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NAD+ prevents chronic kidney disease by activating renal tubular metabolism - single nuclei RNA-sequencing

ABSTRACT: Chronic kidney disease (CKD) is associated with renal metabolic disturbances, including impaired fatty acid oxidation (FAO). Nicotinamide adenine dinucleotide (NAD+) is a small molecule that participates in hundreds of metabolism-related reactions. NAD+ levels are decreased in CKD, and NAD+ supplementation is protective. However, both the mechanism of how NAD+ supplementation protects from CKD, as well as the cell types involved, are poorly understood. Using a mouse model of Alport syndrome, we show that nicotinamide riboside (NR), an NAD+ precursor, stimulates renal peroxisome proliferator-activated receptor α signaling and restores FAO in the proximal tubules, thereby protecting from CKD in both sexes. Bulk RNA-sequencing shows that renal metabolic pathways are impaired in Alport mice and activated by NR in both sexes. These transcriptional changes are confirmed by orthogonal imaging techniques and biochemical assays. Single nuclei RNA-sequencing and spatial transcriptomics, both the first of their kind from Alport mice, show that NAD+ supplementation restores FAO in proximal tubule cells. Finally, we also report, for the first time, sex differences at the transcriptional level in this Alport model. In summary, the data herein identify a nephroprotective mechanism of NAD+ supplementation in CKD, and they demonstrate that this benefit localizes to the proximal tubule cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE261871 | GEO | 2025/03/10

REPOSITORIES: GEO

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NAD+ prevents chronic kidney disease by activating renal tubular metabolism - spatial transcriptomics

Project description:Chronic kidney disease (CKD) is associated with renal metabolic disturbances, including impaired fatty acid oxidation (FAO). Nicotinamide adenine dinucleotide (NAD+) is a small molecule that participates in hundreds of metabolism-related reactions. NAD+ levels are decreased in CKD, and NAD+ supplementation is protective. However, both the mechanism of how NAD+ supplementation protects from CKD, as well as the cell types involved, are poorly understood. Using a mouse model of Alport syndrome, we show that nicotinamide riboside (NR), an NAD+ precursor, stimulates renal peroxisome proliferator-activated receptor α signaling and restores FAO in the proximal tubules, thereby protecting from CKD in both sexes. Bulk RNA-sequencing shows that renal metabolic pathways are impaired in Alport mice and activated by NR in both sexes. These transcriptional changes are confirmed by orthogonal imaging techniques and biochemical assays. Single nuclei RNA-sequencing and spatial transcriptomics, both the first of their kind from Alport mice, show that NAD+ supplementation restores FAO in proximal tubule cells. Finally, we also report, for the first time, sex differences at the transcriptional level in this Alport model. In summary, the data herein identify a nephroprotective mechanism of NAD+ supplementation in CKD, and they demonstrate that this benefit localizes to the proximal tubule cells.

2025-03-10 | GSE261872 | GEO

NAD+ prevents chronic kidney disease by activating renal tubular metabolism - bulk RNA-sequencing

2025-03-10 | GSE261869 | GEO

Nicotinamide riboside augments the human skeletal muscle NAD+ 1 metabolome and induces transcriptomic and anti-inflammatory signatures in aged subjects: a placebo-controlled, randomized trial

Project description:NAD+is modulated by conditions of metabolic stress and has been reported to decline with aging, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome, and questioned if tissue NAD+levels are depressed with aging. We supplemented 12 aged men with NR 1g per day for 21-days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways. NR also depressed levels of circulating inflammatory cytokines. In an additional study, 31P magnetic resonance spectroscopy-based NAD+ measurement in muscle and brain showed no difference between young and aged individuals. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR, while suggesting that NAD+ decline is not associated with chronological aging per se in human muscle or brain.

