l-Arginine metabolism in dog kidney and isolated nephron segments

Abstract

The renal basic amino acid metabolism often differs in rodents, strict carnivore, and omnivore species. Given the pivotal role of L-arginine and L-ornithine in several metabolic pathways and the fact that the dog is closely related to humain being also an omnivore, we tested whether L-arginine metabolism and L-ornithine catabolism take place in the dog kidney. We examined the metabolic of L-arginine in dog cortical tubules to integrate local L-arginine metabolism into a general physiological and metabolic framework. To achieve these goals, we first ascertained the protein expression of relevant enzymes identified by Western blotting. Larginine catabolism was studied in suspensions of canine cortical proximal tubules, medullary thick ascending limbs, and papillary collecting ducts either incubated without exogenous Larginine being added (small endogenous quantities) or incubated with L-arginine being added in supraphysiological amounts (2 mmol/L with or without the presence of alternative metabolic substrates, 2 mmol/L L-glutamine, or lactate). The results revealed that dog kidneys consumed L-citrulline and released L-arginine and L-ornithine. Argininosuccinate synthetase and lyase, arginase II, and ornithine aminotransferase were detected in the renal cortex. Arginase II activity was found in a suspension of proximal tubules by measuring the amounts of urea and L-ornithine produced. A fraction of this L-ornithine was further partially metabolized through the intramitochondrial ornithine aminotransferase pathway, leading to changes in L-glutamate, glucose, L-alanine, and ammonia metabolism without L-proline accumulation. Medullary thick ascending limbs expressed a very low arginase activity whereas papillary collecting ducts did not. In conclusion, the dog kidney produces L-arginine. Part of this L-arginine is further catabolized by arginase II, suggesting that its physiological role was to produce L-ornithine for the body.-3 -

l-Citrulline Protects from Kidney Damage in Type 1 Diabetic Mice

“…In the kidneys, arginase II (ArgII) is the only isoform expressed in mouse and humans (13). ArgII is present in the proximal tubules (PT) and in the inner medullary collecting ducts (14) and plays an important role in renal physiology and homeostasis (15). Arginase metabolizes l -arg to urea and ornithine.…”

Increased nitric oxide plasma concentration in dogs with naturally acquired chronic renal disease

“…Surprisingly, total L-arginine synthesis is reportedly preserved in patients in end-stage renal disease. The plasma levels of L-arginine did not change significantly in rats with subtotal nephrectomy compared with normal rats (Levillan et al 2008). This suggests that there was increased synthesis of L-arginine per nephron in the remaining renal mass and/or increased synthesis/ release of this amino acid at extra renal sites (Levillan et al 2008).…”

“…due to impaired renal L-Arginine biosynthesis, decreased transport of L-Arginine into endothelial cells and possible competition between NO synthase (NOS) and competing metabolic pathways, such as arginase (Archer 1993, Levillan et al 2008. Surprisingly, total L-arginine synthesis is reportedly preserved in patients in end-stage renal disease.…”

“…The sources of this extra renal arginine synthesis certainly includes arginine regeneration from citrulline produced in macrophages, intestine and endothelial cells (Yu et al 1996). In experimentally induced CKD caused by renal mass reduction, the combination of increased plasma citrulline concentration and proximal tubular hypertrophy can compensate and maintain renal L-arginine production (Modlinger et al 2004, Levillan et al 2008. Appreciable quantities of arginine are synthesized in the kidney from citrulline produced by the intestine (Levillan et al 2008).…”

“…The reason for this is probably related to the elevation in plasma citrulline concentration seen in chronic renal insufficiency. The dog metabolism does not strongly differ from that of humans and might constitute an excellent experimental model when human kidneys are not available (Levillan et al 2008). Yu et al (1996) and Levillain et al (2008) demonstrated that the dog arterial plasma exhibited appropriate levels of L-citrulline.…”