Creatine synthesis: production of guanidinoacetate by the rat and human kidney in vivo

Abstract

A fraction of the body's creatine and creatine phosphate spontaneously degrades to creatinine, which is excreted by the kidneys. In humans, this amounts to ∼1–2 g/day and demands a comparable rate of de novo creatine synthesis. This is a two-step process in which l-arginine:glycine amidinotransferase (AGAT) catalyzes the conversion of glycine and arginine to ornithine and guanidinoacetate (GAA); guanidinoacetate methyltransferase (GAMT) then catalyzes the S-adenosylmethionine-dependent methylation of GAA to creatine. AGAT is found in the kidney and GAMT in the liver, which implies an interorgan movement of GAA from the kidney to the liver. We studied the renal production of this metabolite in both rats and humans. In control rats, [GAA] was 5.9 μM in arterial plasma and 10.9 μM in renal venous plasma for a renal arteriovenous (A-V) difference of −5.0 μM. In the rat, infusion of arginine or citrulline markedly increased renal GAA production but infusion of glycine did not. Rats fed 0.4% creatine in their diet had decreased renal AGAT activity and mRNA, an arterial plasma [GAA] of 1.5 μM, and a decreased renal A-V difference for GAA of −0.9 μM. In humans, [GAA] was 2.4 μM in arterial plasma, with a renal A-V difference of −1.1 μM. These studies show, for the first time, that GAA is produced by both rat and human kidneys in vivo.