scholarly journals Differential role of nicotinamide adenine dinucleotide deficiency in acute and chronic kidney disease

2020 ◽  
Vol 36 (1) ◽  
pp. 60-68
Author(s):  
Anna Faivre ◽  
Elena Katsyuba ◽  
Thomas Verissimo ◽  
Maja Lindenmeyer ◽  
Renuga Devi Rajaram ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Nicotinamide Adenine Dinucleotide ◽  
De Novo ◽  
Nicotinamide Adenine ◽  
Sequencing Analysis ◽  
Salvage Pathway ◽  
De Novo Synthesis ◽  
Nad Synthesis ◽  
Ckd Stage

Abstract Background Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous coenzyme involved in electron transport and a co-substrate for sirtuin function. NAD+ deficiency has been demonstrated in the context of acute kidney injury (AKI). Methods We studied the expression of key NAD+ biosynthesis enzymes in kidney biopsies from human allograft patients and patients with chronic kidney disease (CKD) at different stages. We used ischaemia–reperfusion injury (IRI) and cisplatin injection to model AKI, urinary tract obstruction [unilateral ureteral obstruction (UUO)] and tubulointerstitial fibrosis induced by proteinuria to investigate CKD in mice. We assessed the effect of nicotinamide riboside (NR) supplementation on AKI and CKD in animal models. Results RNA sequencing analysis of human kidney allograft biopsies during the reperfusion phase showed that the NAD+de novo synthesis is impaired in the immediate post-transplantation period, whereas the salvage pathway is stimulated. This decrease in de novo NAD+ synthesis was confirmed in two mouse models of IRI where NR supplementation prevented plasma urea and creatinine elevation and tubular injury. In human biopsies from CKD patients, the NAD+de novo synthesis pathway was impaired according to CKD stage, with better preservation of the salvage pathway. Similar alterations in gene expression were observed in mice with UUO or chronic proteinuric glomerular disease. NR supplementation did not prevent CKD progression, in contrast to its efficacy in AKI. Conclusion Impairment of NAD+ synthesis is a hallmark of AKI and CKD. NR supplementation is beneficial in ischaemic AKI but not in CKD models.

scholarly journals Impaired Nicotinamide Adenine Dinucleotide Biosynthesis in the Kidney of Chronic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Xinhui Liu ◽  
Denggui Luo ◽  
Shiying Huang ◽  
Siqi Liu ◽  
Bing Zhang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Nicotinamide Adenine Dinucleotide ◽  
De Novo ◽  
Periodic Acid ◽  
Public Health Problem ◽  
Nicotinamide Adenine ◽  
High Morbidity ◽  
Rat Models ◽  
Key Enzymes

Chronic kidney disease (CKD) is a global public health problem with high morbidity and mortality. Decreased nicotinamide adenine dinucleotide (NAD+) levels were found to be associated with aging, cancer, and neurodegenerative and metabolic disorders. However, the alteration of renal NAD+ levels and biosynthesis pathways in CKD is less known. In the present study, we aimed to evaluate renal NAD+ levels and tested the expression of key enzymes in three NAD+ biosynthesis pathways in two different types of CKD rat model. CKD rat models were established by 5/6 nephrectomy (5/6 Nx) and feeding with adenine-containing feed, respectively. Renal function was assessed by serum creatinine (Scr) and blood urea nitrogen (BUN). Renal pathology was evaluated by periodic acid-Schiff (PAS) and Masson’s trichrome staining. The expression of key enzymes in three NAD+ biosynthesis pathways was determined and quantified by Western blot analysis. The results showed CKD rat models were successfully established as evidenced by increased Scr and BUN levels, upregulation of neutrophil gelatinase-associated lipocalin (NGAL), glomerular hypertrophy, and renal fibrosis. Renal NAD+ and NADH content were both declined in two CKD rat models, and NAD+ levels were negatively correlated with Scr and BUN levels in CKD rats. Three key enzymes involved in NAD+ biosynthesis were significantly downregulated in the kidney of both of the two CKD models. They were quinolinate phosphoribosyltransferase (QPRT) in the de novo pathway, nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), and NMNAT3 in the salvage pathway. Moreover, the expression of NAD+-consuming enzymes sirtuin 3 (SIRT3) and CD38 decreased significantly in CKD rats. In conclusion, NAD+ biosynthesis was significantly impaired in CKD, which may attribute to downregulation of QPRT and NMNAT 1/3.