2019-08-29 | GSE133261 | GEO

Prophylactic or therapeutic NAD+ repletion can prevent or rescue HFpEF, but dietary intervention and weight loss cannot

Project description:Left ventricular (LV) diastolic dysfunction is a hallmark of Heart Failure with preserved Ejection Fraction (HFpEF), an escalating global health challenge. We demonstrated selective depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD+) and the rate-limiting enzyme of the NAD+ biosynthetic salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT), in human myocardium with LV diastolic dysfunction. We showed that NAD+ can be replenished in human myocardium with diastolic impairment ex vivo, despite reduced NAMPT expression. In a murine model of HFpEF [a combination exposure to high-fat diet (HFD) and L-NG-Nitro arginine methyl ester (L-NAME)], we compared the benefits of NAD+ precursor supplementation versus dietary intervention. We tested NAD+ repletion by nicotinamide riboside (NR) supplementation using two clinically-relevant strategies: 1) Prophylactic NR repletion before HFpEF onset, and 2) Therapeutic NR repletion after the development of HFpEF. We found that dietary intervention (replacement of HFD and L-NAME with healthy diet) restored myocardial insulin-dependent glucose uptake and glycolysis but did not rescue HFpEF. In contrast, both NAD+ repletion strategies prevented or rescued HFpEF, respectively, plausibly due to restoration of myocardial iron homeostasis, recoupling of glycolysis to the TCA cycle, and upregulation of antioxidant defense.

2024-08-09 | PXD033027 | Pride

APOL1 renal-risk variants induce mitochondrial dysfunction (Affymetrix 2)

Project description:To assess differential gene expression by APOL1 renal-risk (2 risk alleles) vs. non-risk (G0G0) genotypes in primary proximal tubule cells (PTCs), global gene expression (mRNA) levels were examined on Affymetrix HTA 2.0 arrays in primary PTCs cultured from non-diseased kidney in African Americans without CKD who underwent nephrectomy for localized renal cell carcinoma. To detect differentially expressed gene profiles attributable to APOL1 renal-risk genotypes, African American primary proximal tubule cells with two APOL1 renal-risk alleles (N=5) and lacking renal-risk alleles (N=25) were included in comparisons of global gene expression.

2016-08-23 | E-GEOD-85920 | biostudies-arrayexpress

Hepatocyte-specific knockout of Nicotinamide phosphoribosyltransferase increases susceptibility for liver fibrosis in mice

Project description:Nicotinamide adenine dinucleotide (NAD+) supplementation has been suggested as a therapy against non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). We investigated whether hepatocyte-specific knockout of nicotinamide phosphoribosyltransferase (Nampt) caused increased susceptibility towards liver damage in mice fed a low-methionine, choline-free 60% high-fat (MCD) diet. Knockout mice (HNKO) accumulated less hepatic triglyceride than WT littermates after 3 weeks of MCD, but had increased scores for liver inflammation, necrosis, and fibrosis. We found that fibrosis, necrosis, and portal inflammation was also present in HNKO mice on a purified control diet (PD) but not in chow-fed HNKO mice due to a higher content of NAD+ precursors in the diet. The PD induced fibrosis within 3 days of exposure could be prevented by supplementation with the NAD+ precursor nicotinamide riboside (NR). When NR was supplied after fibrosis induction, hepatic NAD+ levels markedly increased, and portal inflammation was attenuated. The fibrosis phenotype was associated with a decreased abundance of proteins involved in oxidation and reduction processes, particularly for proteins in oxidative phosphorylation (OXPHOS). NR supplementation increased abundance of these proteins. High-resolution respirometry revealed that PD-fed HNKO mice had decreased oxygen consumption when stimulated with succinate, and a decrease in maximal uncoupled respiratory capacity. Conclusions: We show that HNKO mice have increased susceptibility towards liver fibrosis when dietary NAD+ content is restricted, and that low NAD+ levels can affect hepatic mitochondrial function. Furthermore, our data suggest NR treatment has potential for preventing liver damage and NASH progression.

