and might be central to the development of PD. We also discuss the processes whereby bacterial inflammagens may be involved in causing nucleation of proteins, including of α-Syn. Lastly, we review evidence that iron chelation, pre-and probiotics, as well as antibiotics and faecal transplant treatment might be valuable treatments in PD. A most important consideration, however, is that these therapeutic options need to be validated and tested in randomized controlled clinical trials. However, targeting underlying mechanisms of PD, including gut dysbiosis and iron toxicity, have potentially opened up possibilities of a wide variety of novel treatments, which may relieve the characteristic motor and nonmotor deficits of PD, and may even slow the progression and/or accompanying gut-related conditions of the disease.

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