The metabolites of<i>de novo</i>NAD+ synthesis are a valuable predictor of acute kidney injury

Wang, Yujia; Guan, Yi; Xie, Qionghong; Gong, Weiyuan; Li, Jianhua; Chen, Mo; Chen, Shaohao; Xu, Ning; Chen, Tong; Wang, Zhengxin; Hao, Chuan‐Ming

doi:10.1093/ckj/sfac262

Cited by 6 publications

(6 citation statements)

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“…Given that KMO deficiency was reported to cause proteinuria in zebrafish and mice ( 37 ), we speculated that KMO is involved in the pathogenic mechanisms of DKD and explored the distribution of KMO in murine kidneys. In our study, KMO was predominantly expressed in proximal tubules, with the other two key enzymes of de novo NAD+ synthesis pathway, QPRT and HAAO, implying proximal tubules as active sites for de novo NAD+ synthesis to fulfill its high demand for energy consumption, consistent to present human data and our previous human study ( 24 ). KMO has also been reported in mice glomeruli, particular in podocyte ( 37 , 38 ).…”

Section: Discussionsupporting

confidence: 92%

“…KMO was predominantly expressed in the cytoplasm of the proximal tubule, as evidenced by immunofluorescence analysis with Lotus tetragonolobus lectin (LTL) ( Figure 4B ). Moreover, QPRT and 3-hydroxyanthranilic acid oxygenase (HAAO), two other pivotal enzymes with predictive value of AKI in the de novo pathway ( 21 , 22 , 24 ), were also present in the same pattern. These observations indicated that the proximal tubule may serve as the primary site for the de novo synthesis pathway of NAD+ in the mouse kidneys.…”

Section: Resultsmentioning

confidence: 94%

“…QPRT deficiency ( 21 , 22 ) or α-amino-β-carboxymuconate-ϵ-semialdehyde decarboxylase increase ( 23 ) induce AKI injury. Additionally, urinary/and plasma metabolites such as QA/3-hydroxyanthranilic acid ratio ( 24 ) and QA/TRP ( 21 , 22 ) are proposed as potential predictive biomarkers for AKI/and AKI progression to CKD. However, these studies predominantly focus on AKI, leaving the dynamics of NAD+ level alterations in CKD, particularly DKD, and the intricate mechanisms underlying its complex downregulation unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Human urinary KYN was quantified using LC-MS. The procedure and specifics of LC-MS conditions were detailed as described in reference ( 24 ).…”

Section: Methodsmentioning

confidence: 99%

“…Although salvage pathway is responsible for most NAD+ production ( 18 , 19 ), supplementation with TRP has long been recognized as a treatment for vitamin B3 deficiency, suggesting an important role for the de novo pathway in NAD+ homeostasis ( 20 ). Besides, manipulation of the de novo pathway has been shown to change NAD+ levels and resistance to acute kidney injury (AKI) ( 13 , 21 – 24 ). Loss-of-function of enzymes in the de novo pathway have been reported to result in NAD+ deficiency during embryogenesis and led to congenital renal defects ( 25 ), suggesting NAD+ de novo biosynthesis pathway as an important factor in renal health.…”

Section: Introductionmentioning

confidence: 99%

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Unraveling the nexus of NAD+ metabolism and diabetic kidney disease: insights from murine models and human data

Yang,

Gong,

Wang

et al. 2024

Front. Endocrinol.

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BackgroundNicotinamide adenine dinucleotide (NAD+) is a critical coenzyme involved in kidney disease, yet its regulation in diabetic kidney disease (DKD) remains inadequately understood.ObjectiveTherefore, we investigated the changes of NAD+ levels in DKD and the underlying mechanism.MethodsAlternations of NAD+ levels and its biosynthesis enzymes were detected in kidneys from streptozotocin-induced diabetic mouse model by real-time PCR and immunoblot. The distribution of NAD+ de novo synthetic enzymes was explored via immunohistochemical study. NAD+ de novo synthetic metabolite was measured by LC-MS. Human data from NephroSeq were analyzed to verify our findings.ResultsThe study showed that NAD+ levels were decreased in diabetic kidneys. Both mRNA and protein levels of kynurenine 3-monooxygenase (KMO) in NAD+ de novo synthesis pathway were decreased, while NAD+ synthetic enzymes in salvage pathway and NAD+ consuming enzymes remained unchanged. Further analysis of human data suggested KMO, primarily expressed in the proximal tubules shown by our immunohistochemical staining, was consistently downregulated in human diabetic kidneys.ConclusionOur study demonstrated KMO of NAD+ de novo synthesis pathway was decreased in diabetic kidney and might be responsible for NAD+ reduction in diabetic kidneys, offering valuable insights into complex regulatory mechanisms of NAD+ in DKD.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

“…Human urinary KYN was quantified using LC-MS. The procedure and specifics of LC-MS conditions were detailed as described in reference ( 24 ).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Unraveling the nexus of NAD+ metabolism and diabetic kidney disease: insights from murine models and human data

Yang,

Gong,

Wang

et al. 2024

Front. Endocrinol.

