Fluxomics reveals cellular and molecular basis of increased renal ammoniagenesis

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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Article number49
Number of pages10
JournalNPJ systems biology and applications
Issue number1
Publication statusPublished - 20 Dec 2022


  • Rats
  • Animals
  • Ammonia/metabolism
  • Kidney/metabolism
  • Amino Acids/metabolism
  • Acidosis/metabolism
  • Glycine/metabolism

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