5‐Aminolevulinic acid exerts renoprotective effect via Nrf2 activation in murine rhabdomyolysis‐induced acute kidney injury

Uchida, Atsushi; Kidokoro, Kengo; Sogawa, Yuji; Itano, Seiji; Nagasu, Hajime; Satoh, Minoru; Sasaki, Tatsuya; Kashihara, Naoki

doi:10.1111/nep.13189

Cited by 27 publications

(28 citation statements)

References 27 publications

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“…9,10 ALA reportedly exerts a broad range of cytoprotective effects against cisplatin-induced nephrotoxicity, rhabdomyolysis-induced acute kidney injury, hypoxia-induced cardiomyocyte injury, and low phosphorus loading-induced neurotoxicity through its antioxidant abilities. [10][11][12][13] Herein, we investigated the potential use of ALA as a novel radioprotective drug for normal rectal and bladder mucosa.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, Terada et al reported that cisplatin-induced nephrotoxicity and tubular apoptosis was prevented by ALA treatment; an effect that was mediated by five mitochondria-related proteins and enzymes: HMOX1, ATP5α, cytochrome c oxidase 4 (COX4), PGC-1α, and UCP2. 10 Other groups have indicated that ALA exerts antioxidant activity via nuclear factor erythroid 2-related factor 2 (Nrf2)-associated antioxidant factors to provide a renoprotective effect against rhabdomyolysis-induced injury, 11 ischemia-reperfusion injury, 30 and hypoxia-induced cardiomyocyte injury. 13 Although relevant proteins vary with the stresses and targeted organs, ALA administration exerts cytoprotective roles by maintaining mitochondrial functions.…”

Section: Discussionmentioning

confidence: 99%

“…ALA is distributed ubiquitously in mammalian cells and is a precursor of tetrapyrole compounds such as heme, which is essential in aerobic energy metabolism and the electron transport system . ALA reportedly exerts a broad range of cytoprotective effects against cisplatin‐induced nephrotoxicity, rhabdomyolysis‐induced acute kidney injury, hypoxia‐induced cardiomyocyte injury, and low phosphorus loading‐induced neurotoxicity through its antioxidant abilities . Herein, we investigated the potential use of ALA as a novel radioprotective drug for normal rectal and bladder mucosa.…”

Section: Introductionmentioning

confidence: 99%

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Dual benefit of supplementary oral 5‐aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model

et al. 2018

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Background Normal tissue damage caused by radiotherapy remains the largest dose‐limiting factor in radiotherapy for cancer. Therefore, the aim of this study was to investigate the supplementary oral 5‐aminolevulinic acid (ALA) to standard radiation therapy as a novel radioprotective approach that would not compromise the antitumor effect of radiation in normal rectal and bladder mucosa in a syngenic prostate cancer (PCa) model. Methods To evaluate the radiosensitizing effect of ALA in vitro, clonogenic survival assays were performed in DU145, PC3, and MyC‐CaP cell lines. To evaluate the effect of ALA in vivo a single dose (25 Gy) of radiation with or without ALA was given to healthy mice. Next, a syngenic PCa model of MyC‐CaP cells in FVB mice was created, and multiple doses (12 Gy total) of radiation were administered to the mouse pelvic area with or without ALA administration. Resected tumors, recta, and urinary bladders were immunostained with antibodies against Ki‐67, γ‐H2AX, CD204, and uroplakin‐III. Total RNA levels in recta and urinary bladders were analyzed via RT2 Profiler polymerase chain reaction (PCR) arrays related to “Stress & Toxicity PathwayFinder,” “Mitochondria,” and “Inflammasomes.” Results The addition of in vitro single or in vivo repeated administration of exogenous ALA acted as a radiosensitizer for PCa cells. Rectal toxicity was characterized by histological changes including loss of surface epithelium, fibrosis, severe DNA damage, and the aggregation of M2 macrophages. Urinary bladder toxicity was characterized by bladder wall thickening and urothelium denuding. The higher dose (300 mg/kg/day) of ALA exerted a better radioprotective profile than the lower dose (30 mg/kg/day) in normal recta and urinary bladders. Out of the 252 genes tested, 35 (13.4%) were detected as relevant genes which may be involved in the radioprotective role of ALA administration. These included interleukin‐1a (IL‐1a), IL‐1b, IL‐12, chemokine (C‐X‐C motif) ligand 1 (CXCL1), CXCL3, and NLRP3. Conclusions Our study provides novel and comprehensive insights into the dual benefits including radiosensitizing PCa tumor tissues and radioprotection of normal pelvic organs from radiation therapy. Knowledge of the underlying mechanism will facilitate the search for optimal treatment parameters for supplemental oral ALA during radiotherapy for PCa.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dual benefit of supplementary oral 5‐aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model

et al. 2018

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“…protect kidneys from acute injury [15,16]. Moreover, both in vivo and in vitro studies show that 5-ALA can induce heme oxygenase-1 (HO-1) expression in kidney cells [17,18].…”

