A systematic analysis of diet-induced nephroprotection reveals overlapping changes in cysteine catabolism

Koehler, Felix C.; Fu, Chun-Yu; Späth, Martin Richard; Hoyer-Allo, Karla Johanna Ruth; Bohl, Katrin; Göbel, Heike; Lackmann, Jan-Wilm; Grundmann, Franziska; Osterholt, Thomas; Gloistein, Claas; Steiner, Joachim D.; Antebi, Adam; Benzing, Thomas; Schermer, Bernhard; Schwarz, Günter; Burst, Volker

doi:10.1016/j.trsl.2022.02.003

Cited by 6 publications

(8 citation statements)

References 59 publications

(90 reference statements)

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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: 99%

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

Späth

Hoyer-Allo

Seufert

et al. 2023

JASN

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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.

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Section: Discussionmentioning

confidence: 99%

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

Späth

Hoyer-Allo

Seufert

et al. 2023

JASN

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“…Specific metabolic changes induced by dietary strategies are linked to cellular stress-resistance. Although caloric restriction shows an intriguing potential to protect organ function from damaging stimuli in animal models, there is little data among living kidney and liver organ donors [3,4,7,13–15,16 ▪▪ ,17 ▪ ,18–20]. Interestingly, the early graft dysfunction rate in living kidney and liver recipients may be reduced in donors adhering to caloric restriction in small randomized controlled trials [15,16 ▪▪ ].…”

Section: Dietary Preconditioning Strategies In Living Solid Organ Don...mentioning

confidence: 99%

“…There are several dietary interventions that change the macro-and micronutrient content known to augment resilience [2]. The simplest dietary regimen, caloric restriction, has been studied in various organisms and protects organ function, including kidney, liver and heart in different animal models of organ damage [3][4][5][6]. Knowledge of the underlying conserved mechanisms of resilience is an important prerequisite for potential translation to human medicine [7].…”

Section: Introductionmentioning

confidence: 99%

Fueling the success of transplantation through nutrition: recent insights into nutritional interventions, their interplay with gut microbiota and cellular mechanisms

Koehler,

Späth,

Meyer

et al. 2024

Current Opinion in Organ Transplantation

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Purpose of review The role of nutrition in organ health including solid organ transplantation is broadly accepted, but robust data on nutritional regimens remains scarce calling for further investigation of specific dietary approaches at the different stages of organ transplantation. This review gives an update on the latest insights into nutritional interventions highlighting the potential of specific dietary regimens prior to transplantation aiming for organ protection and the interplay between dietary intake and gut microbiota. Recent findings Nutrition holds the potential to optimize patients’ health prior to and after surgery, it may enhance patients’ ability to cope with the procedure-associated stress and it may accelerate their recovery from surgery. Nutrition helps to reduce morbidity and mortality in addition to preserve graft function. In the case of living organ donation, dietary preconditioning strategies promise novel approaches to limit ischemic organ damage during transplantation and to identify the underlying molecular mechanisms of diet-induced organ protection. Functioning gut microbiota are required to limit systemic inflammation and to generate protective metabolites such as short-chain fatty acids or hydrogen sulfide. Summary Nutritional intervention is a promising therapeutic concept including the pre- and rehabilitation stage in order to improve the recipients’ outcome after solid organ transplantation.

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“…[274,275] Fasting significantly protects against acute liver and kidney injury, as well as renal fibrosis, in animal models of IR. [74,[276][277][278][279] Mechanistically, IF can increase the levels of NADH: ubiquinone oxidoreductase subunit B8, cytochrome c oxidase subunit I, and dynamin 1 like, indicating a role in preserving mitochondrial homeostasis. IF can also upregulate catalase and glutamate-cysteine ligase modifier subunit but downregulate NADPH oxidase 4 and 8-hydroxy-2 deoxyguanosine, thereby reducing IR injury-induced oxidative damage.…”

Section: Agingmentioning

confidence: 99%

Fasting: From Physiology to Pathology

Tang

Huang

et al. 2023

Advanced Science

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Overnutrition is a risk factor for various human diseases, including neurodegenerative diseases, metabolic disorders, and cancers. Therefore, targeting overnutrition represents a simple but attractive strategy for the treatment of these increasing public health threats. Fasting as a dietary intervention for combating overnutrition has been extensively studied. Fasting has been practiced for millennia, but only recently have its roles in the molecular clock, gut microbiome, and tissue homeostasis and function emerged. Fasting can slow aging in most species and protect against various human diseases, including neurodegenerative diseases, metabolic disorders, and cancers. These centuried and unfading adventures and explorations suggest that fasting has the potential to delay aging and help prevent and treat diseases while minimizing side effects caused by chronic dietary interventions. In this review, recent animal and human studies concerning the role and underlying mechanism of fasting in physiology and pathology are summarized, the therapeutic potential of fasting is highlighted, and the combination of pharmacological intervention and fasting is discussed as a new treatment regimen for human diseases.

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A systematic analysis of diet-induced nephroprotection reveals overlapping changes in cysteine catabolism

Cited by 6 publications

References 59 publications

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

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

Fueling the success of transplantation through nutrition: recent insights into nutritional interventions, their interplay with gut microbiota and cellular mechanisms

Fasting: From Physiology to Pathology

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