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353 EFFECT OF CHRONIC RENAL FAILURE ON ARGINOSUCCINATE SYNTHASE AND ARGINASE I AND II EXPRESSION IN THE LIVER AND REMNANT KIDNEY.
  1. V. Kwok,
  2. H. Moradi,
  3. N. D. Vaziri
  1. Division of Nephrology and Hypertension, University of California, Irvine, CA

Abstract

Apart from serving as a structural constituent of numerous proteins, l-arginine plays a central role in elimination of nitrogenous waste products via the urea cycle. In addition, as the precursor in the synthesis of nitric oxide (NO), l-arginine participates in a wide array of biological functions including regulation of arterial pressure, tissue perfusion, renal/cardiovascular function/structure, neurological function, innate immunity, hemostasis, and numerous other functions. The l-arginine pool in the body is derived from the diet and endogenous biosynthesis. l-Arginine is synthesized from l-citrulline by the coordinated actions of arginosuccinate synthase and arginosuccinate lyase in both liver and the kidney. It is converted to urea and ornithine by arginase I in the liver and by arginase II in the kidney. Under normal conditions, all available l-arginine in the liver enters the urea cycle and, as such, the liver does not appreciably contribute to the circulating pool of this amino acid. Instead, much of the circulating l-arginine is thought to be the product of its biosynthesis by the kidney. If true, severe reduction of nephron mass in chronic renal failure (CRF) should result in marked reduction of the circulating l-arginine level. However, according to several clinical and animal studies, plasma l-arginine level is frequently unchanged or only minimally reduced in CRF. In an attempt to gain insight into l-arginine metabolism in CRF, we quantified immunodetectable arginosuccinate synthase (the rate-limiting step in l-arginine synthesis) and arginase I and II isoforms in the liver and kidneys of rats 6 weeks after 5/6 nephrectomy or sham operation. The CRF animals exhibited proteinuria and significant reductions of glomerular filtration rate and body weight. However, no difference was observed in the liver arginosuccinate synthase or arginase I protein concentrations among the CRF and control animals. Likewise, concentrations of immunodetectable arginase II and arginosuccinate synthase in the kidney were similar among the CRF and control groups. However, due to marked reduction of nephron mass, the total l-arginine biosynthetic capacity must be substantially reduced in the CRF compared to the control animals. Thus, the mechanisms responsible for maintenance of plasma l-arginine level despite diminished renal biosynthetic capacity must involve other pathways. It is of note that CRF results in down-regulation of NO synthase isoforms (which use l-arginine as substrate) and significant reduction of protein synthesis—hence amino acid incorporation as evidence by weight loss in the CRF animals. These events may, in part, contribute to the reduction of l-arginine consumption, which can, in turn, preserve circulating l-arginine concentration despite its diminished renal biosynthesis.

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