N-methyl-2-pyridone-5-carboxamide (N-Me-2PY) has potent anti-fibrotic and anti-inflammatory activity in a fibrotic kidney model : is it an old uremic toxin?
© 2023. The Author(s), under exclusive licence to The Japanese Society of Nephrology..
BACKGROUND: Uremic toxins accumulate in renal tissues and cells due to chronic kidney disease (CKD). Abnormalities in nicotinamide adenine dinucleotide (NAD +) metabolism lead to the progression of CKD. NAD + metabolites, such as N-methyl-2-pyridone-5-carboxamide (N-Me-2PY) and N-methyl-4-pyridone-5-carboxamide (N-Me-4PY), have been recognized as uremic toxins. However, no reports have validated whether they are actually harmful to the body. Therefore, we focused on the structural similarity of these metabolites to the anti-fibrotic drug pirfenidone and evaluated their effects on renal fibrosis.
METHODS: Each NAD + metabolite was treated with TGFβ1 to kidney fibroblasts or tubular epithelial cells, and quantitative RT-PCR and Western blot analysis were conducted. N-Me-2PY was orally administered to a ligated murine kidney fibrosis model (UUO) to evaluate its anti-fibrotic and toxic effects on the body.
RESULTS: N-Me-2PY, N-Me-4PY, and nicotinamide N-oxide (NNO) inhibited TGFβ1-induced fibrosis and inflammatory gene expression in kidney fibroblasts. N-Me-2PY strongly suppressed the expression of types I and III collagen, αSMA, and IL-6. N-Me-2PY also suppressed TGFβ1-induced type I collagen and IL-6 expression in renal tubular epithelial cells. No toxic effect was observed with N-Me-2PY treatment, while attenuating renal fibrosis and tubular dilation in UUO mice. Suppression of various fibrosis- and inflammation-related genes was also observed. N-Me-2PY did not inhibit TGFβ1-induced Smad3 phosphorylation but inhibited Akt phosphorylation, suggesting that N-Me-2PY exerts anti-fibrotic and anti-inflammatory effects through Akt inhibition, similar to pirfenidone.
CONCLUSIONS: NAD + metabolites, such as N-Me-2PY, are not uremic toxins but are potential therapeutic agents that have anti-fibrotic effects in CKD.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:27 |
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| Enthalten in: |
Clinical and experimental nephrology - 27(2023), 11 vom: 25. Nov., Seite 901-911 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yoshimura, Norito [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 23.10.2023 Date Revised 23.10.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s10157-023-02379-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM359903371 |
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| 100 | 1 | |a Yoshimura, Norito |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a N-methyl-2-pyridone-5-carboxamide (N-Me-2PY) has potent anti-fibrotic and anti-inflammatory activity in a fibrotic kidney model |b is it an old uremic toxin? |
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| 500 | |a Date Completed 23.10.2023 | ||
| 500 | |a Date Revised 23.10.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s), under exclusive licence to The Japanese Society of Nephrology. | ||
| 520 | |a BACKGROUND: Uremic toxins accumulate in renal tissues and cells due to chronic kidney disease (CKD). Abnormalities in nicotinamide adenine dinucleotide (NAD +) metabolism lead to the progression of CKD. NAD + metabolites, such as N-methyl-2-pyridone-5-carboxamide (N-Me-2PY) and N-methyl-4-pyridone-5-carboxamide (N-Me-4PY), have been recognized as uremic toxins. However, no reports have validated whether they are actually harmful to the body. Therefore, we focused on the structural similarity of these metabolites to the anti-fibrotic drug pirfenidone and evaluated their effects on renal fibrosis | ||
| 520 | |a METHODS: Each NAD + metabolite was treated with TGFβ1 to kidney fibroblasts or tubular epithelial cells, and quantitative RT-PCR and Western blot analysis were conducted. N-Me-2PY was orally administered to a ligated murine kidney fibrosis model (UUO) to evaluate its anti-fibrotic and toxic effects on the body | ||
| 520 | |a RESULTS: N-Me-2PY, N-Me-4PY, and nicotinamide N-oxide (NNO) inhibited TGFβ1-induced fibrosis and inflammatory gene expression in kidney fibroblasts. N-Me-2PY strongly suppressed the expression of types I and III collagen, αSMA, and IL-6. N-Me-2PY also suppressed TGFβ1-induced type I collagen and IL-6 expression in renal tubular epithelial cells. No toxic effect was observed with N-Me-2PY treatment, while attenuating renal fibrosis and tubular dilation in UUO mice. Suppression of various fibrosis- and inflammation-related genes was also observed. N-Me-2PY did not inhibit TGFβ1-induced Smad3 phosphorylation but inhibited Akt phosphorylation, suggesting that N-Me-2PY exerts anti-fibrotic and anti-inflammatory effects through Akt inhibition, similar to pirfenidone | ||
| 520 | |a CONCLUSIONS: NAD + metabolites, such as N-Me-2PY, are not uremic toxins but are potential therapeutic agents that have anti-fibrotic effects in CKD | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Ono, Takashi |e verfasserin |4 aut | |
| 700 | 1 | |a Notoya, Mitsuru |e verfasserin |4 aut | |
| 700 | 1 | |a Yukioka, Hideo |e verfasserin |4 aut | |
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| 700 | 1 | |a Kanda, Takeshi |e verfasserin |4 aut | |
| 700 | 1 | |a Itoh, Hiroshi |e verfasserin |4 aut | |
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