NAD+ precursor supplementation prevents mtRNA/RIG-I-dependent inflammation during kidney injury

Doke, Tomohito; Mukherjee, Sarmistha; Mukhi, Dhanunjay; Dhillon, Poonam; Abedini, Amin; Davis, James G.; Chellappa, Karthikeyani; Chen, Beishan; Baur, Joseph A.; Suszták, Katalin

doi:10.1038/s42255-023-00761-7

Cited by 31 publications

(17 citation statements)

References 41 publications

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“…These reactions can ultimately lead to an increase in nicotinamide adenine dinucleotide (NADþ), which indeed was confirmed by our metabolomic analysis. These findings are consistent with previous reports showing that NADþ is reno-protective by its involvement in reducing oxidative stress [35,36].…”

Section: Lysine Effectively Slows the Progression Of Salt-sensitive H...supporting

confidence: 94%

Lysine and salt-sensitive hypertension

Dissanayake,

Palygin,

Staruschenko

2024

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of review Salt-sensitive (SS) hypertension and its associated kidney damage have been extensively studied, yet proper therapeutic strategies are lacking. The interest in altering the metabolome to affect renal and cardiovascular disease has been emerging. Here, we discuss the effect and potential mechanism behind the protective effect of lysine, an essential amino acid, on the progression of SS hypertension. Recent findings We have recently demonstrated that administering lysine in an SS rodent model can control the progression of hypertension. Both the animal and pilot human studies showed that lysine can efficiently inhibit tubular reabsorption of albumin and protect the kidneys from further damage. In addition, we conducted multilevel omics studies that showed increased lysine conjugation and excretion, leading to the depletion of harmful metabolites and an increase in useful ones. Summary Lysine's twofold action involves both mechanically flushing protein from proximal tubules to shield the kidneys and initiating metabolic adaptations in the kidneys. This results in a net positive impact on SS hypertension. While further research is necessary to apply the current findings in clinical settings, this study offers some evidence suggesting that lysine supplementation holds promise as a therapeutic approach for hypertensive kidney disease.

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Section: Lysine Effectively Slows the Progression Of Salt-sensitive H...supporting

confidence: 94%

Lysine and salt-sensitive hypertension

Dissanayake,

Palygin,

Staruschenko

2024

Current Opinion in Nephrology &Amp; Hypertension

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“…A full list of mouse models studied in this article was provided in Supplemental Dataset 1. Specifically, the FAN (GEO accession number GSE156686 ), 3 UUO (GEO accession numbers GSE182256 and GSE210716 ), 4 IRI (GEO accession number GSE180420 ), 5 LPS (GEO accession number GSE151658 ), 15 APOL1 (GEO accession numbers GSE181671 and GSE81492 ), 6,16 Cisplatin (GEO accession number GSE207587 ), 17 and DKD (GEO accession number GSE184652 ) 12 models and their respective datasets were published in previous studies. In addition to these published datasets, for this study, we produced the Esrra, Notch1, and PGC1a mouse models and their respective datasets, which we deposited in GEO with accession number GSE220493 .…”

Section: Methodsmentioning

confidence: 99%

“…We analyzed bulk RNA-seq data from whole-kidney samples of the following disease models previously published by our laboratory (Supplemental Dataset 1, Methods): FAN, 3 UUO, 4 long and short IRI (longIRI1d, longIRI3d, longIRI14d, short-IRI1d, shortIRI3d, and shortIRI14d), 5 Cisplatin, 17 and the APOL1 transgenic (APOL1) model. 6 We performed differential gene expression analysis to understand changes in disease states.…”

Section: Cell Fraction Changes Account For Shared Bulk Gene Expressio...mentioning

confidence: 99%

Unified Mouse and Human Kidney Single-Cell Expression Atlas Reveal Commonalities and Differences in Disease States