CSIG-02. NRF2-GUIDED GLUTATHIONE SYNTHESIS IS AN ESSENTIAL METABOLIC PATHWAY IN IN IDH1-MUTATED GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi33-vi33
Author(s):  
Yang Liu ◽  
Di Yu ◽  
Chunzhang Yang
Keyword(s):  
Metabolic Pathway ◽  
Nicotinamide Adenine Dinucleotide ◽  
De Novo ◽  
Redox Homeostasis ◽  
Nicotinamide Adenine ◽  
De Novo Synthesis ◽  
Who Grade ◽  
Glutathione Synthesis ◽  
Synergistic Cytotoxicity ◽  
Idh Mutations

Abstract BACKGROUND Isocitrate dehydrogenase (IDH) mutations are common genetic abnormalities in WHO Grade II/III glioma, which result in the reprogramming of cellular metabolism and redox homeostasis. Many lines of evidence showed that IDH mutations are critical for glioma formation, whereas the therapeutic options for IDH-mutated cancers remain limited. METHODS In the present study, we used the patient-derived glioma cell lines to investigate the role of nuclear factor erythroid 2-related factor 2 (NRF2) governed glutathione de novo synthesis. Further, we evaluated the therapeutic value of NRF2 inhibitors in IDH1-mutated cells and preclinical orthotopic models. RESULTS The neomorphic activity of mutant IDH reprogrammed the metabolic pathways involving enzyme cofactors such as nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The depletion of NAD(P) in IDH1-mutated cells resulted in elevated oxidative stress and constitutive activation of NRF2-governed cytoprotective pathways through the decoupling of NRF2 from its E3 ligase Kelch-like ECH-associated protein 1 (Keap1). Activation of NRF2 enhanced glutathione synthesis by enhancing the gene transcription of GCLC, GCLM, and SLC7A11, which are the critical for glutathione de novo synthesis. Further, evidence from both in vitro assays and patient cohort indicated that NRF2 governed glutathione synthesis is important for maintaining the redox homeostasis and cell survival, especially in IDH1-mutated glioma. Finally, Blockade of the NRF2/glutathione metabolic pathway exhibited synergistic cytotoxicity with the metabolic stress in IDH1-mutated cells, which results in overwhelming oxidative damage, as well as a substantial reduction in tumor cell proliferation and xenograft expansion. CONCLUSION In this study, we highlighted that NRF2 plays critical roles in the disease progression of IDH1-mutated glioma by prompting glutathione synthesis. Targeting NRF2 governed glutathione metabolism could serve as a valuable synthetic lethality approach for IDH1-mutated malignancies.

scholarly journals Adenine Nucleotide Metabolites in Uremic Erythrocytes as Metabolic Markers of Chronic Kidney Disease in Children

2021 ◽  
Vol 10 (21) ◽  
pp. 5208
Author(s):  
Joanna Piechowicz ◽  
Andrzej Gamian ◽  
Danuta Zwolińska ◽  
Dorota Polak-Jonkisz
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Nicotinic Acid ◽  
Nicotinamide Adenine Dinucleotide ◽  
Positive Impact ◽  
Adenine Nucleotide ◽  
Group Iv ◽  
Nicotinamide Adenine ◽  
Reduced Form ◽  
Group Ii

Chronic kidney disease (CKD) is associated with multifaceted pathophysiological lesions including metabolic pathways in red blood cells (RBC). The aim of the study was to determine the concentration of adenine nucleotide metabolites, i.e., nicotinamide adenine dinucleotide (NAD)-oxidized form, nicotinamide adenine dinucleotide hydrate (NADH)-reduced form, nicotinic acid mononucleotide (NAMN), β-nicotinamide mononucleotide (NMN), nicotinic acid adenine dinucleotide (NAAD), nicotinic acid (NA) and nicotinamide (NAM) in RBC and to determine a relationship between NAD metabolites and CKD progression. Forty-eight CKD children and 33 age-matched controls were examined. Patients were divided into groups depending on the CKD stages (Group II-stage II, Group III- stage III, Group IV- stage IV and Group RRT children on dialysis). To determine the above-mentioned metabolites concentrations in RBC liquid chromatography-mass spectrometry was used. Results: the only difference between the groups was shown concerning NAD in RBC, although the values did not differ significantly from controls. The lowest NAD values were found in Group II (188.6 ± 124.49 nmol/mL, the highest in group IV (324.94 ± 63.06 nmol/mL. Between Groups II and IV, as well as III and IV, the differences were statistically significant (p < 0.032, p < 0.046 respectively). Conclusions. CKD children do not have evident abnormalities of RBC metabolism with respect to adenine nucleotide metabolites. The significant differences in erythrocyte NAD concentrations between CKD stages may suggest the activation of adaptive defense mechanisms aimed at erythrocyte metabolic stabilization. It seems that the implementation of RRT has a positive impact on RBC NAD metabolism, but further research performed on a larger population is needed to confirm it.

