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Title: Extrarenal citrulline disposal in mice with impaired renal function

item MARINI, JUAN - Children'S Nutrition Research Center (CNRC)
item DIDELIJA, INKA - Children'S Nutrition Research Center (CNRC)
item FIOROTTO, MARTA - Children'S Nutrition Research Center (CNRC)

Submitted to: American Journal of Physiology - Renal Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/9/2014
Publication Date: 7/23/2014
Citation: Marini, J.C., Didelija, I.C., Fiorotto, M.L. 2014. Extrarenal citrulline disposal in mice with impaired renal function. American Journal of Physiology - Renal Physiology. 307(6):F660-F665.

Interpretive Summary: The synthesis of the amino acid arginine is a process that involves multiple organs. Citrulline, the precursor for arginine synthesis, is made in the gut and after entering the blood, reaches the kidney where it is converted into arginine. Arginine is available to multiple tissues and is utilized for protein synthesis and for other metabolic processes. When renal function is impaired the synthesis of arginine is disrupted. Because the enzymes needed to convert citrulline into arginine are present in most tissues, we have shown that arginine synthesis can take place at the tissue level. The implication of this research is that the endogenous synthesis of arginine can still take place despite renal dysfunction.

Technical 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 about 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 (1/2 and 5/6) and anesthetized acutely kidney-ligated mouse models. Nephrectomy increased plasma citrulline concentration but did not affect citrulline synthesis rates, thus reducing its clearance. Nephrectomy (5/6) 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.