Effect of chronic renal failure on arginase and argininosuccinate synthetase expression.
BACKGROUND
L-arginine (L-arg) participates in numerous biological functions including urea and nitric oxide synthesis. Sources of L-arg include dietary proteins and endogenous synthesis by argininosuccinate synthetase and argininosuccinate lyase. L-arg is converted to urea by arginase I in the liver and arginase II in the kidney. Normally, the liver fully consumes L-arg for urea generation and does not contribute to its circulating pool. Instead, much of the circulating L-arg is produced by the kidney. If true, plasma L-arg should be severely reduced in chronic renal failure (CRF); however, plasma L-arg is frequently unchanged in CRF. We hypothesized that preservation of plasma L-arg in CRF may be, partly, due to downregulation/inhibition of arginase.


METHODS
Argininosuccinate synthetase, arginase I and II protein abundance and activity were measured in the liver and kidneys of rats 6 weeks after 5/6 nephrectomy or sham operation. In addition, arginase activity was measured in the presence of different urea concentrations to simulate azotemia in vitro.


RESULTS
Arginases I and II protein abundance as well as arginase activity in the liver, measured in the physiological buffer, were similar among the CRF and control groups. However, in vitro experiments simulating a uremic milieu revealed a marked concentration-dependent inhibition of arginase activity by urea in the tissue lysates. CRF had no significant effect on argininosuccinate synthetase abundance in the kidney, liver, spleen or intestine.


CONCLUSIONS
Although CRF does not change the abundance or intrinsic properties of arginase, the inherent rise in urea concentration inhibits its enzymatic activity. The latter, in turn, attenuates L-arg catabolism and urea production and, thereby, mitigates the fall in plasma L-arg.
Moradi
Hamid
H
Division of Nephrology and Hypertension, University of California, Irvine, CA 92868, USA.
Kwok
Vincent
V
Vaziri
Nosratola D
ND
D000818:Animals; D001124:Argininosuccinate Synthase / Q000378:metabolism*; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D007668:Kidney / Q000201:enzymology*; D007676:Kidney Failure, Chronic / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000201:enzymology*; D014018:Tissue Distribution
D001124:Argininosuccinate Synthase