NMN protects cisplatin induced AKI via NAD+/SIRT1 pathway
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE306603 | GEO | 2026/01/01
REPOSITORIES: GEO
Similar Datasets
Project description:CD4+ T cells mediate the pathogenesis of ischemic and nephrotoxic acute kidney injury (AKI), as well as acute injury to other organs. However, the underlying mechanisms of CD4+ T cell-mediated pathogenesis are largely unknown. We therefore conducted unbiased RNA-sequencing to discover novel mechanistic pathways of kidney CD4+ T cells post-ischemia compared to normal mouse kidney. Unexpectedly, lipocalin-2 (Lcn2) gene, which encodes neutrophil gelatinase-associated lipocalin (NGAL) had the highest (~60)-fold increase. The NGAL increase in CD4+ T cells during AKI was confirmed at the mRNA level with real-time PCR and at the protein level with ELISA. NGAL is a potential biomarker for the early detection of AKI and has multiple potential biological functions during organ injury. However, the role of NGAL produced by CD4+ T cells has not been investigated. We found that ischemic AKI in NGAL knockout (KO) mice had worse renal outcomes compared to wild type (WT) mice. Adoptive transfer of NGAL-deficient CD4+ T cells from NGAL KO mice into CD4 KO or WT mice led to worse renal function than transfer of WT CD4+ T cells. In vitro simulated ischemia reperfusion showed that NGAL-deficient CD4+ T cells express higher levels of IFN-γ mRNA compared to WT CD4+ T cells. In vitro differentiation of naive CD4+ T cells to Th17, Th1 and Th2 cells led to significant increase in Lcn2 expression. Human kidney CD4+ T cell NGAL also increased significantly post-ischemia. These results demonstrate an important role for CD4+ T cell NGAL as a mechanism by which CD4+ T cells mediate AKI and extend the importance of NGAL in AKI beyond diagnostics.
2019-11-25 | GSE139171 | GEO
Project description:Type 2 diabetes (T2D) has become an epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a novel intervention against diet- and age-induced T2D. 4 regular chow fed mice (RC1-4) vs 4 high-fat diet fed (HFD) (HFD1a-4a) mice were analyzed on one chip (Chip-A). 4 HFD mice (HFD1b-4b) vs 4 HFD-NMN treated mice (NMN1-4) were examined on the other chip (Chip-B).
2011-12-05 | E-GEOD-31647 | biostudies-arrayexpress
Project description:NMN is the direct precursor of the nicotinamide adenine dinucleotide (NAD+) and is considered a key component to increase NAD+ levels and mitochondrial activity in cells. In this study, based on transcriptome analysis, we showed that NMN alleviates poly(I:C)-induced inflammatory response in two types of human primary cell cultures, human pulmonary microvascular endothelial cells (HPMEC) and human coronary artery endothelial cells (HCAEC). The major inflammatory mediators including IL-6 and PARP family members are grouped into co-expressed gene modules and significantly down-regulated under NMN-dosage in poly(I:C)-induced conditions in both cell types. The Bayesian network analysis of module hub genes predicted common genes including eukaryotic translation initiation factor 1B (EIF1B) and distinct genes such as platelet-derived growth factor binding molecules in HCAEC, which potentially regulate the identified inflammation modules. These results have suggested the robust regulatory mechanism of NMN to alleviate inflammatory pathways, which may open up the possibility of a new role for NMN replenishment in chronic or acute inflammation treatment.
2023-07-09 | GSE233679 | GEO
Project description:Type 2 diabetes (T2D) has become an epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a novel intervention against diet- and age-induced T2D.
2011-12-05 | GSE31647 | GEO
Project description:NAD+ homeostasis is an important determinant of lifespan and may be a key mechanism of caloric restriction (CR) expansion of lifespan. Ketone bodies such as beta-hydroxybutyrate (BHB) that regulate NAD+ abundance and NAD+ precursors such nicotinamide mononucleotide (NMN), are known to extend life in experimental animals and ameliorate age-related conditions in humans. We tested the hypothesis that chronic BHB and NMN exposure can extend lifespan similarly to the effect of CR treatment in a model organism Daphnia, a freshwater zooplankton crustacean. We also measured fecundity, lipofuscin accumulation, and lipid investments into offspring in Daphnia fed the full diet, full diet with BHB, NMN, and combined treatments, and fed the CR diet (25% of the full diet). We show that BHB exposure, but not NMN exposure, reduces early life mortality in fully fed Daphnia to levels similar to those observed under CR without compromising fecundity. We also observed that in a combined exposure cohort, NMN nearly eliminates the beneficial effect of BHB. None of the treatments affected lipofuscin accumulation, but the NMN and the combined treatment mimicked the effect of CR on neonate size in older females. An RNAseq experiment comparing the two diets and the two exposure treatments showed showed that BHB-treated Daphnia change expression of a variety of genes, including genes with known longevity extending effects, but differential expression of few genes is consistent with the effects of CR and their functionality is not clear.
2025-12-11 | GSE292526 | GEO
Project description:Aging and age-relataed pathologies can be delayed by specifically targeting the senescence-associated secretory phenotype (SASP), a hallmark feature of senescent cells. Achieving the goal using small molecules would have a tremendous impact on the quality of lifespan and burden of age-related chronic diseases. We report the potential of two metabolic molecules, NAD+ and NMN, to control the development of the pro-inflammatory phenotype of senescent human stromal cells. This study discloses the impact of NAD+ and NMN on the expression profile of senescent cells and provides a framework for future anti-aging administration with clear rationale.
