Renal synthesis of arginine in chronic renal failure: In vivo and in vitro studies in rats with 5/6 nephrectomy

Abstract

Synthesis of arginine (Arg) from citrulline (Cit) by the kidney is a major source of Arg for the body. The high level of plasma Cit in chronic renal failure is often thought to result from the impairment of the renal conversion of Cit to Arg. To verify this assumption, we performed two studies in Sprague-Dawley rats with 5/6 nephrectomy (CRF rats) and in sham-operated rats (CONT rats). In study I synthesis of Arg by isolated proximal convoluted tubules (PCT; the nephron segment exhibiting the highest Arg synthesis) was measured in vitro with two concentrations of Cit (200 or 50 μM) corresponding to those observed in plasma of rats with or without renal failure. In study II the net renal uptake of Cit and release of Arg were determined in vivo by measuring PAH clearance and arterial and renal venous Arg, and Cit concentrations in anesthetized rats. The in vitro results showed that Arg synthesis increased only in proportion to the hypertrophy of remnant PCT (+50%), and was highly and similarly dependent on Cit concentration in PCT of remnant and normal kidneys (Arg production with 200 μM Cit was 3 times higher than with 50 μM Cit for both CONT and CRF). The in vivo results showed that renal Cit uptake and Arg release were not altered in CRF: -286 ± 28 versus -326 ± 16 nmol Cit. min-1 (NS), and +390 ± 47 versus +399 ± 22 nmol Arg·min-1 (NS) in CONT and CRF rats, respectively. This maintenance of a normal Arg synthesis in CRF in the face of a significant reduction in renal plasma flow (-30%) and glomerular filtration rate (-60%), probably results from the cumulative effects of hypertrophy of remnant PCTs, hyperfiltration in remnant nephrons and high plasma Cit concentration increasing the amount of Cit filtered. Thus, the high plasma level of Cit in CRF, being a consequence of the progressive decline in functioning nephrons able to synthetize Arg, also represents a peripheral adaptation that enables a reduced mass of functional tissue to maintain a constant renal Arg synthesis.