Section: A C C E P T E D a R T I C L Ementioning

confidence: 99%

Protective effects of 5-aminolevulinic acid on heat stress in bovine mammary epithelial cells

et al. 2021

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Cells have increased susceptibility to activation of apoptosis when suffering heat stress (HS). An effective supplementation strategy to mimic heat-induced apoptosis of bovine mammary epithelial cells (MECs) is necessary to maintain optimal milk production. This study aimed to investigate possible protective effects of the anti-apoptotic activity of 5-aminolevulinic acid (5-ALA) against HS-induced damage of bovine MECs. Methods: Bovine MECs were pretreated with or without 5-ALA at concentrations of 10, 100, and 500 μM for 24 h followed by HS (42.5°C for 24 h and 48 h). Cell viability was measured with MTT assays. Real-time qPCR and Western blotting were used to explore the regulation of genes associated with apoptosis, oxidative stress, and endoplasmic reticulum (ER) stress genes. Results: We found that 5-ALA induces cytoprotection via inhibition of apoptosis markers after HS-induced damage. Pretreatment of bovine MECs with 5-ALA resulted in dramatic upregulation of mRNA for nuclear factor erythroid-derived 2-like factor 2 (NRF2), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase 1 (NQO1), all of which are antioxidant stress genes. Moreover, 5-ALA pretreatment significantly suppressed HS-induced ER stress-associated markers, glucose-regulated protein 78 (GRP78), and C/EBP homologous protein (CHOP) expression levels. Conclusion: 5-ALA has the ability to ameliorate the ER stress in heat stressed bovine mammary epithelial cell via enhancing the expression of antioxidant gene.

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“…5‐ALA is an endogenous amino acid in animals and is the first compound produced by 5‐ALA synthase in the heme biosynthetic pathway . Recent studies have shown that 5‐ALA has cardioprotective, antifibrotic, antitumor, anti‐inflammatory, and antioxidative effects . Furthermore, 5‐ALA is known to induce HO‐1 expression in kidney cells, both in vivo and in vitro .…”

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confidence: 99%

5‐ALA/SFC enhances HO‐1 expression through the MAPK/Nrf2 antioxidant pathway and attenuates murine tubular epithelial cell apoptosis

et al. 2019

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Cyclosporin A (CsA) is a common immunosuppressant, but its use is limited as it can cause chronic kidney injury. Oxidative stress and apoptosis play a key role in CsA‐induced nephrotoxicity. This study investigated the protective effect of 5‐aminolevulinic acid and iron (5‐ALA/SFC) on CsA‐induced injury in murine proximal tubular epithelial cells (mProx24). 5‐ALA/SFC significantly inhibited apoptosis in CsA‐treated mProx24 cells with increases in heme oxygenase (HO)‐1, nuclear factor E2‐related factor 2 (Nrf2), and p38, and Erk‐1/2 phosphorylation. Moreover, 5‐ALA/SFC suppressed production of reactive oxygen species in CsA‐exposed cells and inhibition of HO‐1 suppressed the protective effects of 5‐ALA/SFC. In summary, 5‐ALA/SFC may have potential for development into a treatment for the anti‐nephrotoxic/apoptotic effects of CsA.

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5‐Aminolevulinic acid exerts renoprotective effect via Nrf2 activation in murine rhabdomyolysis‐induced acute kidney injury

Abstract: These findings indicate that ALA exerts its antioxidant activity via Nrf2-associated antioxidant factors to provide a renoprotective effect against rhabdomyolysis-induced AKI.

Cited by 27 publications

References 27 publications

Dual benefit of supplementary oral 5‐aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model

Dual benefit of supplementary oral 5‐aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model

Protective effects of 5-aminolevulinic acid on heat stress in bovine mammary epithelial cells

5‐ALA/SFC enhances HO‐1 expression through the MAPK/Nrf2 antioxidant pathway and attenuates murine tubular epithelial cell apoptosis

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