2022-12-31 | GSE156038 | GEO
Project description:Our study provides compelling support to an effective CAR-T cell anti-aging intervention using NMN, a key NAD+ intermediate. We found the clinical potential of NMN for CAR-T cell immunotherapy for human cancers, attributed to their central memory phenotype. The cells are more viable, proliferative, and long-lived in vivo. Furthermore, these CAR-T cells exerted great antitumor efficacy against tumors in human xenograft mouse models. Detailed molecular mechanisms responsible for the pleiotropic effects of NMN need to be investigated further. So RNA-seq was used to analyze the different gene expression of these CAR-T cells.
2023-04-01 | GSE200367 | GEO
Project description:Background: Cardiac surgery-associated acute kidney injury (CS-AKI) is reported in 20-30% of patients undergoing cardiac surgery and, leading to poor outcomes and increased healthcare costs. Because the pathophysiology of CS-AKI is complex and has not been fully elucidated, no effective preventive and interventional strategy has been reported. Nitrite, a nitric oxide (NO) donor under hypoxic conditions, has shown to exert organ-protective effects in various kind of preclinical models, however, its efficacy in CS-AKI remains unclear. Objectives: This study aimed to generate a rat cardiopulmonary bypass (CPB) model to induce AKI, identify key molecular pathways involved in its pathophysiology, and evaluate the renoprotective effects of nitrite. Methods: A CPB model was established using rats and AKI was confirmed through molecular and histological analysis. RNA-seq was performed to identify differentially expressed genes and enriched pathway. Nitrite (2 mg/kg) was intravenously administered prior to CPB, and its effects on kidney injury markers and inflammation-related pathways were evaluated. Results: AKI was successfully produced in our rat CPB model, as evidenced by increased KIM-1 and NGAL expression and renal histological damage. RNA-seq revealed significant activation of multiple inflammation-related pathways, including TNF and NFκB signaling pathway. Nitrite administration significantly reduced KIM-1 and NGAL expression and suppressed these pathways associated with development of AKI. Conclusion: This study underscores the role of inflammation in CS-AKI pathophysiology and demonstrates the renoprotective potential of nitrite. These findings provide a foundation for further investigations into nitrite's mechanisms and its potential clinical application in cardiac surgery.
2025-03-01 | GSE290044 | GEO
Project description:NAD+ levels decline in multiple tissues over age, causing various age-associated pathophysiologies. Nicotinamide mononucleotide (NMN) is a key NAD+ intermediate that promotes NAD+biosynthesis and counteracts age-associated physiological decline. However, how NMN transport is regulated remains unknown. Here we report a novel NMN transporter encoded by the Slc12a8 gene. Slc12a8 is highly expressed and regulated by NAD+ in the small intestine. Knocking down this gene abrogates the transport of NMN in vitro and in vivo. Slc12a8 exhibits specificity to NMN and dependency on the sodium ion. Slc12a8 deficiency significantly decreases NAD+ levels in the jejunum and ileum, due to decreases in NMN uptake traced by doubly labeled isotopic NMN. Slc12a8 expression is upregulated in the aged ileum, contributing to the maintenance of NAD in aged mice. Thus, this newly identified NMN transporter plays a critical role in counteracting NAD+ decline during aging.
2019-01-01 | GSE118365 | GEO
Project description:Upon axonal injury, Sterile alpha (SAM) and Toll/interleukin-1 receptor (TIR) motif containing 1 (SARM1) is activated by nicotinamide mononucleotide (NMN) to deplete NAD and consequently promote the process of axon degeneration (AxD). Currently, only the inactive form of SARM1 in its auto-inhibitory conformation has been resolved. The flexibility of the enzymatically active form of SARM1 has so far precluded its structural determination. To solve the problem, we generated a stabilizing nanobody, Nb-C6, that specifically recognized 30 only the NMN-activated form of SARM1. The conformation specificity was verified by immunoprecipitation and surface plasmon resonance. Fluorescently labeled Nb-C6 could immunostain only the activated SARM1 in cells stimulated with CZ-48, a permeant mimetic of NMN. Expression of Nb-C6 in live cells resulted in stabilization of the active form of the endogenous and exogenous SARM1, producing and elevating cellular levels of cyclic ADP-ribose, a calcium messenger. Cryo-EM of the NMN-activated SARM1 complexed by Nb-C6 showed an octameric structure resembling a “blooming lotus” with the ARM domains bending significantly inward and swinging out together with the TIR domains to form the “petals of the lotus”. Nb-C6 bound to the SAM domain of the activated SARM1 and stabilized its Armadillo repeat motif domain. Analyses using hydrogen-deuterium exchange mass spectrometry (HDX-MS), and cross-linking MS (XL-MS) indicate that the activated SARM1 is highly dynamic and flexible and the neighboring TIRs form dimers via the surface close to one BB loop. The Nanobody is thus a valuable tool for delineating the mechanism of activation of SARM1 in AxD and other cellular processes.
2022-11-29 | PXD033528 | Pride