Kidney International

2022

DOI: 10.1016/j.kint.2022.04.033

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Caloric restriction reduces the pro-inflammatory eicosanoid 20-hydroxyeicosatetraenoic acid to protect from acute kidney injury

Karla Johanna Ruth Hoyer-Allo¹,

Martin Richard Späth²,

Susanne Brodesser³

et al.

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Cited by 9 publications

(8 citation statements)

References 104 publications

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“…51,74,[84][85][86][87] Consequently, one protective mediator may rescue for the other, and threshold effects may play a role in the variability observed by both this and previous studies. 51,87,88 Another aspect is that KYNU deficiency might also affect the severity of AKI by immunoregulation because Trp metabolites such as 3OH-AA have been shown to have direct effects on immune cells and cytokines. 57,89 Importantly, identification and combination of all these players will be important in future translational studies.…”

Section: Discussionmentioning

confidence: 53%

“…51,74,84–87 Consequently, one protective mediator may rescue for the other, and threshold effects may play a role in the variability observed by both this and previous studies. 51,87,88 Another aspect is that KYNU deficiency might also affect the severity of AKI by immunoregulation because Trp metabolites such as 3OH-AA have been shown to have direct effects on immune cells and cytokines. 57,89…”

Section: Discussionmentioning

confidence: 56%

“…87,90–96 We and others have previously shown that IRI is significantly less pronounced in female mice compared with male mice. 87,97–99 Besides, CR-mediated protection seems to be less potent in female mice. 87 One connecting element between sex dependency, diet, and susceptibility to IRI in rodents is the androgen-dependent renal expression of Cyp4a12a and its metabolic product, 20-HETE.…”

Section: Discussionmentioning

confidence: 87%

“…Moreover, the susceptibility to IRI and differences in the response to CR are sex-dependent in rodents. 87,90–96 We and others have previously shown that IRI is significantly less pronounced in female mice compared with male mice. 87,97–99 Besides, CR-mediated protection seems to be less potent in female mice.…”

Section: Discussionmentioning

confidence: 87%

“…87,97–99 Besides, CR-mediated protection seems to be less potent in female mice. 87 One connecting element between sex dependency, diet, and susceptibility to IRI in rodents is the androgen-dependent renal expression of Cyp4a12a and its metabolic product, 20-HETE. 100–102…”

Section: Discussionmentioning

confidence: 99%

See 4 more Smart Citations

Organ Protection by Caloric Restriction Depends on Activation of the De Novo NAD+ Synthesis Pathway

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,

²

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³

et al. 2023

Self Cite

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Significance Statement AKI is a major clinical complication leading to high mortality, but intensive research over the past decades has not led to targeted preventive or therapeutic measures. In rodent models, caloric restriction (CR) and transient hypoxia significantly prevent AKI and a recent comparative transcriptome analysis of murine kidneys identified kynureninase (KYNU) as a shared downstream target. The present work shows that KYNU strongly contributes to CR-mediated protection as a key player in the de novo nicotinamide adenine dinucleotide biosynthesis pathway. Importantly, the link between CR and NAD+ biosynthesis could be recapitulated in a human cohort. Background Clinical practice lacks strategies to treat AKI. Interestingly, preconditioning by hypoxia and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown. Methods Kynureninase (KYNU) knockout mice were generated by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and comparative transcriptome, proteome and metabolite analyses of murine kidneys pre- and post-ischemia-reperfusion injury in the context of CR or ad libitum diet were performed. In addition, acetyl-lysin enrichment and mass spectrometry were used to assess protein acetylation. Results We identified KYNU as a downstream target of CR and show that KYNU strongly contributes to the protective effect of CR. The KYNU-dependent de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway is necessary for CR-associated maintenance of NAD+ levels. This finding is associated with reduced protein acetylation in CR-treated animals, specifically affecting enzymes in energy metabolism. Importantly, the effect of CR on de novo NAD+ biosynthesis pathway metabolites can be recapitulated in humans. Conclusions CR induces the de novo NAD+ synthesis pathway in the context of IRI and is essential for its full nephroprotective potential. Differential protein acetylation may be the molecular mechanism underlying the relationship of NAD+, CR, and nephroprotection.

