Extrarenal citrulline disposal in mice with impaired renal function

Abstract

The endogenous synthesis of arginine, a semiessential amino acid, relies on the production of citrulline by the gut and its conversion into arginine by the kidney in what has been called the "intestinal-renal axis" for arginine synthesis. Although the kidney is the main site for citrulline disposal, it only accounts for ~60-70% of the citrulline produced. Because the only known fate for citrulline is arginine synthesis and the enzymes that catalyze this reaction are widespread among body tissues, we hypothesized that citrulline can be utilized directly by tissues to meet, at least partially, their arginine needs. To test this hypothesis, we used stable and radioactive tracers in conscious, partially nephrectomized (½ and ⅚) and anesthetized acutely kidney-ligated mouse models. Nephrectomy increased plasma citrulline concentration but did not affect citrulline synthesis rates, thus reducing its clearance. Nephrectomy (⅚) reduced the amount of citrulline accounted for as plasma arginine from 88 to 42%. Acute kidney ligation increased the half-life and mean retention time of citrulline. Whereas the rate of citrulline conversion into plasma arginine was reduced, it was not eliminated. In addition, we observed direct utilization of citrulline for arginine synthesis and further incorporation into tissue protein in kidney-ligated mice. These observations indicate that a fraction of the citrulline produced is utilized directly by multiple tissues to meet their arginine needs and that extrarenal sites contribute to plasma arginine. Furthermore, when the interorgan synthesis of arginine is impaired, these extrarenal sites are able to increase their rate of citrulline utilization.

Vitamin E in New‐Generation Lipid Emulsions Protects Against Parenteral Nutrition–Associated Liver Disease in Parenteral Nutrition–Fed Preterm Pigs

“…The kinetics of 13 C‐CDCA clearance were estimated using an exponential model, and goodness of fit of the model was determined by graphical residual analysis (PROC NLIN, SAS v. 9.2, SAS Institute Inc, Cary, NC). The terminal half‐life after reaching pseudo‐equilibrium and mean residence time were calculated as described previously 38 . Results are presented as mean ± standard error of the mean (SEM).…”

Arginine Depletion by Arginine Deiminase Does Not Affect Whole Protein Metabolism or Muscle Fractional Protein Synthesis Rate in Mice

“…The endogenous synthesis of arginine is a multi-organ process that involves the synthesis of citrulline by the gut and further conversion into arginine by the kidney [ 12 ], where argininosuccinate synthase and lyase (ASS and ASL, enzymes that catalyze the conversion of citrulline into arginine) are highly expressed. In addition, these two enzymes are expressed in multiple tissues and it is likely that a fraction of the citrulline produced in the gut is utilized directly by the tissues to meet, at least partially, their arginine needs [ 13 , 14 ].…”

The construction of a panel of serum amino acids for the identification of early chronic kidney disease patients

“…Citrulline is a nonessential amino acid involved in the urea cycle ( Figure 4). 27,28 Glutamine is metabolized by the gut into ammonia (NH 3 ) and citrulline, thus CIT levels are closely associated with intestinal diseases such as short bowel syndrome. In recent years, use of CIT as a biomarker for rheumatoid arthritis has drawn attention.…”