scholarly journals Aspects of Tryptophan and Nicotinamide Adenine Dinucleotide in Immunity: A New Twist in an Old Tale

2017 ◽  
Vol 10 ◽  
pp. 117864691771349 ◽  
Author(s):  
Hector Rodriguez Cetina Biefer ◽  
Anju Vasudevan ◽  
Abdallah Elkhal
Keyword(s):  
Immune Responses ◽  
Nicotinamide Adenine Dinucleotide ◽  
Tryptophan Hydroxylase ◽  
De Novo ◽  
Kynurenine Pathway ◽  
Nicotinamide Adenine ◽  
De Novo Synthesis ◽  
Major Pathway ◽  
Adaptive Immune ◽  
Tryptophan Catabolism

Increasing evidence underscores the interesting ability of tryptophan to regulate immune responses. However, the exact mechanisms of tryptophan’s immune regulation remain to be determined. Tryptophan catabolism via the kynurenine pathway is known to play an important role in tryptophan’s involvement in immune responses. Interestingly, quinolinic acid, which is a neurotoxic catabolite of the kynurenine pathway, is the major pathway for the de novo synthesis of nicotinamide adenine dinucleotide (NAD+). Recent studies have shown that NAD+, a natural coenzyme found in all living cells, regulates immune responses and creates homeostasis via a novel signaling pathway. More importantly, the immunoregulatory properties of NAD+ are strongly related to the overexpression of tryptophan hydroxylase 1 (Tph1). This review provides recent knowledge of tryptophan and NAD+ and their specific and intriguing roles in the immune system. Furthermore, it focuses on the mechanisms by which tryptophan regulates NAD+ synthesis as well as innate and adaptive immune responses.

scholarly journals Initiation of sodium polystyrene sulphonate and the risk of gastrointestinal adverse events in advanced chronic kidney disease: a nationwide study

2019 ◽  
Vol 35 (9) ◽  
pp. 1518-1526 ◽  
Author(s):  
Paola Laureati ◽  
Yang Xu ◽  
Marco Trevisan ◽  
Lovisa Schalin ◽  
Illaria Mariani ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Adverse Events ◽  
De Novo ◽  
Patterns Of Use ◽  
Hazard Ratios ◽  
Ckd Stage ◽  
Gastrointestinal Adverse Events ◽  
Polystyrene Sulphonate

Abstract Background Despite long-standing clinical use of sodium polystyrene sulphonate (SPS) for hyperkalaemia management in chronic kidney disease (CKD), its safety profile remains poorly investigated. Methods We undertook an observational analysis of nephrology-referred adults with incident CKD Stage 4+ in Sweden during 2006–16 and with no previous SPS use. We studied patterns of use and adverse events associated to SPS initiation during follow-up. Patterns of SPS use were defined by chronicity of treatment and by prescribed dose. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) associated with SPS initiation (time-varying exposure) for the risk of severe (intestinal ischaemia, thrombosis or ulceration/perforation) and minor (de novo dispensation of laxatives or anti-diarrheal drugs) gastrointestinal (GI) events. Results Of 19 530 SPS-naïve patients with CKD, 3690 initiated SPS during follow-up. A total of 59% took SPS chronically, with an average of three dispensations/year. The majority (85%) were prescribed lower dosages than specified on the product label. During follow-up, 202 severe and 1149 minor GI events were recorded. SPS initiation was associated with a higher incidence of severe adverse events [adjusted HR 1.25 95% CI 1.05–1.49)], particularly in those receiving per label doses [1.54 (1.09–2.17)] and mainly attributed to ulcers and perforations. SPS initiation was also associated with higher incidence of minor GI events [adjusted HR 1.11 (95% CI 1.03–1.19)], regardless of dose, and mainly accounted for by de novo dispensation of laxatives. Conclusions Initiation of SPS in patients with advanced CKD is associated with a higher risk of severe GI complications as well as the initiation of GI-related medications, particularly when prescribed at per label doses.

scholarly journals DDRE-08. NRF2/GLUTATHIONE METABOLISM AS A NOVEL THERAPEUTIC TARGET FOR IDH1-MUTATED GLIOMA

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i8-i8
Author(s):  
Yang Liu ◽  
Di Yu ◽  
Orieta Celiku ◽  
Aiguo Li ◽  
Mioara Larion ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Tumor Cell ◽  
Cell Lines ◽  
Nicotinamide Adenine Dinucleotide ◽  
Cell Biology ◽  
De Novo ◽  
Nicotinamide Adenine ◽  
Glutathione Metabolism ◽  
De Novo Synthesis ◽  
Cox Regression Analysis