“…51,74,[84][85][86][87] Consequently, one protective mediator may rescue for the other, and threshold effects may play a role in the variability observed by both this and previous studies. 51,87,88 Another aspect is that KYNU deficiency might also affect the severity of AKI by immunoregulation because Trp metabolites such as 3OH-AA have been shown to have direct effects on immune cells and cytokines. 57,89 Importantly, identification and combination of all these players will be important in future translational studies.…”

Section: Discussionmentioning

confidence: 53%

“…51,74,84–87 Consequently, one protective mediator may rescue for the other, and threshold effects may play a role in the variability observed by both this and previous studies. 51,87,88 Another aspect is that KYNU deficiency might also affect the severity of AKI by immunoregulation because Trp metabolites such as 3OH-AA have been shown to have direct effects on immune cells and cytokines. 57,89…”

Section: Discussionmentioning

confidence: 56%

“…87,90–96 We and others have previously shown that IRI is significantly less pronounced in female mice compared with male mice. 87,97–99 Besides, CR-mediated protection seems to be less potent in female mice. 87 One connecting element between sex dependency, diet, and susceptibility to IRI in rodents is the androgen-dependent renal expression of Cyp4a12a and its metabolic product, 20-HETE.…”

Section: Discussionmentioning

confidence: 87%

“…Moreover, the susceptibility to IRI and differences in the response to CR are sex-dependent in rodents. 87,90–96 We and others have previously shown that IRI is significantly less pronounced in female mice compared with male mice. 87,97–99 Besides, CR-mediated protection seems to be less potent in female mice.…”

Section: Discussionmentioning

confidence: 87%

“…87,97–99 Besides, CR-mediated protection seems to be less potent in female mice. 87 One connecting element between sex dependency, diet, and susceptibility to IRI in rodents is the androgen-dependent renal expression of Cyp4a12a and its metabolic product, 20-HETE. 100–102…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Organ Protection by Caloric Restriction Depends on Activation of the De Novo NAD+ Synthesis Pathway

¹

,

²

,

³

et al. 2023

Self Cite

View full text Add to dashboard Cite

Significance Statement AKI is a major clinical complication leading to high mortality, but intensive research over the past decades has not led to targeted preventive or therapeutic measures. In rodent models, caloric restriction (CR) and transient hypoxia significantly prevent AKI and a recent comparative transcriptome analysis of murine kidneys identified kynureninase (KYNU) as a shared downstream target. The present work shows that KYNU strongly contributes to CR-mediated protection as a key player in the de novo nicotinamide adenine dinucleotide biosynthesis pathway. Importantly, the link between CR and NAD+ biosynthesis could be recapitulated in a human cohort. Background Clinical practice lacks strategies to treat AKI. Interestingly, preconditioning by hypoxia and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown. Methods Kynureninase (KYNU) knockout mice were generated by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and comparative transcriptome, proteome and metabolite analyses of murine kidneys pre- and post-ischemia-reperfusion injury in the context of CR or ad libitum diet were performed. In addition, acetyl-lysin enrichment and mass spectrometry were used to assess protein acetylation. Results We identified KYNU as a downstream target of CR and show that KYNU strongly contributes to the protective effect of CR. The KYNU-dependent de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway is necessary for CR-associated maintenance of NAD+ levels. This finding is associated with reduced protein acetylation in CR-treated animals, specifically affecting enzymes in energy metabolism. Importantly, the effect of CR on de novo NAD+ biosynthesis pathway metabolites can be recapitulated in humans. Conclusions CR induces the de novo NAD+ synthesis pathway in the context of IRI and is essential for its full nephroprotective potential. Differential protein acetylation may be the molecular mechanism underlying the relationship of NAD+, CR, and nephroprotection.

20-Hydroxyeicosatetraenoic acid (20-HETE): Bioactions, receptors, vascular function, cardiometabolic disease and beyond

Wolf²,

et al. 2023

Advances in Pharmacology

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Qing-Zhi-Tiao-Gan-Tang (QZTGT) prevents nonalcoholic steatohepatitis (NASH) by expression pattern correction

¹

,

²

,

³

et al. 2023

Journal of Ethnopharmacology

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No abstract

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