Inhibition of Hepatic Arginase activity in Chronic Renal Failure (CRF)

L‐arginine (L‐Arg) plays a central role in urea and nitric oxide production. L‐Arg is synthesized by argininosuccinate synthetase (ASS) in liver and kidney and is converted to urea by arginase. Normally, liver converts L‐Arg to urea and plasma L‐Arg is derived from synthesis by kidney. Thus, CRF is expected to reduce plasma L‐Arg. However, plasma L‐Arg is unchanged in CRF. This may be due to its diminished hepatic catabolism by arginase‐I. ASS, arginases‐I and II protein levels and arginase activity were measured in the liver and kidney of rats 6 weeks after 5/6 nephrectomy or sham operation. Serum L‐Arg (140±23 vs. 144±22umol/L), liver ASS and arginase‐I protein abundance were similar in the two groups but arginase activity was significantly diminished in CRF animals (3098 vs. 2613nmol/mg protein/min, P <0.0001). In vitro experiments revealed a concentration‐dependent inhibition of hepatic arginase activity by urea (r² =−0.96, P <.0001) in the liver lysate. Although, arginase‐II and ASS protein concentrations in the kidney were unchanged, due to marked reduction of nephron mass, their total body pool was reduced in the CRF animals. Thus, elevation of urea concentration in CRF results in inhibition of hepatic arginase activity which helps to preserve plasma L‐Arg level by lowering its catabolism. In addition, the reduction of hepatic arginase activity and hence urea biosynthesis, serves a compensatory response to elevated urea burden in CRF.