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Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects

Bozon,

Cuny,

Sheng

et al. 2024

Preprint

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Severe congenital malformations are a frequent cause of premature death and morbidity in children worldwide. Malformations can originate from numerous genetic or non-genetic factors but in most cases the underlying causes are unknown. Genetic disruption of nicotinamide adenine dinucleotide (NAD) de novo synthesis drives the formation of multiple congenital malformations, collectively termed Congenital NAD Deficiency Disorder (CNDD), highlighting the necessity of this pathway during embryogenesis. Previous work in mice shows that NAD deficiency perturbs embryonic development specifically during a critical period when organs are forming. While NAD de novo synthesis is predominantly active in the liver postnatally, the site of activity prior to and during organogenesis is unknown. Here, we used a mouse model of human CNDD and applied gene expression, enzyme activity and metabolic analyses to assess pathway functionality in the embryonic liver and extraembryonic tissues. We found that the extra-embryonic visceral yolk sac endoderm exclusively performs NAD de novo synthesis during early organogenesis before the embryonic liver takes over this function. Furthermore, under CNDD-inducing conditions, mouse visceral yolk sacs had reduced NAD levels and altered NAD-related metabolic profiles which affected embryo metabolism. Expression of requisite genes for NAD de novo synthesis is conserved in the equivalent yolk sac cell type in humans. Our findings show that visceral yolk sac-mediated NAD de novo synthesis activity is essential for mouse embryonic development and perturbation of this pathway results in CNDD. Given the functional homology between mouse and human yolk sacs, our data improve the understanding of human congenital malformation causation.

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Genes Selectively Expressed in Rat Organs

Li,

Wan,

Yun

et al. 2024

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Background: Understanding organic functions at a molecular level is important for scientists to unveil the disease mechanism and to develop diagnostic or therapeutic methods. background: Understanding organic functions at a molecular level are important for scientists to unveil the mechanism of disease and to develop diagnostic or therapeutic methods. Aim: The present study tried to find genes selectively expressed in 11 rat organs, including the adrenal gland, brain, colon, duodenum, heart, ileum, kidney, liver, lung, spleen, and stomach. objective: Understanding organic functions at a molecular level are important for scientists to unveil the mechanism of disease and to develop diagnostic or therapeutic methods. The present study tried to find genes selectively expressed in 11 rat organs, including the adrenal gland, brain, colon, duodenum, heart, ileum, kidney, liver, lung, spleen, and stomach. Method: Three normal male Sprague-Dawley (SD) rats were anesthetized, their organs mentioned above were harvested, and RNA in the fresh organs was extracted. Purified RNA was reversely transcribed and sequenced using the Solexa high-throughput sequencing technique. The abundance of a gene was measured by the expected value of fragments per kilobase of transcript sequence per million base pairs sequenced (FPKM). Genes in organs with the highest expression level were sought out and compared with their median value in organs. If a gene in the highest expressed organ was significantly different (p < 0.05) from that in the medianly expressed organ, accompanied by q value < 0.05, and accounted for more than 70% of the total abundance, the gene was assumed as the selective gene in the organ. Results & Discussion: The Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO) pathways were enriched by the highest expressed genes. Based on the criterion, 1,406 selective genes were screened out, 1,283 of which were described in the gene bank and 123 of which were waiting to be described. KEGG and GO pathways in the organs were partly confirmed by the known understandings and a good portion of the pathways needed further investigation. Conclusion: The novel selective genes and organic functional pathways are useful for scientists to unveil the mechanisms of the organs at the molecular level, and the selective genes’ products are candidate disease markers for organs.

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The metabolites ofde novoNAD+ synthesis are a valuable predictor of acute kidney injury

Cited by 6 publications

References 36 publications

Unraveling the nexus of NAD+ metabolism and diabetic kidney disease: insights from murine models and human data

Unraveling the nexus of NAD+ metabolism and diabetic kidney disease: insights from murine models and human data

Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects

Genes Selectively Expressed in Rat Organs

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