2021-11-03 | GSE144443 | GEO

Voluntary running and IV nicotinamide riboside synergise to boost mouse skeletal muscle NAD+ without impacting OXPHOS capacity or insulin sensitivity

Project description:In clinical trials, oral supplementation with nicotinamide riboside (NR) fails to increase muscle mitochondrial respiratory capacity and insulin sensitivity, but also does not increase muscle NAD+ levels. This study tests the feasibility of chronically elevating skeletal muscle NAD+ in mice and investigates the putative effects on mitochondrial respiratory capacity, insulin sensitivity, and gene expression. Accordingly, to improve bioavailability to skeletal muscle, we developed an experimental model for administering NR repeatedly through a jugular vein catheter. Mice on a Western diet were treated with various combinations of NR, pterostilbene (PT), and voluntary wheel running, but metabolic effects of NR and PT treatment were modest. We conclude that chronic elevation of skeletal muscle NAD+ by intravenous injection of NR is possible but does not affect muscle respiratory capacity or insulin sensitivity in either sedentary or physically active mice. Our data have implications for NAD+ precursor supplementation regimes.

2022-02-08 | GSE194193 | GEO

Boosting NAD preferentially blunts TH17 inflammation via arginine biosynthesis and redox regulatory control in control and psoriasis subjects [NR or placebo]

Project description:To evaluate whether NAD+-boosting modulates adaptive immunity, primary CD4+ T cells from healthy control and psoriasis subjects were exposed to vehicle or nicotinamide riboside (NR) supplementation. NR blunts IFNg and IL-17 secretion with greater effects on TH17 polarization. RNA-seq analysis implicates NR blunting of sequestosome 1 (SQSTM1/p62)-coupled oxidative stress. NR administration increases SQSTM1 and reduces reactive oxygen species (ROS) levels. Furthermore NR activates NRF2, and genetic knockdown of NRF2 and of the NRF2-dependent gene, SQSTM1 diminish NR amelioratory effects. Metabolomic analysis identify that NAD+-boosting increases arginine and fumarate biosynthesis and genetic knockdown of argininosuccinate lyase ameliorates NR-effects on IL-17 production. Hence, NR via amino acid metabolites orchestrate NRF2 activation, augments CD4+ T cell antioxidant defenses and attenuates TH17 responsiveness. Oral NR supplementation in healthy volunteers similarly increase serum arginine, SQSTM1 and antioxidant enzyme gene expression and blunts TH17 immune responsiveness, supporting evaluation of NAD+-boosting in CD4+ T cell linked inflammation.

2023-07-18 | GSE237555 | GEO

Boosting NAD preferentially blunts TH17 inflammation via arginine biosynthesis and redox regulatory control in control and psoriasis subjects [healthy or psoriasis]

2023-07-18 | GSE237552 | GEO

Urolithin A and Nicotinamide Riboside differentially regulate innate immune defenses and metabolism.

Project description:During aging, general cellular processes such as autophagic clearance, DNA repair, mitochondrial health, metabolism, nicotinamide adenine dinucleotide (NAD+) levels, and immunological responses become compromised. Urolithin A (UA) and NAD+ supplementation stimulate mitophagy, reduce pathological plaque load, and inflammation while improving learning in models of Alzheimer’s disease (Hou et al 2021; Fang et al 2019). Here we have performed a During aging, general cellular processes such as autophagic clearance, DNA repair, mitochondrial health, metabolism, nicotinamide adenine dinucleotide (NAD+) levels, and immunological responses become compromised. Urolithin A (UA) and NAD+ supplementation stimulate mitophagy, reduce pathological plaque load, and inflammation while improving learning in models of Alzheimer’s disease (Hou et al 2021; Fang et al 2019). Here we have performed a pairwise analysis of UA and nicotinamide riboside (NR) to investigate how these compounds modulate inflammation. The role of microglia in driving neuroinflammation is becoming more recognized in several neurodegenerative diseases, yet the effects of these drugs on microglia cells have not been thoroughly investigated. As both UA and NR are recognized as safe dietary supplements, their function in normal cells is equally important to understand as in a disease state. Here we investigated the effects of UA and NR in the human microglia cell line, HMC3.

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