Abstract BACKGROUND IDH1-mutated glioma is a recently defined disease entity with distinctive patterns of tumor cell biology, metabolism, and resistance to therapy. Although IDH1 mutations are highly prevalent in patients with WHO II/III glioma, curative molecular targeting approaches remain unavailable for this disease cluster. METHODS In the present study, we investigated the glutathione de novo synthesis pathway through the TCGA patient cohort and patient-derived cell lines with IDH1 mutation. The biologic function of nuclear factor erythroid 2-related factor 2 (NRF2) was analyzed by biochemistry and cell biology assays. Finally, NRF2 inhibitors were evaluated in IDH1-mutated cell lines and preclinical models as an experimental therapy. RESULTS IDH1 mutant neomorphic activity depletes the cellular pools of enzyme cofactors such as nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The limitation of NAD(P) not only affects the anabolic reactions, but also results in oxidative stress and damages on DNA and protein. Further, we showed that the reprogrammed redox landscape results in constitutive activation of NRF2-governed cytoprotective pathways through the decoupling of NRF2 from its E3 ligase Kelch-like ECH-associated protein 1. NRF2 mediated the transcriptional activation of GCLC, GCLM, and SLC7A11, which not only strengthens the glutathione de novo synthesis, but also relieves the metabolic burden in IDH1-mutated cells. The importance of the glutathione synthesis is further confirmed through COX regression analysis on lower-grade glioma. Blockade of the NRF2/glutathione metabolic pathway synergizes with the elevated intrinsic oxidative stress, which results in overwhelming oxidative damage, as well as a substantial reduction in tumor cell proliferation and xenograft expansion. CONCLUSION We report that the NRF2-guided cytoprotective pathways play pivotal roles in the disease progression of IDH1-mutated glioma. Targeting NRF2 and glutathione metabolism could be novel targeting strategies for IDH1-mutated glioma.

scholarly journals Evaluation of functional outcome of bilateral kidney tumors after sequential surgery

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jung Kwon Kim ◽  
Hwanik Kim ◽  
Hakmin Lee ◽  
Jong Jin Oh ◽  
Sangchul Lee ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Glomerular Filtration ◽  
Functional Outcomes ◽  
Cox Regression ◽  
De Novo ◽  
Negative Impact ◽  
Renal Tumors ◽  
Cox Regression Analysis ◽  
Ckd Stage

Abstract Background There are limited data concerning patients treated with sequential bilateral kidney surgery. Current guidelines still lack an optimal surgical sequencing approach. We evaluated renal functional outcomes after sequential partial nephrectomy (PN) and radical nephrectomy (RN) in patients with bilateral renal cell carcinoma (RCC). Methods A propensity score matched cohort of 267 patients (synchronous bilateral RCCs, N = 44 [88 lesions]; metachronous bilateral, N = 45 [90 lesions]; unilateral, N = 178) from two tertiary institutions were retrospectively analyzed. Synchronous bilateral RCCs were defined as diagnosis concomitantly or within 3 months of former tumor. Renal functional outcomes were defined as estimated glomerular filtration rate (eGFR) changes and de novo chronic kidney disease (CKD, stage ≥3) after surgery. Renal functional outcomes and clinical factors predicting de novo CKD were assessed using descriptive statistics and Cox regression analysis. Results In subgroup of bilateral RCCs, patients underwent sequential PN (N = 48), PN followed by RN (N = 8), or RN followed by PN (N = 25). Final postoperative estimated glomerular filtration rates (eGFRs) were 79.4, 41.4, and 61.2 ml/minute/1.73 m2, respectively (p = 0.003). There were significant differences in eGFR decline from baseline and de novo chronic kidney disease (CKD stage ≥ III) among groups, with PN followed by RN group showing the worst functional outcomes (all p <  0.05). Moreover, sequential PN subgroup in bilateral RCC showed significantly higher rate of de novo CKD than unilateral RCC group (13.8% vs. 6.9%, p = 0.016). On multivariate analysis, hypertension (p = 0.010) and surgery sequence (PN followed by RN, p <  0.001) were significant predictors of de novo CKD. Conclusions The surgery sequence should be prudently determined in bilateral renal tumors. PN followed by RN showed a negative impact on renal functional preservation. Nephron-sparing surgery should be considered for all amenable bilateral RCCs.

Sign in / Sign up

Export Citation Format

Share Document