Knock-out of dipeptidase CN2 in human proximal tubular cells disrupts dipeptide and amino acid homeostasis and para- and transcellular solute transport
© 2024 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society..
AIM: Although of potential biomedical relevance, dipeptide metabolism has hardly been studied. We found the dipeptidase carnosinase-2 (CN2) to be abundant in human proximal tubules, which regulate water and solute homeostasis. We therefore hypothesized, that CN2 has a key metabolic role, impacting proximal tubular transport function.
METHODS: A knockout of the CN2 gene (CNDP2-KO) was generated in human proximal tubule cells and characterized by metabolomics, RNA-seq analysis, paracellular permeability analysis and ion transport.
RESULTS: CNDP2-KO in human proximal tubule cells resulted in the accumulation of cellular dipeptides, reduction of amino acids and imbalance of related metabolic pathways, and of energy supply. RNA-seq analyses indicated altered protein metabolism and ion transport. Detailed functional studies demonstrated lower CNDP2-KO cell viability and proliferation, and altered ion and macromolecule transport via trans- and paracellular pathways. Regulatory and transport protein abundance was disturbed, either as a consequence of the metabolic imbalance or the resulting functional disequilibrium.
CONCLUSION: CN2 function has a major impact on intracellular amino acid and dipeptide metabolism and is essential for key metabolic and regulatory functions of proximal tubular cells. These findings deserve in vivo analysis of the relevance of CN2 for nephron function and regulation of body homeostasis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:240 |
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| Enthalten in: |
Acta physiologica (Oxford, England) - 240(2024), 4 vom: 08. Apr., Seite e14126 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pfeffer, Tilman [VerfasserIn] |
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| Links: |
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| Themen: |
Amino Acids |
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| Anmerkungen: |
Date Completed 17.04.2024 Date Revised 17.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/apha.14126 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Pfeffer, Tilman |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Knock-out of dipeptidase CN2 in human proximal tubular cells disrupts dipeptide and amino acid homeostasis and para- and transcellular solute transport |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Revised 17.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society. | ||
| 520 | |a AIM: Although of potential biomedical relevance, dipeptide metabolism has hardly been studied. We found the dipeptidase carnosinase-2 (CN2) to be abundant in human proximal tubules, which regulate water and solute homeostasis. We therefore hypothesized, that CN2 has a key metabolic role, impacting proximal tubular transport function | ||
| 520 | |a METHODS: A knockout of the CN2 gene (CNDP2-KO) was generated in human proximal tubule cells and characterized by metabolomics, RNA-seq analysis, paracellular permeability analysis and ion transport | ||
| 520 | |a RESULTS: CNDP2-KO in human proximal tubule cells resulted in the accumulation of cellular dipeptides, reduction of amino acids and imbalance of related metabolic pathways, and of energy supply. RNA-seq analyses indicated altered protein metabolism and ion transport. Detailed functional studies demonstrated lower CNDP2-KO cell viability and proliferation, and altered ion and macromolecule transport via trans- and paracellular pathways. Regulatory and transport protein abundance was disturbed, either as a consequence of the metabolic imbalance or the resulting functional disequilibrium | ||
| 520 | |a CONCLUSION: CN2 function has a major impact on intracellular amino acid and dipeptide metabolism and is essential for key metabolic and regulatory functions of proximal tubular cells. These findings deserve in vivo analysis of the relevance of CN2 for nephron function and regulation of body homeostasis | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a dipeptidase | |
| 650 | 4 | |a glutathione | |
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| 650 | 7 | |a Amino Acids |2 NLM | |
| 700 | 1 | |a Krug, Susanne M |e verfasserin |4 aut | |
| 700 | 1 | |a Kracke, Tamara |e verfasserin |4 aut | |
| 700 | 1 | |a Schürfeld, Robin |e verfasserin |4 aut | |
| 700 | 1 | |a Colbatzky, Florian |e verfasserin |4 aut | |
| 700 | 1 | |a Kirschner, Philip |e verfasserin |4 aut | |
| 700 | 1 | |a Medert, Rebekka |e verfasserin |4 aut | |
| 700 | 1 | |a Freichel, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Schumacher, Dagmar |e verfasserin |4 aut | |
| 700 | 1 | |a Bartosova, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Zarogiannis, Sotiris G |e verfasserin |4 aut | |
| 700 | 1 | |a Muckenthaler, Martina U |e verfasserin |4 aut | |
| 700 | 1 | |a Altamura, Sandro |e verfasserin |4 aut | |
| 700 | 1 | |a Pezer, Silvia |e verfasserin |4 aut | |
| 700 | 1 | |a Volk, Nadine |e verfasserin |4 aut | |
| 700 | 1 | |a Schwab, Constantin |e verfasserin |4 aut | |
| 700 | 1 | |a Duensing, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Fleming, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Heidenreich, Elena |e verfasserin |4 aut | |
| 700 | 1 | |a Zschocke, Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Hell, Rüdiger |e verfasserin |4 aut | |
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| 700 | 1 | |a Schmitt, Claus P |e verfasserin |4 aut | |
| 700 | 1 | |a Peters, Verena |e verfasserin |4 aut | |
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