| Autor: |
Liliane Mpabanzi, Jessica Wainwright, Bas Boonen, Hans van Eijk, Dipok Dhar, Esther Karssemeijer, Cees H. C. Dejong, Rajiv Jalan, Jean-Marc Schwartz, Steven W. M. Olde Damink, Zita Soons |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
npj Systems Biology and Applications, Vol 8, Iss 1, Pp 1-10 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2056-7189 |
| DOI: |
10.1038/s41540-022-00257-2 |
| Popis: |
Abstract The kidney plays a critical role in excreting ammonia during metabolic acidosis and liver failure. The mechanisms behind this process have been poorly explored. The present study combines results of in vivo experiments of increased total ammoniagenesis with systems biology modeling, in which eight rats were fed an amino acid-rich diet (HD group) and eight a normal chow diet (AL group). We developed a method based on elementary mode analysis to study changes in amino acid flux occurring across the kidney in increased ammoniagenesis. Elementary modes represent minimal feasible metabolic paths in steady state. The model was used to predict amino acid fluxes in healthy and pre-hyperammonemic conditions, which were compared to experimental fluxes in rats. First, we found that total renal ammoniagenesis increased from 264 ± 68 to 612 ± 87 nmol (100 g body weight)−1 min−1 in the HD group (P = 0.021) and a concomitated upregulation of NKCC2 ammonia and other transporters in the kidney. In the kidney metabolic model, the best predictions were obtained with ammonia transport as an objective. Other objectives resulting in a fair correlation with the measured fluxes (correlation coefficient >0.5) were growth, protein uptake, urea excretion, and lysine and phenylalanine transport. These predictions were improved when specific gene expression data were considered in HD conditions, suggesting a role for the mitochondrial glycine pathway. Further studies are needed to determine if regulation through the mitochondrial glycine pathway and ammonia transporters can be modulated and how to use the kidney as a therapeutic target in hyperammonemia. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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