Predicting the Effective Dose of 5-Aminolevulinic Acid to Protect Humans From Renal Ischemia-Reperfusion Injury: A Study in Micro Miniature Pigs

Fujine, Kiyotaka; Sano, Motoaki; Katsumata, Yoshinori; Sato, Kazuki; Kobayashi, Eiji

doi:10.14740/jcs429

Cited by 4 publications

(2 citation statements)

References 16 publications

(21 reference statements)

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“…Recently, 5-ALA has received much attention as a therapeutic agent [ 8 , 11 ] and feed additive [ 10 ]. Metabolomic analysis revealed that 5-ALA levels were significantly higher in the portal and abdominal veins of LAO1 KO mice.…”

Section: Methodsmentioning

confidence: 99%

L-amino acid oxidase-1 is involved in the gut-liver axis by regulating 5-aminolevulinic acid production in mice

Qasimi

FUKUZAWA

SUENAGA

et al. 2023

The Journal of Veterinary Medical Science

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L-amino acid oxidase (LAAO) is a metabolic enzyme that converts L-amino acids into ketoacids, ammonia, and hydrogen peroxide (H 2 O 2 ). The generated H 2 O 2 has previously been shown to have antibacterial and gut microbiota-modulatory properties in LAO1 knock-out (KO) mice. Since most microbial metabolites reach the liver through the portal vein, we examined gut-liver interactions in LAO1 KO mice. We found lower total cholesterol levels, higher glutamic pyruvic transaminase (GPT) levels in the serum, and higher pro-inflammatory cytokine mRNA expression in the liver tissue. In wild-type (WT) mice, LAO1 was expressed in gut tissues (ileum and colon). Microbiome analysis revealed that the abundance of some bacteria was altered in LAO1 KO mice. However, short-chain fatty acid (SCFAs) levels in cecal feces and gut permeability did not change. Fecal microbiota transplantation (FMT) revealed that feces from LAO1 KO mice slightly stimulated pro-inflammatory cytokine expression in the liver. During metabolomic analysis, 5-aminolevulinic acid (5-ALA) was the only metabolite found to be significantly upregulated in the portal and abdominal veins of the LAO1 KO mice. Intraperitoneal administration of 5-ALA to WT mice significantly increased IL-6 mRNA expression in the liver. These observations suggest that gut LAO1 plays a role in regulating 5-ALA production and that a high level of 5-ALA stimulates the liver to increase pro-inflammatory cytokine expression by disrupting LAO1 in mice.

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Section: Methodsmentioning

confidence: 99%

L-amino acid oxidase-1 is involved in the gut-liver axis by regulating 5-aminolevulinic acid production in mice

Qasimi

FUKUZAWA

SUENAGA

et al. 2023

The Journal of Veterinary Medical Science

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“…Protocol of a conventional model where 60 min ischemia and subsequent reperfusion injury are induced in the left kidney along with contralateral nephrectomy. This conventional protocol in which 60 min ischemia is induced by clamping left renal vessels followed by a right nephrectomy was used in the previous reports (12,20).…”

Section: Figure S1mentioning

confidence: 99%

Development of a novel porcine ischemia/reperfusion model inducing different ischemia times in bilateral kidneys-effects of hydrogen gas inhalation

Kinoshita¹,

Shirakawa²,

Sano³

et al. 2022

Transl Androl Urol

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Background: Acute kidney injury and its central pathology, renal ischemia reperfusion injury (IRI), have been studied in many animal models. Although renal IRI has been induced in pig models in many ways, simultaneous bilateral ischemia or unilateral ischemia along with contralateral nephrectomy models only provide data on the renal response to a single ischemia time. Moreover, it has been reported that prolonged renal ischemia time in pigs for 120 min or more can cause irreversible renal damage and increase animal mortality. Methods:We developed a model that induces prolonged ischemia time and subsequent reperfusion injury without threatening the lives of pigs by subjecting the left and right kidneys to ischemia for 120 and 60 min, respectively. Using this novel model, we investigated whether hydrogen gas inhalation could alleviate renal IRI.Results: All animals (n=4) survived until the end of the observation period of 3 months in this model.Evaluation of the left and right kidneys immediately before and after IRI could be performed separately by blood sampling from each renal vein and renal biopsy during surgery, although the results of peripheral blood sampling during the follow-up were the mixed results of bilateral kidneys. The release of degraded DNA from the kidneys immediately after IRI and subsequent renal fibrosis at 3 months increased in response to ischemia time. Although the effect of hydrogen gas on pathological findings was not obvious, the release of degraded DNA from the kidney, an acute marker of IRI, appeared to be suppressed. Conclusions:We have developed a novel model in which IRI of different ischemia times is induced in the bilateral kidney that provides two-fold information and allows for safe long-term observation experiments in pigs. Using this model, hydrogen gas inhalation appeared to reduce acute renal IRI, although the effect was not statistically significant.

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Predicting the Effective Dose of 5-Aminolevulinic Acid to Protect Humans From Renal Ischemia-Reperfusion Injury: A Study in Micro Miniature Pigs

Cited by 4 publications

References 16 publications

L-amino acid oxidase-1 is involved in the gut-liver axis by regulating 5-aminolevulinic acid production in mice

L-amino acid oxidase-1 is involved in the gut-liver axis by regulating 5-aminolevulinic acid production in mice

Development of a novel porcine ischemia/reperfusion model inducing different ischemia times in bilateral kidneys-effects of hydrogen gas inhalation

Testing of human equivalent dose of health food 5-aminolevulinic acid using the experimental pig

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