Zhou,

Abedini,

Balzer

et al. 2023

JASN

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Significance Statement Mouse models have been widely used to understand kidney disease pathomechanisms and play an important role in drug discovery. However, these models have not been systematically analyzed and compared. The authors characterized 18 different mouse kidney disease models at both bulk and single-cell gene expression levels and compared single-cell gene expression data from diabetic kidney disease (DKD) mice and from patients with DKD. Although single cell–level gene expression changes were mostly model-specific, different disease models showed similar changes when compared at a pathway level. The authors also found that changes in fractions of cell types are major drivers of bulk gene expression differences. Although the authors found only a small overlap of single cell-level gene expression changes between the mouse DKD model and patients, they observed consistent pathway-level changes. Background Mouse models have been widely used to understand kidney disease pathomechanisms and play an important role in drug discovery. However, these models have not been systematically analyzed and compared. Methods We analyzed single-cell RNA sequencing data (36 samples) and bulk gene expression data (42 samples) from 18 commonly used mouse kidney disease models. We compared single-nucleus RNA sequencing data from a mouse diabetic kidney disease model with data from patients with diabetic kidney disease and healthy controls. Results We generated a uniformly processed mouse single-cell atlas containing information for nearly 300,000 cells, identifying all major kidney cell types and states. Our analysis revealed that changes in fractions of cell types are major drivers of differences in bulk gene expression. Although gene expression changes at the single-cell level were mostly model-specific, different disease models showed similar changes when compared at a pathway level. Tensor decomposition analysis highlighted the important changes in proximal tubule cells in disease states. Specifically, we identified important alterations in expression of metabolic and inflammation-associated pathways. The mouse diabetic kidney disease model and patients with diabetic kidney disease shared only a small number of conserved cell type–specific differentially expressed genes, but we observed pathway-level activation patterns conserved between mouse and human diabetic kidney disease samples. Conclusions This study provides a comprehensive mouse kidney single-cell atlas and defines gene expression commonalities and differences in disease states in mice. The results highlight the key role of cell heterogeneity in driving changes in bulk gene expression and the limited overlap of single-cell gene expression changes between animal models and patients, but they also reveal consistent pathway-level changes.

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“…For example, it was shown that NMN intake in mice increased NAD + levels, influencing the secretory activity of senescent cells to promote cancer progression in vivo (Nacarelli et al, 2019). In contrast, several studies have described that NAD + supplementation with NR reduces neuroinflammation and other inflammatory conditions (Doke et al, 2023;Hou et al, 2021;Stock et al, 2023), suggesting that the role and mechanism of action of these precursors in inflammatory diseases and aging is complex, and it is not fully understood.…”

Section: Nad + Repl Acement (Boos Ting) Ther Apy For Ag Ing and Ag E-...mentioning

confidence: 99%

NAD metabolism: Role in senescence regulation and aging

Chini,

Cordeiro,

Tran

et al. 2023

Aging Cell

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The geroscience hypothesis proposes that addressing the biology of aging could directly prevent the onset or mitigate the severity of multiple chronic diseases. Understanding the interplay between key aspects of the biological hallmarks of aging is essential in delivering the promises of the geroscience hypothesis. Notably, the nucleotide nicotinamide adenine dinucleotide (NAD) interfaces with several biological hallmarks of aging, including cellular senescence, and changes in NAD metabolism have been shown to be involved in the aging process. The relationship between NAD metabolism and cellular senescence appears to be complex. On the one hand, the accumulation of DNA damage and mitochondrial dysfunction induced by low NAD+ can promote the development of senescence. On the other hand, the low NAD+ state that occurs during aging may inhibit SASP development as this secretory phenotype and the development of cellular senescence are both highly metabolically demanding. However, to date, the impact of NAD+ metabolism on the progression of the cellular senescence phenotype has not been fully characterized. Therefore, to explore the implications of NAD metabolism and NAD replacement therapies, it is essential to consider their interactions with other hallmarks of aging, including cellular senescence. We propose that a comprehensive understanding of the interplay between NAD boosting strategies and senolytic agents is necessary to advance the field.

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NAD+ precursor supplementation prevents mtRNA/RIG-I-dependent inflammation during kidney injury

Cited by 31 publications

References 41 publications

Lysine and salt-sensitive hypertension

Lysine and salt-sensitive hypertension

Unified Mouse and Human Kidney Single-Cell Expression Atlas Reveal Commonalities and Differences in Disease States

NAD metabolism: Role in senescence regulation and aging

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